jical Hazard Revi
Furniture Flame Retardancy Partnership:
Environmental Profiles of Chemical Flame-Retardant
Alternatives for Low-Density Polyurethane Foam
Ml *
I
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TABLE OF CONTENTS
Page
Introduction i
Flame Retardant Alternatives: Triphenyl Phosphate 1-1
Flame Retardant Alternatives: Tribromoneopentyl Alcohol 2-1
Flame Retardant Alternatives: Tris(l,3-dichloro-2-propyl) Phosphate 3-1
Flame Retardant Alternatives: Proprietary A: Chloroalkyl phosphate (1) 4-1
Flame Retardant Alternatives: Proprietary B: Aryl phosphate 5-1
Flame Retardant Alternatives: Proprietary C: Chloroalkyl phosphate (2) 6-1
Flame Retardant Alternatives: Proprietary D: Reactive brominated flame retardant 7-1
Flame Retardant Alternatives: Proprietary E: Tetrabromophthalate diol diester 8-1
Flame Retardant Alternatives: Proprietary F: Halogenated aryl ester 9-1
Flame Retardant Alternatives: Proprietary G: Triaryl phosphate, isopropylated 10-1
Flame Retardant Alternatives: Proprietary H: Halogenated aryl ester 11-1
Flame Retardant Alternatives: Proprietary I: Organic phosphate ester 12-1
Flame Retardant Alternatives: Proprietary J: Aryl phosphate 13-1
Flame Retardant Alternatives: Proprietary K: Aryl phosphate 14-1
Flame Retardant Alternatives: Proprietary L: Aryl phosphate 15-1
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LIST OF TABLES
Page
1-1 Summary of available acute fish toxicity studies for triphenyl phosphate
(115-86-6) 1-27
1-2 Summary of available acute invertebrate toxicity studies on triphenyl phosphate
(115-86-6) 1-36
1-3 Summary of available algal toxicity studies for triphenyl phosphate 1-41
1-4 Summary of available chronic fish toxicity studies for triphenyl phosphate
(115-86-6) 1-46
3-1 Summary of available acute fish toxicity studies for tris(l,3-dichloro-2-propyl)
phosphate [TDCPP] (CASRN: 13674-87-8) 3-30
3-2 Summary of available acute invertebrate toxicity studies for tris(l,3-dichloro-2-
propyl)phosphate [TDCPP] (CASRN: 13674-87-8) 3-35
3-3 Summary of available algal toxicity studies for tris(l,3-dichloro-2-propyl)
phosphate [TDCPP] (CASRN: 13674-87-8) 3-38
4-1 Summary of available acute fish toxicity studies for Proprietary A 4-30
4-2 Summary of available acute invertebrate toxicity studies for Proprietary A 4-35
4-3 Summary of available algal toxicity studies for Proprietary A 4-38
13-1 Composition data (%) for selected t-butylated aryl phosphate products 13-4
11
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Introduction
This volume contains detailed hazard reviews of available information for each of the chemicals
in the 14 flame-retardant formulations evaluated through the Furniture Flame Retardancy
Partnership.
These detailed hazard reviews are the basis for the summary assessments in section 4 of volume
I. The summary assessments were in turn used as the basis for summary table 4.1, which
provides top-level information on all of the alternatives.
The goal of the Furniture Flame Retardancy Partnership is to enable informed decision making
in the process of selecting alternatives to pentaBDE. Production of pentaBDE ceased at the end
of 2004. The industry is now adopting alternative flame retardants to meet performance
requirements. Given the large quantities of flame retardants used in foam and furniture
manufacture, the potential for adverse effects to health and the environment should be addressed.
EPA developed this flame-retardant alternatives evaluation through stakeholder participation.
The information in this volume represents the first phase of data collection. The data were
collected in a manner consistent with the HPV Chemical Challenge Program guidance on
searching for existing chemical information and data
(http://www.epa.gov/chemrtk/srchguid.htm). This information was collected and data were
evaluated for adequacy following HPV data adequacy guidelines
(http://www.epa.gov/chemrtk/datadfm.htm). The evaluation protocol differed from the HPV
program in that EPA reviewed the experimental studies and developed the summaries. In the
FIPV Program, EPA and the public participate in the review of the robust summaries developed
by FIPV Challenge Program sponsors. The purpose of data collection in this Partnership was to
identify data gaps, not determine data needs.
EPA used EPA's New Chemicals Program criteria to interpret the data contained in the detailed
hazard reviews and identify potential hazard concerns in volume 1 for the purposes of informing
decision making. When measured data were not available, estimates for chemicals were
determined when possible to identify areas with a potentially high hazard concern. EPA also
identified potentially low and moderate hazard concerns.
The information presented in this volume will provide an appropriate starting point for
longer-term efforts to fully characterize hazard, exposure and risk issues associated with
flame-retardant alternatives.
in
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Flame Retardant Alternatives
Triphenyl Phosphate
Hazard Review
1-1
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Triphenyl Phosphate:
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
/
*
/
/
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
*
*
*
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
*
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
/
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
/
/
X
Immunotoxicity
Immunotoxicity
/
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
/
/
1-2
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Triphenyl Phosphate:
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
/
/
/
/
/
/
/
/
/
X
/
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
/
*
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
/
*
/
/
/
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic NOAEL,
LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
Sediment organisms
/
/
*
/
/
*
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
1-2
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Chemical Identity
Triphenyl phosphate
CAS 115-86-6
MF C18H1504P
MW 326.29
SMILES c 1 ccccc 1 OP(=O)(Oc2ccccc2)Oc3 cccccS
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401).
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Several acute oral lethality studies were available in a variety of species: rats, mice, rabbits,
guinea pigs, and hens. These studies were from the older (pre 1980) literature, and do not fully
conform to OPPTS or OECD guidelines, but together may be adequate to support the evaluation
of acute oral toxicity. The toxic potency of TPP tended to be somewhat lower when it was
administered in aqueous vehicle (usually as a suspension) than when administered in oil. Deaths
generally did not occur following administration in aqueous vehicle ([LD50 >5,000-20,000
mg/kg), and were seen at relatively high doses (LD50 = 10,800 mg/kg) from administration in
oil. Two of the better studies in the preferred species (rat), one using an aqueous vehicle and the
other using an oil vehicle, and one each in mice and rabbits using an aqueous vehicle, are
summarized below as the critical studies.
Critical Studies:
Type: Acute oral limit test
Species, strain, sex, number: Rat, Wistar, 5 male and 5 female
Dose: 20,000 mg/kg
Purity: Not reported, Monsanto commercial TPP
Vehicle: Water: 25% aqueous "solution"
Method: Similar to limit test, but higher dose; 24-hour fasting period prior to dosing; 14-day
post-dosing observation period; observations limited to mortality and necropsy
Results: No deaths, therefore LD50 >20,000 mg/kg. Necropsy revealed sporadic visceral
hemorrhages.
Reference: Food and Drug Research Labs, 1976
1-4
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Type: Acute oral LD50
Species, strain, sex, number: Rat, Sprague-Dawley, male and female, number not specified
Dose: Up to 15,800 mg/kg
Purity: GC-verified, but not specifically reported
Vehicle: Corn oil
Observation period: 14 days post dosing
Method: LD50 calculated according to DeBeer (1945); not specified whether fed or fasted at
time of dosing; 14-day post-exposure observation period; mortality only
Results: LD50 = 10,800 mg/kg; actual mortality data not reported
Reference: Johannsen et al., 1977
Type: Acute oral limit test
Species, strain, sex, number: Mouse, strain not specified, male and female, 5 total/dose
Doses: 2,500 and 5,000 mg/kg
Purity: Not specified
Vehicle: Emulsion in aqueous gum acacia
Method: Similar to limit test; not specified whether fed or fasted at time of dosing; 8-day
observation period; observations limited to mortality and overt signs
Results: No deaths at either dose; therefore, LD50 >5,000 mg/kg; slight stupor
Reference: Ciba-Geigy Ltd., 1954
Type: Acute oral limit test
Species, strain, sex, number: Rabbit, strain and sex not specified, I/dose
Purity: Technical grade TPP
Doses: 3,000 and 5,000 mg/kg
Vehicle: Suspended in aqueous gum acacia
Method: Preliminary limit test, observation was for "several days", observations limited to
clinical signs and mortality
Results: Neither rabbit died, indicating LD >5,000 mg/kg; both had diarrhea
Reference: Dow Biochemical Research, 1934
Additional Studies and Information:
Other studies that were of lesser quality or were reported in less detail are generally consistent
with the above studies (Houghton EF & Company, no date; Kettering Lab, 1945; Smith et al.,
1932; Suttonetal., 1960).
Specific organ toxicity was generally not observed in the studies that include gross pathological
examinations. Some signs possibly indicative of neurotoxicity (lassitude incoordination,
tremors, or weakness) were observed in a few studies (Ciba-Geigy Ltd. 1954; Kettering Lab,
1945; Smith et al., 1932). It has been suggested that at the very high doses employed in these
acute toxicity studies, even small amounts of impurities could be responsible for the apparent
neurotoxicity, which has not been seen with purified TPP (see section on neurological effects),
or that the signs may have been secondary to other effects.
1-5
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Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The available studies predate the preferred study guidelines, and lack details including purity and
discussion of necropsy results, but together indicate a low order of toxicity (LD50>7,900-10,000
mg/kg), consistent with the acute oral studies.
Type: Acute dermal toxicity
Species, strain, sex, number: Rabbit, albino, sex not specified, 10
Dose: 10,000 mg/kg
Purity: No data, commercial product provided by Monsanto, white flakes
Vehicle: Not reported, but the concurrent acute oral study used water
Method: U.S. Federal Hazardous Substances Act Regulations study guideline!6 CFR 1500.40; 5
rabbits tested with intact skin and 5 with abraded skin; 14-day observation period
Results: Mortality after 14 days 0/5 intact, 0/5 abraded. Therefore, LD50 >10,000 mg/kg.
Reference: Food and Drug Research Labs, 1976
Type: Acute dermal toxicity
Species, strain, sex, number: Rabbit, New Zealand albino, sex and number not specified
Dose: Highest dose = 7,900 mg/kg
Purity: No data, prepared from pure phenol
Vehicle: None ("undiluted")
Method: Intact skin, occlusive dressing, test material washed off after 24 hours, 14-day
observation period. Necropsy.
Results: No deaths; therefore, LD50 >7,900 mg/kg; necropsy results not discussed.
Reference: Johanssen et al., 1977
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint, unless
data regarding particle size in the TPP powder study are provided.
Basis for Conclusion:
The available studies on TPP predate the preferred guidelines, but the study using TPP powder
(Food and Drug Research Labs, 1976) was reported to be conducted according to a guideline that
was relevant at the time. The duration was shorter than currently recommended and the
1-6
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concentration was much higher, but no signs of toxicity and no deaths were observed. Analysis
of particle size, however, was not mentioned, so it is not known whether the size was respirable.
Necropsies apparently were not performed. The other available study, on TPP vapor (Sutton et
al., 1960), was conducted at an exposure level lower than recommended for a limit test, the
observation period was inadequate, and it appears that the chamber was a closed chamber, which
is not according to guideline.
Type: Acute inhalation toxicity
Species, strain, sex, number: Rat, Wistar, 5 males and 5 females
Doses: 200 mg/L (nominal); administered as a powder; particle size not reported
Purity: No data, commercial product provided by Monsanto, white flakes
Vehicle: None
Duration: 1 hour
Method: 16 CFR 1500.3; 300 mL chamber with air flow of 5 L/minute. Observation period =
14 days. Observed daily for signs of toxicity and for mortality.
Results: Mortality after 14 days 0/5 males, 0/5 females; no overt signs of toxicity
Reference: Food and Drug Research Labs, 1976
Type: Acute inhalation toxicity
Species, strain, sex, number: Mouse, Carworth Farms CF 1, male
Doses, duration, number: 363 mg/m3 (6 hours exposure, 5 mice) and 757 mg/m3 (2 and 4 hours
exposure, 7 mice/duration)
Purity: Practical Grade Eastman
Vehicle: None
Method: The mice were exposed to TPP vapor in a battery jar following generation of the vapor
by flowing preheated air through molten TPP at 175-180°C. Observation period = 24 hours.
The mice were observed for signs of cholinergic toxicity and blood cholinesterase was measured
at termination.
Results: No overt signs of toxicity; cholinesterase determinations not considered valid because
controls did not appear to have been sham exposed.
Reference: Sutton et al., 1960
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available eye irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Two reasonably adequate studies report similar results in rabbits: mild reversible irritation
primarily of the conjunctiva. The studies are summarized below.
Type: Acute eye irritation
1-7
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Species, strain, sex, number: Rabbit, albino, sex not specified; 9
Doses: 100 mg
Purity: No data, commercial product provided by Monsanto, white flakes
Vehicle: Not reported
Method: Patterned after U.S. Federal Hazardous Substances Act Regulations study guideline
16 CFR 1500.42, except 6 rabbits-eyes not washed after instillation of TPP, 3 rabbits-eyes
washed 4 seconds following instillation of TPP; eyes examined at 24, 48, and 72 hours, and 7
days after instillation of TPP.
Results: Mild conjunctival effects (slight redness 6/6, slight discharge 4/6) at 24 hours in the
eyes that were not washed out, which cleared by 72 hours; no effects in eyes that had been
washed out (incidence 0/3).
Reference: Food and Drug Research Labs, 1976
Type: Acute eye irritation
Species, strain, sex, number: Rabbit, New Zealand, 3 males and 3 females
Doses: 100 mg
Purity: No data, commercial product provided by Monsanto, white flakes
Vehicle: None
Method: Patterned after U.S. Federal Hazardous Substances Labeling Act Section 191.12
(February 1965). Eyes of 3 (of the 6) rabbits were washed out 30 seconds following instillation
of TPP; eyes examined at 1, 24, 48, and 72 hours and 6 days after TPP instillation.
Results: Mild conjunctival effects (slight redness 6/6) at 24 hours in all exposed eyes, which
cleared in all but 1 (unwashed) eye by 72 hours; and in that eye by 6 days. Slight corneal
opacity was seen in one unwashed eye at 24 hours, which cleared by 48 hours.
Reference: Ciba-Geigy Pharmaceuticals Division, 1983a
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available dermal irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Two reasonably adequate studies, patterned after guidelines in effect at the time, provide similar
results, indicating that TPP was not a skin irritant in rabbits. Additional studies provide support.
The studies are summarized below.
Critical Studies:
Type: Acute dermal irritation
Species, strain, sex, number: Rabbit, albino, sex not specified, 6
Doses: 500 mg
Purity: No data, commercial product provided by Monsanto, white flakes
1-8
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Vehicle: Not reported, but acute oral study used water
Method: Patterned after U.S. Federal Hazardous Substances Act Regulations study guideline
16 CFR 1500.41; shaved back, each rabbit tested on intact and abraded skin, semiocclusive
dressing removed after 24 hours, observations at 24 and 72 hours.
Results: No erythema or edema on intact or abraded skin in any of the 6 rabbits.
Reference: Food and Drug Research Labs, 1976
Type: Acute dermal irritation
Species, strain, sex, number: Rabbit, New Zealand, 3 males and 3 females
Doses: 1.0 mL of suspension of 10,000 mg/20 mL = 500 mg
Purity: No data, white flakes
Vehicle: 50% aqueous solution of polyethylene glycol
Method: U.S. Federal Hazardous Substances Labeling Act Section 191.12 (February 1965);
shaved back, each rabbit tested on intact and abraded skin, occlusive dressing removed after
24 hours, observations at 24 and 72 hours.
Results: No erythema or edema on intact or abraded skin in any of the 6 rabbits.
Reference: Ciba-Geigy Pharmaceuticals Division, 1983b
Additional Studies:
Other studies, reported in less detail, also reported no effects in rabbits from dermal exposure on
intact skin to the dry powdered TPP, and only slight dryness during repeated application as a
saturated solution in ethanol (13 times in 16 days) (Dow Biochemical Research, 1933).
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The available skin sensitization data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential skin sensitization study with negative results in guinea pigs was submitted. These
data allow this endpoint to be adequately characterized.
No experimental studies of skin sensitization in animals were located in the published literature.
A few human cases of TPP allergic dermatitis have been reported. An example is a case of
allergy to TPP from cellulose acetate eyeglass frames that contained TPP as an additive (Carlsen
et al., 1986). Patch testing of dermatological patients, however, has not generally implicated this
chemical as a sensitizer. For example, of 343 patients tested because of suspected sensitivity to
plastics and glues components, none reacted to TPP (Tarvainen, 1995). In a study of 23,192
patents with eczema who were patch tested with cellulose acetate film containing 7-10% TPP
and 4-5 % phthalic acid, positive reactions were observed in only 15 (0.065%) (Hjorth 1964).
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SUBCHRONIC TOXICITY
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Conclusion.
The available subchronic oral toxicity data were judged inadequate to meet the endpoint, but an
existing unpublished Food and Drug Administration (FDA) study, if provided, could address this
data gap.
Basis for Conclusion:
A single 35-day study in rats (Sutton et al., 1960) provides limited relevant information. The
study was not adequate to characterize this endpoint because of the small number of rats in each
dose group, testing of only one sex, lack of clinical chemistry and histopathology data, and lack
of detailed reporting. A set of concurrent approximately 120-day studies performed by FDA
investigated general toxicity, reproductive and developmental toxicity, neurotoxicity, and
immunotoxicity (Hinton et al., 1987, 1996; Sobotka et al., 1986; Welsh et al., 1987). The
general toxicity study, however, was not published, and the associated studies do not report
adequate information on the general toxicity of this chemical.
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
The only relevant available study is a 35-day repeated oral study that does not satisfy the
guideline. A summary of the study is as follows:
Type: 35-Day repeated oral
Species, strain, sex, number: Rat, Holtzman, male, 5/dose
Doses: 0, 0.1, and 0.5% in the diet (the 0.1% group received 5% for the first 3 days, but refused
to eat, and therefore was switched to a lower dietary concentration)
Purity: Practical Grade Eastman Organic, purity not specified
Vehicle: None; added to diet
Exposure period, frequency: 35 days, daily
Post Exposure Period: 2 weeks
Method: Two rats/group killed at end of 35 days; 3 rats/group observed for 2 week recovery
period; body weight, hematology (hemoglobin, cell volume, red and white cell count, and
differential), necropsy with organ weights.
Results: Slight depression in body weight gain in high dose group at day 35, but not after 2-
week recovery period. Slight but statistically significant increase (Student's t test) in mean
relative liver weight in high dose group-not specified whether all 5 rats/group were included in
organ weight determinations. No gross abnormalities seen at necropsy. No statistically
significant differences in hematological values.
Reference: Sutton et al., 1960
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90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
The only >90 day subchronic studies of TPP toxicity were specialized studies of reproductive,
developmental, neurological, and immunological endpoints in the rat conducted by the FDA
(Hinton et al., 1987; Sobotka et al., 1986; Welsh et al., 1987). These studies provide only
limited information on other systemic toxicities, and therefore do not satisfy the guideline.
In the reproductive and developmental toxicity study in the rat, males and females were
fed TPP at dietary levels up to 1% for 91 days prior to mating, continuing through
mating, and the females were continued on the diet until day 20 of gestation. This study
reported no differences in behavior or gross pathology of the treated dams, a slight but
significant decrease on day 0 of gestation in the body weight of the dams fed the 1% diets
(690 mg/kg/day), a slight but significant increase in food consumption primarily at 0.5
and 0.75% in the diet(not dose-related), and a non-significant decrease in body weight
gain (minus the gravid uterus) at day 20 of gestation in dams fed >0.5% (341 mg/kg/day)
(Welsh etal., 1987).
The neurological study, in which male rats were fed up to 1% TPP in the diet for 4
months, provided no evidence of neurobehavioral effects, but also noted a decrease in
body weight gain. The NOAEL and LOAEL for this effect were 0.25% in the diet (161
mg/kg/day) and 0.50% in the diet (345 mg/kg/day) (Sobotka et al., 1986).
In the immunotoxicity study, in which male and female rats were fed up to 1% TPP in the
diet for 4 months, the only effects seen were a decrease in body weight gain at 1.0%
(approximately 700 mg/kg/day) in the diet, and non-dose related increases in the relative
percentages of cc-globulins in treated females and p-globulins in treated males, which
were interpreted as a possible sign of liver activity of uncertain toxicological significance
(Hinton et al., 1987). Because of the lack of dose-response, these findings may not be
indicative of a chemical effect. The NOAEL and LOAEL for decreased body weight
gain were 0.75% in the diet (517 mg/kg/day) and 1.0% in the diet (700 mg/kg/day).
Details of these studies are provided in the appropriate sections. These studies are not adequate
to fulfill the requirements of the 90-day subchronic oral toxicity guideline.
An associated, concurrent FDA subchronic toxicity study, mentioned in the other FDA reports
(Hinton et al., 1987, 1996; Sobotka et al., 1986; Welsh et al., 1987), has not been published. The
study has been requested for review.
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
No studies of this type were located.
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Subchronic Dermal Toxicity (21/28-day or 90-day)
Conclusion:
The available subchronic dermal toxicity data were judged inadequate to meet the endpoint,
unless further information is provided for the available 21-day study.
Basis for Conclusion:
The only study available for this endpoint, a 21-day dermal toxicity study, has a design similar to
that of the OPPTS guideline, but the reporting of the study is deficient. Only the text portion of
the results was available, but the tables summarizing the data were omitted, as were data
regarding the outcome of tests of purity of the TPP. Because it is the only relevant study, more
detailed reporting of information from this study is needed if it is to be used to satisfy the
endpoint. The study is summarized below.
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD
Guideline 410)
Type: 21-Day dermal toxicity
Species, strain, sex, number: Rabbit, New Zealand white, 10 males and 10 females/dose
Doses: 0 (vehicle control), 100, and 1,000 mg/kg body weight
Purity: Determined at start and end of test but results not reported
Vehicle: Absolute ethanol
Exposure period, frequency: 21-23 days, 5 days/week
Post Exposure Period: none
Method: Similar to 870.3200 but functional observational battery omitted, number of
tissues/organs examined histopathologically was not as extensive, and histopathological
examinations were performed on all control and high dose rabbits and "as required" on low dose
rabbits. The skin of 5 males and 5 females in each dose group was abraded twice a week; the
skin of the other 5 males and 5 females in each group was not. No dressing was used after
application of the vehicle or test substance, but collars were used to prevent contact with the
material, and the excess was removed after 6 hours.
Results: No treatment-related changes were seen in clinical signs, mortality, body weight,
hematology, gross or histopathology, or routine clinical chemistry. Low-dose females had
decreased mean thyroid/body weight ratio and increased mean kidney weight. Dose-related
depressions in serum, erythrocyte, and brain cholinesterase were observed. The tables
summarizing the actual data were omitted from the report.
Reference: Bio/Dynamics, Inc., 1970
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
No studies of this type were located.
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Subchronic Inhalation Toxicity: 90-Day Inhalation Toxicity (OPPTS Harmonized
Guideline 870.3465; OECD Guideline 413)
Conclusion:
No available subchronic inhalation toxicity data.
Basis for Conclusion:
No repeated-exposure inhalation toxicity studies were located.
REPRODUCTIVE TOXICITY
Conclusion:
The available reproductive toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A study of reproduction and development in rats exposed for 91 days prior to mating, and
continuing through mating until day 20 of gestation (Welsh et al., 1987) partially characterizes
this endpoint, but is not fully adequate. No other data relevant to this endpoint were located.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
A study of reproduction and development in rats exposed for 91 days prior to mating, and
continuing through mating until day 20 of gestation (Welsh et al., 1987) partially satisfies the
reproductive screening component of this guideline, but is not fully adequate, primarily because
it lacks histopathology of male and female reproductive organs. The study is summarized below
under Developmental Toxicity. Findings relevant to reproduction were that there were no
significant differences in number of corpora lutea, implants, implantation efficiency, viable
fetuses, and number of early or late deaths at dietary levels as high as 1.0% TPP (690
mg/kg/day). Because both sexes were treated, and there were no effects on litter size (as
measured by number of viable fetuses), the study provides some evidence that fertility is not
affected by TPP in the rat.
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
No studies with this specific design were available.
1-13
-------
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
No studies with this specific design (two-generation reproduction) were available.
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
A study of reproduction and development in rats exposed for 91 days prior to mating, and
continuing through mating until day 20 of gestation (Welsh et al., 1987) appears to fulfill the
requirements of the Prenatal Developmental Toxicity Study guideline, and is adequate to
characterize developmental toxicity. Details of this study are as follows:
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Type: Reproductive screen, prenatal developmental toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 40 males and 40 females/dose
Purity: Commercial grade, Aldrich, 98% pure
Doses: 0, 0.25, 0.50, 0.75, or 1.00% in the diet (0, 166, 341, 516, and 690 mg/kg/day based on
food consumption and body weight of pregnant females)
Exposure duration, frequency: Starting at 4 weeks post weaning, males and females exposed
for 91 days prior to mating, continuing through mating and, for the dams, through gestation day
20; daily
Method: Body weight, food consumption, clinical signs, and necropsy of dams; uterine contents
at day 20 of gestation; fetal weight, crown-rump length, external, visceral, and skeletal
abnormalities; extensive statistical analyses.
Results: The body weights of the females fed the 1.0 % diets were slightly but significantly
lower than those of controls on day 0 of gestation. During gestation, the dams that consumed
TPP in the diet generally consumed slightly more food than controls; but their body weight gains
during gestation and the adjusted body weight gain (excluding gravid uterus) at day 20 were not
significantly different from controls. No differences in behavior or gross pathology were
reported. Fertility (pregnancy rate) was higher in the treated females than in controls, but control
fertility was relatively low. No significant differences between treated and control groups were
seen for numbers of corpora lutea, implants, implantation efficiency, viable fetuses, or
resorptions (total or early or late deaths). Male and female fetuses from the treated groups
tended to weigh more than control fetuses, but the differences were minimal (<10% increase in
fetal weight), not dose-related, and significant (p<0.05) only for the males in the 0.50 and 1.00%
groups (but not the 0.75% group). Significant, slight increases in visceral variations (moderate
1-14
-------
hydroureter, enlarged ureter proximal to kidney) were seen in litters of all treated groups, but the
increases were not dose-related, and the controls had a relatively high incidence of moderate
hydroureter. Given the lack of dose response and uncertain biological significance of the slight
fetal changes in this study, the highest dose level (1.0% TPP in the diet, 690 mg/kg/day) may be
a NOAEL for fetotoxicity. TPP did not produce teratogenic effects in this study. This study
suggests a minimal LOAEL for decreased body weight gain of 1.0% TPP in the diet (690
mg/kg/day) for the dams. Although the highest dose in the study (1.0% in the diet, 690
mg/kg/day) is not as high as a limit dose of 1,000 mg/kg/day, it did produce slight body weight
depression in the dams, and in the two associated studies (on neurotoxicity and immunotoxicity),
produced more striking depressions in body weight gain in male and female rats at the same
dietary level, particularly in the first few weeks on test, and in the absence of a depression in
food consumption. A higher dietary level (5%) was tested in a 35-day study in rats and resulted
in food refusal (Sutton et al., 1960). Thus testing with dietary levels substantially higher than
1.0% TPP may not be advisable.
Reference: Welsh et al., 1987
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
No studies with this specific design were available.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
A study of reproduction and developmental toxicity is available (Welsh et al., 1987); the
developmental toxicity portion of the study is consistent with a full prenatal developmental
toxicity study, and was discussed previously under that category.
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion:
No relevant studies were located.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
No studies of this type were located.
1-15
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Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline
870.4300; OECD Guideline 453)
No studies of this type were located.
CARCINOGENICITY
Conclusion:
The available carcinogenicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available study, a strain A mouse pulmonary adenoma study, is not a suitable type of study
to characterize the potential carcinogenicity of chemicals for chronic oral exposure. The study is
summarized below.
Type: Strain A mouse pulmonary adenoma
Species, strain, sex, number: Mouse, strain A/St, 20 males/dose
Identity: Uncertainreported as triphenyl phosphate, and also as phosphorous acid, triphenyl
ester (which is triphenyl phosphite, a different chemical)
Purity: Not reported, Aldrich, reagent grade
Doses: 0 (vehicle control), 20, 40, and 80 mg/kg
Vehicle: Tricaprylin
Route: Intraperitoneal injection
Exposure duration, frequency: 3 injections/week; for 20 mg/kg-18 injections (6 weeks), for
40 mg/kg-3 injections (1 week), for 80 mg/kg-1 injection (the experimental design was to give
24 injections, but fewer injections were given for the "more toxic chemicals".
Method: 24 weeks after the first injection, the mice were killed and the lungs were examined for
surface nodules; a few of the nodules were examined histologically to confirm that they were
adenomas; positive controls received urethan; Student t test.
Results: Survival at 24 weeks was 46/50 for controls, 18/20 at 20 mg/kg (18 injections), 3/20 at
40 mg/kg (3 injections), and 12/20 at 80 mg/kg (1 injection). No increase in the number of
pulmonary adenomas/mouse was seen.
Reference: Theiss et al., 1977
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
No studies of this type were located.
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline
870.4300; OECD Guideline 453)
No studies of this type were located.
1-16
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NEUROTOXICITY
Conclusion:
The available neurotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
Some components of this endpointdelayed neurotoxicity and neurotoxicity screening (in adult
animals)are satisfied by the existing data, but no study of developmental neurotoxicity has
been conducted. This endpoint could be addressed in combination with the reproductive toxicity
endpoint. TPP gave negative results in several acute oral delayed neurotoxicity studies in the
hen as well as a subcutaneous study in the cat, and also in a subchronic oral neurotoxicity
screening study in the rat. Further information is provided in the following subsections.
Delayed Neurotoxicity
Conclusion:
The available delayed neurotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The available acute delayed neurotoxicity studies in the hen and in the cat (another sensitive
species), summarized below, give no evidence of acute cholinergic toxicity or of delayed
neurotoxicity. These studies, performed prior to the existence of the guidelines, do not entirely
conform to the guidelines, and lack detail including, in the hen studies, purity of the TPP sample.
Nevertheless, together they indicate a lack of delayed neurotoxicity for TPP. Neurotoxic
esterase (NTE) assays were not conducted in these studies. In a separate unpublished study,
summarized in a review of structure-activity studies, an NTE assay in brain homogenate
following a single oral dose of 700 mg/kg TPP (>99% purity) to the hen (Johnson, 1975) gave
negative results. This dose is lower than those used in the critical studies of delayed
neurotoxicity in hens but given the lack of signs and histopathological evidence for delayed
neurotoxicity, additional NTE assays do not appear necessary.
Because of the lack of signs or histopathology indicating delayed neurotoxicity in the acute
studies, 28-day studies are not required. In addition, structure-activity studies indicate that TPP
would not be expected to cause delayed neurotoxicity (Johnson, 1975).
1-17
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Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
1-18
-------
Critical Studies
Type: Delayed neurotoxicity
Species, strain, sex, number: Hen, White Leghorn, 9 for TPP
Purity: Not reported, prepared from pure phenol
Doses: 5,000 mg/kg twice daily; thus, 10,000 mg/kg/day
Vehicle: Corn oil
Route: Gavage
Exposure duration, frequency: Twice a day on days 1-3 and 21-23 of the study (6 days of
dosing); interval between doses not reported.
Method: Dosing twice daily for 6 days was needed because of the low toxicity of TPP (no
lethality at 5 mg/kg, the largest feasible dose). Hens were fasted for 16 hours before dosing
(further explanation not provided). Daily observations for deaths and signs of neurotoxicity
were conducted from day 1 through day 42, at which time hens were necropsied. Brain, sciatic
nerve, and spinal cord were examined histopathologically. Tricresyl phosphate (mixed o-, m-,
p-) was tested concurrently.
Results: For TPP, no overt signs of neurotoxicity and no histopathological effects in the nervous
tissues were observed (0/9). Although the hens were weighed at 0, 21, and 42 days, no body
weight results were presented. Tricresyl phosphate, a known delayed neurotoxicant, resulted in
overt signs and histopathological evidence of delayed neurotoxicity in 6/6. Details of the
histopathological data were not provided.
Reference: Johannsen et al., 1977
Type: Delayed neurotoxicity
Species, strain, sex, number: Hen, Rhode Island Red x Light Sussex, 2/dose
Purity: Not reported, white flakes
Doses: 2,000, 3,000, 5,000, 8,000, or 12,500 mg/kg
Vehicle: Arachis oil
Route: Gavage
Exposure duration, frequency: Single dose
Method: Hens were not fasted. Post-dosing observation period was 21 days. Daily observations
for deaths and signs of neurotoxicity. Necropsy but not histopathology.
Results: No overt signs of neurotoxicity. Necropsy results not mentioned.
Reference: Ciba-Geigy Pharmaceuticals Division, 1980
Type: Delayed neurotoxicity
Species, strain, sex, number: Hen, Rhode Island Red x Light Sussex, 2
Purity: Not reported, white flakes
Doses: 12,000 mg/kg
Vehicle: Arachis oil
Route: Gavage
Exposure duration, frequency: Single dose
Method: Hens were not fasted. Post-dosing observation period was 21 days. Daily observations
for deaths and signs of neurotoxicity. Necropsy but not histopathology.
1-19
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Results: No overt signs of neurotoxicity, and no abnormalities at necropsy.
Reference: Ciba-Geigy Pharmaceuticals Division, 1981a
Type: Delayed neurotoxicity
Species, strain, sex, number: Cat, not further specified, 5
Purity: Zone-refined triphenyl phosphate, purity 99.99%
Doses, number: 400 mg/kg in propylene glycol (2 cats), 700 mg/kg in corn oil (2 cats), and
1,000 mg/kg in corn oil (1 cat)
Vehicle: Propylene glycol (1 cat), corn oil (2 cats)
Route: Subcutaneous injection
Exposure duration, frequency: Single dose
Method: Post-dosing observation period was 4 months. Daily observations for deaths, general
behavior, eating, and drinking. Weighed at intervals. Whole blood, plasma, and erythrocyte
cholinesterase determined for cats given 700 mg/kg of TPP and their controls. Complete
necropsies on cats given 700 mg/kg. Brain stem and spinal cord examined histopathologically in
all cats.
Results: All except one on the lowest dose lost weight (due to cessation of eating); the other on
the lowest dose lost weight initially and then regained it. These cats had no overt signs of
toxicity and were not necropsied or examined further. At 700 mg/kg, the cats stopped eating
during the first week after injection, became moribund, and were euthanized. Cholinesterase
activities in these cats were similar to those in the controls. No evidence of axonal degeneration,
demyelination, or other adverse change was seen in sections from 11 levels of the nervous
system extending from cerebral cortex to peripheral nerve in the 700 mg/kg group. The cat that
received 1,000 mg/kg became anorexic 1 week after injection and was necropsied at 3 weeks
after injection. Sections of this cat's brain stem and spinal cord did not reveal any abnormalities.
Actual data were not presented.
Reference: Wills et al., 1979
Additional studies
Additional oral studies at lower doses in the chicken [one at 500 mg/kg in the hen (Aldridge and
Barnes, 1961), and another at 1,000 mg/kg in the cockerel (young rooster) (Hine et al., 1956)]
also reported no signs of delayed neurotoxicity. Two delayed neurotoxicity studies that reported
some axonal lesions in the spinal cord of hens following 5,000 mg/kg/day of TPP (unknown
purity) for 5 days are considered invalid because the doses were so high that most of the hens
died or were killed in extremis during the study, severe weight loss occurred in the hens, and the
same mild axonal lesions were seen in both controls and treated hens (Ciba-Geigy
Pharmaceuticals Division, 1982), or because no controls were used (Ciba-Geigy Pharmaceuticals
Division, 198 la).
1-20
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Neurotoxicity (Adult)
Conclusion:
The available adult neurotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The available study of neurobehavioral effects following subchronic feeding of TPP to rats
(Sobotka et al., 1986) predates the guidelines, but fulfills some of the criteria for a Neurotoxicity
Screening Battery. It includes some of the observations from the functional observational
battery, and a few additional measures (rearing activity, rotorod, negative geotaxis). It does not
include neurohistopathological examinations, and testing was conducted in only one sex rather
than both sexes as recommended. In other reasonably well-conducted studies of this chemical,
however, there is no evidence that one sex is significantly more sensitive than the other or that
the chemical is neurotoxic. Structure-activity studies do not indicate neurotoxic potential for
TPP (Johnson, 1975). Therefore, the existing study, in context with the other information
regarding TPP toxicity, may be adequate to satisfy the adult neurotoxicity component of the
neurotoxicity endpoint. The study description follows:
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Type: Neurotoxicity screening, oral
Species, strain, sex, number: Rat, Sprague-Dawley, 10 males/dose
Doses: 0, 0.25, 0.50, 0.75, or 1.0% in the diet; 0, 161, 345, 517, or 711 mg/kg/day
Vehicle: None
Purity: 98% (commercial grade, Aldrich); homogeneity and stability of TPP diets confirmed by
gas chromatography
Exposure duration, frequency: 4 months, daily
Method: Observations included food consumption, body weight, in-cage observation for overt
signs, open-field exploratory behavior (motor activity and rearing), rotorod, forelimb grip
strength, and negative geotaxis. Extensive statistical analysis.
Results: Overt signs and test results for neurobehavioral endpoints were not statistically
significantly different in treated versus control rats. Body weight gain, but not food
consumption, was statistically and lexicologically significantly lower (>10% decrease) in the
0.5, 0.75, and 1.0% dietary groups than in controls, and there was a negative dose-related linear
trend for weight gain. Thus, no LOAEL for neurotoxicity was demonstrated. The NOAEL and
LOAEL for effects on body weight gain were 0.25% in the diet (161 mg/kg/day) and 0.50% in
the diet (345 mg/kg/day).
Reference: Sobotka et al., 1986
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS Harmonized
Guideline 870.6300)
1-21
-------
Conclusion:
No available developmental neurotoxicity data.
Basis for Conclusion:
No studies of this type were located.
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat)
OPPTS Harmonized Guideline 870.6500
Peripheral Nerve Function (rodent)
OPPTS Harmonized Guideline 870.6850
Sensory Evoked Potentials (rat, pigmented strain preferred)
OPPTS Harmonized Guideline 870.6855
These studies may be indicated, for example, to follow up neurotoxic signs seen in other studies,
or because of structural similarity of the substance to neurotoxicants that affect these endpoints.
These studies may be combined with other toxicity studies.
Conclusion: These endpoints do not appear to be applicable to TPP.
Basis for Conclusion: Although there are no studies addressing these endpoints, there are no
reliable data for TPP, and no structure-activity considerations, that indicate a need for these
follow-up studies.
IMMUNOTOXICITY
Conclusion:
The available immunotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The potential immunotoxicity of TPP was examined in a subchronic dietary study in rats (Hinton
et al., 1987, reprinted as Hinton et al., 1996) which predates the guideline for immunotoxicity.
This study appears to satisfy most of the requirements of the guideline, although no positive
control was included, and the anti-sheep red blood cell assay is not the currently recommended
assay. The study, which was negative for immunotoxicity, is summarized below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
Type: Immunotoxicity, oral subchronic
1-22
-------
Species, strain, sex, number: Rat, Sprague-Dawley, 10 males and 10 females/dose
Doses: 0. 0.25, 0.50, 0.75, or 1.00% TPP in the diet; approximately equivalent (based on
measured dosages in the related studies by Sobotka et al., 1986 and Welsh et al., 1987) to 0, 163,
343, 517, and 700 mg/kg/day. No positive control.
Purity: Aldich, 98% pure, confirmed by gas chromatography, stable under the experimental
conditions of this study
Exposure duration, frequency: 120 days, daily
Method: Observations included body weight, food consumption, midterm and terminal sacrifice,
necropsy, spleen and thymus weights, histopathology of spleen, thymus, and mesenteric lymph
nodes, immunohistochemical evaluation of B- and T-lymphocyte regions in these tissues, total
serum protein and electrophoretic analysis of serum proteins, humoral response to sheep red
blood cells (relative antibody liters by hemolytic assay). Extensive statistical analysis.
Results: The only statistically significant effects were a decreased growth rate (>10% difference
in body weight) during the first 4 weeks in males and females of the 1.00% dietary group, and
non-dose related increases in the relative percentages of oc-globulins in treated females and P-
globulins in treated males, which were interpreted by the study authors as a possible sign of liver
activity but of uncertain toxicological significance. Because of the lack of dose-response, these
findings may not be indicative of a chemical effect. This study did not demonstrate a LOAEL
for immunotoxicity. The NOAEL and LOAEL for decreased body weight gain were 0.75% in
the diet (517 mg/kg/day) and 1.0% in the diet (700 mg/kg/day).
Reference: Hinton et al., 1987
GENOTOXICITY
Conclusion: The available genotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
Three studies of gene mutation in vitro report negative results. These studies, two in bacteria
and one in mammalian cells, predate the relevant guidelines, but were conducted in a manner
similar to them, and together, characterize the gene mutation in vitro endpoint. Studies of
chromosomal aberrations were not available, however, and are needed for adequate
characterization of the genotoxicity endpoint.
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100;
OECD Guideline 471)
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537
Metabolic activation: Tested with and without Aroclor 1254-induced liver S9 from male Syrian
hamsters (10% in S9 mix for all strains and also 50% for TA1535 and TA1537), and male
Sprague-Dawley rats (10% for all strains)
1-23
-------
Concentrations: 0, 100, 333, 1,000, 3,333, and 10,000 jig/plate. Solvent was 95% ethanol. A
precipitate was present in the plates at >3,333 ug/plate; tested in triplicate; plus replicate
Purity: 98% +
Method: Preincubation (20 minutes) and plate incorporation (48 hours) at 37°C. Positive
controls were 2-aminoanthracene for all strains with S9, and sodium azide (TA1535 and TA100),
9-aminoacridine (TA1537), and 4-nitro-o-phenylenediamine (TA98) in the absence of S9.
Results: No increase over negative control at any concentration; no apparent cytotoxicity; the
two highest concentrations tested may have exceeded solubility limits.
Reference: Zeiger et al., 1987
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538
Metabolic activation: Tested with and without Aroclor 1254-induced liver S9 from male
Sprague-Dawley rats
Concentrations: 0, 10, 100, 500, and 1,000 [ig/plate. Solvent was DMSO; tested in triplicate;
plus replicate
Purity: No data, white crystals
Method: Plate incorporation, 48 hour incubation at 37°C; apparently only one plate for each
concentration. Negative and positive controls.
Results: No increase in revertants over negative control at any concentration; highest
concentration reportedly produced some evidence of physiological effect. Saccharomyces
cerivisiae D4 also tested.
Reference: Litton Bionetics, Inc., 1978a
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
Type: Mammalian Cell Gene Mutation Test: Forward Mutation
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: Tested with and without Aroclor 1254-induced liver S9 from male
Sprague-Dawley rats
Concentrations: 0, 3.13 (only without S9), 6.26, 12.5, 25, 50, and 75 (only with S9) jig/plate.
Solvent was DMSO; tested in triplicate; plus replicate
Purity: No data, white crystals
Method: Plate incorporation, 48 hour incubation at 37°C. Negative and positive controls
(ethylmethanesulfonate without S9; dimethylnitrosamine with S9).
Results: No increase over negative control at any concentration; highest concentration selected
during prescreening as a level that reduced growth potential.
Reference: Litton Bionetics, Inc., 1978b
Other
Mitotic Gene Conversion in Saccharomyces cerevisiae (OPPTS Harmonized
Guideline 870.5575)
1-24
-------
Type: Mitotic Gene Conversion
Species, strain: Saccharomyces cerevisiae D4
Metabolic activation: Tested with and without Aroclor 1254-induced liver S9 from male
Sprague-Dawley rats
Concentrations: 0, 10, 100, 500, and 1,000 jig/plate. Solvent was DM SO
Purity: No data, white crystals
Method: Plate incorporation, 3- to 5-day incubation at 30°C (without S9) or 37°C (with S9).
Negative and positive controls
Results: No increase over negative control at any concentration; highest concentration
reportedly produced some evidence of physiological effect.
Reference: Litton Bionetics, Inc. 1978a
No studies were available on the genotoxicity of triphenyl phosphate in the following types of
types of tests:
Gene Mutation in Vivo
Chromosomal Aberrations in Vitro
Chromosomal Aberrations in Vivo
DNA Damage and Repair
1-25
-------
Ecotoxicity
Acute Toxicity to Fish (OPPTS Harmonized Guideline 850.1075; OECD Guideline 203)
Conclusion:
The available acute fish toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The available acute fish toxicity studies are summarized in Table 1-1. Acute 96-hour toxicity
studies in freshwater fish species including rainbow trout, fathead minnows, goldfish, bluegill
sunfish, medaka, channel catfish, and carp and in saltwater species including silverside and
sheepshead minnow were located. Most of the 96-hour LC50 values reported in the available
literature are consistent with each other and ranged from 300 to 1,200 |ig/L. One study (Dawson
et al., 1977), however, reported substantially higher LC50 values for TPP (95,000 |ig/L in
silverside and 290,000 |ig/L in bluegill). A reason for this discrepancy is not clear. However,
the data reported by Dawson et al. (1977) were considered unreliable because the reported LC50
values are approximately 50 to 150 times greater than the solubility limit of TPP (approximately
2,000 |ag/L). Also, the results reported by Dawson et al. (1977) are inconsistent with results
from multiple other studies.
Overall, the available acute fish toxicity endpoint appears to be satisfied by the currently existing
database for the following reasons:
Studies are available in both cold- and warm-water freshwater species and in marine
species;
Numerous studies are available that reported similar LC50 values; and
Although most of the available studies used static conditions, the results from the only
study located that used flow-through conditions and analytically confirmed the test
concentrations are consistent with results from static studies conducted in the same
species. These data indicate that use of static exposure conditions produces similar
results as flow-through studies.
It should be noted, however, that sufficient detail was not included in many of the study reports
to allow for a comprehensive and independent evaluation of data adequacy, most studies used
static conditions and did not analytically confirm the test concentrations, and many studies were
conducted prior to publication of GLP guidelines.
A summary of the available acute toxicity studies in fish that were located as well as selected
deficiencies in the studies is presented in Table 1-1. Studies that were either published in a
foreign language or that were not readily available AND that were not critical to the hazard
assessment were not retrieved.
1-26
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Table 1-1. Summary of available acute fish toxicity studies for triphenyl phosphate (115-86-6)3
Study
Reference
Ahrens et
al., 1978
Ciba-Geigy,
1981a
Species
Tested
Carp
Rainbow
trout
49mm;
0.94 g
96-Hour
LC50
<1,000
Hg/L
850 |ig/L
Selected Study Design Parameters
Study
Type
Static
Static
Concentration
Range Tested
Not reported
5 concentrations;
0.1 8 to 1,800
^g/L
No. of
Fish/
Cone
10
10
Analytical
Monitoring
No
No
Water
Chemistry"
pH:NR
Temp: "room"
temp.
DO:NR
Hardness: NR
pH: 7.7-8.2
Temp: 14.5-
15.6°C
DO: 5-9 mg/L
Hardness: 172
mg/L
Solvent
Acetone
(0.6 mL/L)
Mixture of
octanol
(>0.004 mL/L),
tween (>0.07
mL/L), and
ethylene glycol
monomethyl
ether (>0.02
mL/L)
Comments on the Data
The study conduct followed
German guidelines.
Reporting deficiencies
preclude an independent
evaluation of data adequacy.
LC50 values were not
reported.
LCI 00 was 1,000 and
10,000 |ig/L with and without
acetone, respectively.
LCD without acetone was
5,000 ng/L. LCD value with
acetone was not observed.
The study reportedly followed
OECD Guideline 203. TPP
purity was 100%; loading rate
was 0.21 g/L. Only minor
reporting deficiencies were
noted. Sublethal effects
included abnormal swimming
behavior and loss of
equilibrium at all
concentrations tested.
1-27
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Table 1-1. Summary of available acute fish toxicity studies for triphenyl phosphate (115-86-6)3
Study
Reference
Dawson et
al., 1977
Food and
Drug
Research
Labs, 1979
Species
Tested
Bluegill
sunfish
Silverside
Rainbow
trout
96-Hour
LC50
290,000
Water
solubility
is approx.
2,000
95,000
Water
solubility
is approx.
2,000
760 |ig/L
Selected Study Design Parameters
Study
Type
Static
Static
Static
Concentration
Range Tested
5 concentrations,
125,000 to
560,000 |ig/L
5 concentrations,
75,000 to
560,000 |ig/L
5 concentrations,
180 to 1,800
No. of
Fish/
Cone
Not
reported
10
Analytical
Monitoring
No
No
Water
Chemistry"
Dilution water
was reported to
have a pH of
7.6-7.9 and a
hardness of 55
mg/L. Target
temp, was 23°C
for bluegill and
20°C for
silverside
pH: 7.2-7.5
Temp:
12°C±1°C
DO: 7.8-10
mg/L
Hardness: 42
mg/L
Solvent
Either distilled
water or solvent
with
(reportedly)
relatively low
toxicity was
used.
Concentration
of solvent, if
used, was not
reported.
Unidentified
solvent
Comments on the Data
The reported LC50 value
from this study is
substantially higher than the
water solubility of TPP
(approx. 2,000 ng/L);
therefore, these data are
unreliable.
Study reportedly followed
U.S. EPA (1975) guidelines.
Solvent and blank controls
were used. Loading rate was
0.15 g/L.
1-28
-------
Table 1-1. Summary of available acute fish toxicity studies for triphenyl phosphate (115-86-6)3
Study
Reference
Geiger et
al., 1986
Species
Tested
Fathead
minnow
Fathead
minnow
(17mm;
0.071 g)
96-Hour
LC50
3,800
Hg/L
Water
solubility
is approx.
2,000
870 |ig/L
Selected Study Design Parameters
Study
Type
Static
Flow-
through
(14.4x
per
day)
Concentration
Range Tested
5 concentrations,
1,000 to
10,000 |ig/L
5 concentrations;
180 to 1,150
Hg/L (mean
measured)
No. of
Fish/
Cone
10
20
Analytical
Monitoring
No
Yes (GLC;
99.8%
recovery)
Water
Chemistry"
pH: 6.8-7.5
Temp:
20.6±0.6°C
DO: 1.3-9.0
mg/L
Hardness: 43
mg/L
pH: 7.8
Temp: 24.5°C
DO: 6.4 mg/L
Hardness: 45.6
mg/L
Values are
averages over
the study
duration; ranges
were not
reported
Solvent
Unidentified
solvent
None used;
1.2 mg/L stock
solution in glass
wool column
Comments on the Data
Dissolved oxygen
concentrations decreased over
the course of the study to as
low as 1.3 mg/L. The LC50
determined from this study
was greater than the water
solubility of TPP.
Fish were 29 days old at
study initiation. Loading rate
was 1.4 g/L, and purity was
98%. In the high-dose group,
1 9/20 fish were dead by the
24-hour observation, and the
remaining fish was dead by
the 48-hour observation
period. Reporting
deficiencies included lack of
water chemistry parameter
values (e.g., pH, dissolved
oxygen, temperature) at each
concentration (although mean
values were given), and a
solvent was not used.
1-29
-------
Table 1-1. Summary of available acute fish toxicity studies for triphenyl phosphate (115-86-6)3
Study
Reference
Huckins et
al., 1991
Industrial
Bio Test
Labs, Inc.,
1972
Species
Tested
Bluegill
sunfish
(0.5-1 g)
Rainbow
trout
Bluegill
sunfish
96-Hour
LC50
780 |ig/L
Between
100 and
1,000
Between
1000 and
10,000
Water
solubility
is approx.
2,000
Selected Study Design Parameters
Study
Type
Static
Static
Static
Concentration
Range Tested
5 concentrations,
500 to
10,000 |ig/Lwith
and without
addition of 1 g/L
soil and clay
4 concentrations;
100 to
100,000 |ig/L
4 concentrations;
100 to
100,000 |ig/L
No. of
Fish/
Cone
10
Not
reported
Not
reported
Analytical
Monitoring
No
No
No
Water
Chemistry"
pH:NR
Temp: 22°C
DO:NR
Hardness: NR
pH: 7.3-7.9
Temp: 12.2°C
DO: 2.9-7.9
mg/L
Hardness: NR
pH: 7.6-8.2
Temp: 18.6°C
DO: 6.9-7.5
mg/L
Hardness: NR
Solvent
Acetone,
unspecified
concentration
Acetone
Acetone
Comments on the Data
TPP purity was 99%.
Selected reporting
deficiencies included
concentration of solvent used,
pH and dissolved oxygen of
the test system during the
study, and loading rate.
Very limited information on
the study was available. Data
were obtained from
unpublished EPA submission
fromTSCATS. Reporting
deficiencies preclude an
independent evaluation of
data adequacy.
1-30
-------
Table 1-1. Summary of available acute fish toxicity studies for triphenyl phosphate (115-86-6)3
Study
Reference
Mayer et al.,
1981
EG&G
Bionomics,
1978a,b
Mayer and
Ellersieck,
1986
Species
Tested
Rainbow
trout
Fathead
minnow
Sheeps-
head
minnow
Rainbow
trout
96-Hour
LC50
400 |ig/L
660 |j,g/L
Between
320 and
560 |ig/L
370 |ig/L
Selected Study Design Parameters
Study
Type
Static
Static
Static
Static
Concentration
Range Tested
Not reported
3 concentrations;
280 to 2200 |ig/L
5 concentrations;
56 to 560 |ig/L
Not reported
No. of
Fish/
Cone
10
10
10
Not
reported
Analytical
Monitoring
No
No
No
Yes
Water
Chemistry"
pH: 7.2
Temp: 12±1°C
DO:NR
Hardness: 272
mg/L
pH: 6.3-7.5
Temp: 22±1°C
DO: 2.5-8.7
mg/L
Hardness: 28-
44 mg/L
pH: 7.9-8.1
Temp: 20±1°C
DO: 3.8-6.3
mg/L
Hardness: NR
Salinity: 17
parts per
thousand
pH: 7.4
Temp: 12°C
DO:NR
Hardness: 40
mg/L
Solvent
Not reported
Triethylene
glycol (up to 7.5
mL)
Acetone
Not reported
Comments on the Data
Data were obtained from
Mayer et al., 1981 and from
unpublished data reported in
TSCATS. Fish age, weight,
and length and loading rate
were not reported.
Data were obtained from
Mayer et al., 1981 and from
unpublished data reported in
TSCATS. Fish age, weight,
and length and loading rate
were not reported.
Data were obtained from
Mayer et al., 1981 and from
unpublished data reported in
TSCATS. Fish age, weight,
and length and loading rate
were not reported.
Results of analytical
monitoring were not reported.
General methods were
reported in the publication
that were not necessarily
specific for the test on TPP.
1-31
-------
Table 1-1. Summary of available acute fish toxicity studies for triphenyl phosphate (115-86-6)3
Study
Reference
Palawski et
al., 1983
Species
Tested
Channel
catfish
Fathead
minnow
Rainbow
trout
(0.1 lg;
24mm)
96-Hour
LC50
420 |ig/L
1,000
Hg/L
360 |ig/L
Selected Study Design Parameters
Study
Type
Static
Static
Static
Concentration
Range Tested
Not reported
Not reported
3 concentrations;
210,240, and
290 |ig/L
No. of
Fish/
Cone
Not
reported
Not
reported
10
Analytical
Monitoring
Yes
Yes
No
Water
Chemistry"
pH: 7.5
Temp: 22°C
DO:NR
Hardness: 38
mg/L
pH: 7.3
Temp: 22°C
DO:NR
Hardness: 44
mg/L
pH:NR
Temp: NR
DO:NR
Hardness: NR
Solvent
Not reported
Not reported
Not reported
Comments on the Data
Results of analytical
monitoring were not reported.
General methods were
reported in the publication
that were not necessarily
specific for the test on TPP.
Results of analytical
monitoring were not reported.
General methods were
reported in the publication
that were not necessarily
specific for the test on TPP.
TPP was 99% pure. The
study followed U.S. EPA
(1975) guidelines. Fry, 12
days past swim-up stage,
were tested. An EC50 based
on immobility, mortality, and
loss of equilibrium of 300
|j,g/L was also determined
from this study.
1-32
-------
Table 1-1. Summary of available acute fish toxicity studies for triphenyl phosphate (115-86-6)3
Study
Reference
Sasaki et al.,
1981
Sitthichai-
kasem.,
1978
Species
Tested
Goldfish
(0.8-
2.8 g)
Killifish
(0.1-
0.2 g)
Rainbow
trout sac-
fry
(0.081 g)
Rainbow
trout
fingerling
s (0.75 g)
96-Hour
LC50
700 |ig/L
1200
389 |ig/L
299 |ig/L
Selected Study Design Parameters
Study
Type
Static
Static
Static
Static
Concentration
Range Tested
Not reported
Not reported
Control and 180-
1000 |ig/L
Control and 180-
1000 |ig/L
No. of
Fish/
Cone
7 to 9
7 to 9
10
10
Analytical
Monitoring
No*
*In a parallel
study, =70%
ofTPPwas
present in
water that
contained
goldfish after
96 hours.
No
No
Water
Chemistry"
pH:NR
Temp: 25°C
DO:NR
Hardness: NR
pH: 7.0-7.2
Temp: 12°C
DO: 7.3-8.5
ppm
Hardness: 40-
48
Solvent
Not reported
Acetone
Acetone
Comments on the Data
Neither goldfish nor killifish
are recommended species for
testing by OECD 203.
Reporting deficiencies
preclude an independent
evaluation of data adequacy.
Selected reporting
deficiencies included: water
chemistry values (pH,
hardness, dissolved oxygen),
identification of test
concentrations, and use of a
vehicle to facilitate
dissolution.
Spine deformation occurred
at 1.1 mg/L.
Fish were acclimated before
exposure. Moribund and
dead fish were counted at 24,
48, 72, and 96 hours.
"Studies that were either published in a foreign language or that were not readily AND that were not critical to the hazard assessment were not retrieved.
bHardness reported as mg/L CaCO3
1-33
-------
Acute Toxicity to Freshwater and Marine/Estuary Invertebrates (OPPTS Harmonized
Guidelines 850.1010 and 850.1035; OECD Guideline 202)
Conclusion:
The available acute freshwater invertebrate toxicity data were judged adequate to meet
the endpoint.
The available acute marine/estuary invertebrate toxicity data were judged inadequate to
meet the endpoint.
Based on the environmental fate of TPP, additional data may be needed on sediment
dwelling organisms. Currently available studies, although inadequate to meet the
endpoint in this review, indicate that TPP may be toxic to sediment-dwelling organisms.
Basis for Conclusion:
Freshwater Organisms
The available data are summarized in Table 1-2. Four studies in daphnids were located. All
studies used static conditions, and none of the available studies analytically confirmed the test
concentrations. The reported EC50 values were consistent with each other and ranged from
1,000 to 1,350 i-ig/L. Sufficient detail was available from three of the four studies located to
allow for an independent evaluation of data adequacy. Reporting deficiencies were noted in
those three studies that included lack of identity of concentrations tested, TPP purity,
concentration of solvent in the test solutions, and water hardness. In the remaining study
(Ziegenfuss et al., 1986), even basic study design parameters were not reported. Due to these
reporting deficiencies and on study design deficiencies (lack of analytical confirmation of the
test concentrations), none of the currently available studies are independently sufficient to be
used as the basis to satisfy the acute freshwater invertebrate toxicity endpoint. Collectively,
however, the data appear adequate because the four studies that were located reported a narrow
range of EC50 values, thus providing confidence in the reported effect levels.
Studies were also located on the toxicity of sediment-dwelling organisms. Two studies using the
midge and one study using the scud were located. These studies indicate that sediment-dwelling
organisms could be particularly sensitive to the toxicity of TPP. EC50 values ranged from 250
to 1,600 |ag/L. All of the studies in sediment-dwelling organisms used static conditions, and
none of the studies analytically confirmed the test concentrations. Based on the inconsistencies
in the reported toxicity values and the lack of a study that analytically confirmed the test
substance concentrations, these data were not judged to be adequate to satisfy the acute toxicity
endpoint for sediment-dwelling organisms. Based on the environmental fate of TPP, additional
testing on sediment-dwelling organisms may be needed.
In addition, a confidential study for acute toxicity to freshwater aquatic invertebrates was
submitted for which study results were consistent (daphnid 48-hour LC50 =1.2 mg/L) with
1-34
-------
those reported in the publicly available literature. The available data were judged adequate to
meet this endpoint.
Marine/Estuarine Organisms
One acute toxicity study in mysid shrimp was located (Table 1-2). The study was a 96-hour
static study that did not analytically confirm the test concentrations. The dissolved oxygen
concentration in this study was <60% of saturation after the 96-hour exposure period. The LC50
from this study was between 180 and 320 |ig/L; a discrete LC50 was not calculated. The
available data in mysid shrimp do not appear to be adequate to satisfy the marine/estuarine
invertebrate toxicity endpoint because only one publically available study was located, and it
used static conditions, did not analytically confirm the test concentrations, and dissolved oxygen
concentration in this study was below values recommended by standard guidelines. Because
only one study was available, and it of questionable reliability, the marine/estuarine invertebrate
toxicity endpoint does not appear to be satisfied by existing data.
1-35
-------
Table 1-2. Summary of available acute invertebrate toxicity studies on triphenyl phosphate (115-86-6)
Study
Reference
Ciba-Geigy
Ltd., 1981b
Food and
Drug
Research
Labs, 1979
Species
Tested
Daphnid
Daphnid
EC50
or
LC50
(Hg/L)
48-
hour:
1,350
48-
hour:
1,280
Selected Study Design Parameters
Study
Type
Static
Static
Concentration
Range Tested
800-3,700 |ig/L
1 80-3,200 |ig/L
No. of
Organisms/
Cone
20
20
Analytical
Monitoring
No
No
Water
Chemistry
pH: 8.6
DO: 7.0-7.2 mg/L
Temp: 20±1°C
Hardness: NR
pH: 8.4-8.5
DO: 7.8-9.4 mg/L
Temp: 20±0.5°C
Hardness: 232
mg/L
Solvent
DMF
Acetone
Comments on the Data
Although reporting
deficiencies were noted,
the study conduct appears
to be consistent with
current standard guidelines.
pH and dissolved oxygen
were only measured at test
termination and only at the
lowest and highest test
concentrations. TPP purity
was not reported.
Although reporting
deficiencies exist, the
details that were reported
appear to be consistent
with current guidelines.
Key deficiencies included
lack of analytical
monitoring of the test
concentrations. TPP purity
was not reported.
1-36
-------
Table 1-2. Summary of available acute invertebrate toxicity studies on triphenyl phosphate (115-86-6)
Study
Reference
Mayeretal.,
1981
Analytical
Bio
Chemistry
Labs, 1978
Ziegenfuss et
al., 1986
Huckins et
al., 1991
Ziegenfuss et
al., 1986
Monsanto
Env. Science
Section,
1982
Species
Tested
Daphnid
Daphnid
Midge
Midge
EC50
or
LC50
(Hg/L)
48-
hour:
1,000
48-
hour:
1,000
48-
hour:
360
48-
hour:
1,600
Selected Study Design Parameters
Study
Type
Static
Static
Static
Static
Concentration
Range Tested
Not reported
Not reported
60-1,000 |ig/L
125-2,000 |ig/L
No. of
Organisms/
Cone
10
Not reported
10
10
Analytical
Monitoring
No
No
No
No
Water
Chemistry
pH: 7.7-8.0
DO: 7.2-8.7
Temp: 19°C
Hardness: <250
mg/L
pH:NR
DO:NR
Temp: NR
Hardness: NR
pH:NR
DO:NR
Temp: 22°C
Hardness: NR
pH: 7.6-8.1
DO: 8.6-9.3
Temp: 21-23°C
Hardness: 268-
284 mg/L
Solvent
Ethanol
Not reported
Acetone
Unspecified
solvent
Comments on the Data
Only 10 daphnids were
exposed to each
concentration. Otherwise,
the details reported on the
study conduct appear to be
consistent with current
standard guidelines. The
concentrations tested were
not identified. TPP purity
was not reported.
Even basic study design
parameters were not
available for evaluation.
Study reportedly followed
U.S. EPA (1975)
guidelines. Results from
monitoring water quality
parameters were not
reported.
The NOAEC was 1,000
Hg/L. The study followed
U.S. EPA (1975)
guidelines.
1-37
-------
Table 1-2. Summary of available acute invertebrate toxicity studies on triphenyl phosphate (115-86-6)
Study
Reference
Huckins et
al., 1991
Mayer etal.,
1981
EG&G
Bionomics.
1978c
Lo and Hsieh,
2000
Species
Tested
Scud
Mysid
shrimp
Golden
apple
snail
EC50
or
LC50
(Hg/L)
96-
hour:
250
96-
hour:
>180
and
<320
72-
hour:
38,200
Selected Study Design Parameters
Study
Type
Static
Static
Static
Concentration
Range Tested
10-560 |ig/L
56-560 |ig/L
10-250 |ig/L
No. of
Organisms/
Cone
Not reported
10
30
Analytical
Monitoring
No
No
Yes
Water
Chemistry
pH:NR
DO:NR
Temp: 17°C
Hardness: NR
pH: 7.8-7.9
DO: 43%-56% of
saturated
Temp: 20±1°C
Hardness: NR
pH: 7.5
DO:NR
Temp: 26°C
Hardness: NR
Solvent
Acetone
Acetone
(ImL)
Not reported
Comments on the Data
Study reportedly followed
U.S. EPA (1975)
guidelines. Reporting
deficiencies preclude an
independent evaluation of
data adequacy.
Dissolved oxygen was
<60% of saturation.
Standard guidelines
indicate that dissolved
oxygen concentration
remain >60% saturation
throughout the study.
Organisms were 35-40
days old at study initiation.
Golden apple snail is not a
common test organism.
1-38
-------
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Conclusion:
The available algal toxicity data were judged tentatively adequate to meet the endpoint, pending
the availability of additional information from the studies that were not included in the published
articles.
Basis for Conclusion:
Seventy-two-hour static studies in Selenastrum capricornutum, Scenedesmus subspicatus,
Chlorella vulgaris (Millington et al., 1988), a 96-hour static study in Selenastrum capricornutum
(Mayer et al., 1981), and a 22-day study in Ankistrodesmus falcatus were located. These data are
summarized in Table 1-3. Taken together, these data may be adequate; however, additional
information is needed from the studies before they can be used as the basis for satisfying the
algal toxicity endpoint.
Millington et al. (1988) conducted a series of 72-hour static studies that were designed to
evaluate the influence of various standard test media (OECD, U.S. EPA, and Bold's basal) on the
toxicity of triphenyl phosphate to three algal species, Selenastrum capricornutum, Scenedesmus
subspicatus, and Chlorella vulgaris. These static studies followed OECD Guideline 201. Five
concentrations ranging from 0.05 to 5 mg/L were tested in triplicate cultures. The test
concentrations were not analytically confirmed. The resulting 72-hour NOAEC values ranged
from 0.1 to 1 mg/L depending on the algal species tested and the test media used. EC50 values
were not derived, and raw data were not available to allow for an independent calculation of
EC50 values. Overall, the studies appear to have been adequately conducted. Deficiencies in
the data included reporting deficiencies (e.g., raw data, water quality values determined during
the study, and growth of control replicates), lack of analytical confirmation of the test
concentrations, and lack of EC50 determinations. Provided that the missing study details can be
obtained and that an EC50 value can be determined, these data appear adequate to satisfy the
algal toxicity endpoint.
Mayer et al. (1981) conducted a 96-hour static test in Selenastrum capricornutum. Many details
from this study were obtained from the unpublished report submitted to EPA (EG&G
Bionomics, 1978d). Five concentrations that ranged from 0.6 to 10 mg/L were tested. Test
concentrations were not analytically confirmed. An EC50 of 2 mg/L (95% confidence interval
of 0.6-4 mg/L) was derived from this study. A clear NOAEC was not established because a 4%
decrease in cell number and a 15% decrease in chlorophyll-a concentration was observed at the
lowest concentration of 0.6 mg/L. Although the study appears to have been adequately
conducted, initial and final cell concentrations of controls or treated cultures were not reported.
Provided that these study details can be obtained, the 96-hour EC50 reported in this study
appears to be adequate to satisfy the short-term algal toxicity endpoint. It should be noted that
the EC50 determined from this study is at the approximate water solubility limit of TPP (2
mg/L). The lack of a clear NOAEC precludes the use of this study as the sole basis to satisfy the
1-39
-------
chronic algal toxicity endpoint. However, the low magnitude of the effect observed at 0.6 mg/L
in this study appears to be consistent with the NOAEC and LOAEC values reported in the other
algal toxicity studies (Mayer et al., 1981; Wong and Chau, 1984).
Wong and Chau (1984) reported a 22-day NOAEC of 0.1 mg/L and a LOAEC of 0.5 mg/L based
on algal growth in Ankistrodesmus falcatus. Sufficient detail was not reported in this study to
allow for an independent evaluation of data adequacy. Virtually no details on the methods or
results were reported. The study also reported 4-hour IC50 values based on incorporation of
radiolabeled CO3 as an indication of primary productivity. These IC50 values ranged from 0.2 to
0.5 mg/L in Ankistrodesmus falcatus, Scenedesmus quadricauda, and Lake Ontario
phytoplankton. The 4-hour IC50 values derived from this study were not considered adequate
for this hazard assessment because TPP concentrations that caused reductions in primary
productivity after 4 hours of exposure did not affect reproduction or growth during a separate 22-
day study conducted by the same laboratory. The NOAEC and LOAEC values derived from the
22-day study were considered inadequate to satisfy the chronic algal toxicity endpoint because
sufficient detail was not available on the study design or results to allow for an independent
evaluation of study adequacy. However, if data are available to demonstrate that the study was
adequately conducted, then the data may be sufficient to satisfy the chronic algal toxicity
endpoint. Further, if concentration-response data are available to allow for a calculation of a 96-
hour EC50, then the data may also be used to support the short-term algal toxicity endpoint.
Taken together, it appears that sufficient data are available to satisfy the algal toxicity endpoint;
however, additional information is needed before the currently available data can be considered
adequate.
1-40
-------
Table 1-3. Summary of available algal toxicity studies for triphenyl phosphate
Study
Reference
Millington
etal., 1988
Species
Tested
Selenastrum
capricornutum
EC50,
NOAEC, and
LOAEC
EC50: NR
72-hour
NOAEC: 0.1-1
mg/L*
72-hour
LOAEC: 0.5-5
mg/L*
*A range of
NOAEC and
LOAEC values is
reported because
tests were
performed using
three different
test media, and
the toxicity of
TPP was
influenced by the
test media used.
Selected Study Design Parameters
Study
Type
Static
Concentration
Range Tested
0.05-5 mg/L
Analytical
Monitoring
No
Water
Chemistry
pH:NR
Temp: 22°C
DO:NR
Hardness: NR
Solvent
Acetone
(<100 uL/L)
Comments on
the Data
The 72-hour
LOAEC was
between 0.5 and
5 mg/L depending
on the test
medium. EC 50
values were not
determined. Test
substance purity
was not reported.
1-41
-------
Table 1-3. Summary of available algal toxicity studies for triphenyl phosphate
Study
Reference
Millington
etal., 1988
Millington
etal., 1988
Species
Tested
Scenedesmus
subspicatus
Chlorella
vulgaris
EC50,
NOAEC, and
LOAEC
72-hour
NOAEC: 0.1-1
mg/L*
72-hour
LOAEC: 0.5-5
mg/L.
*A range of
NOAEC and
LOAEC values is
reported because
tests were
performed using
three different
test media, and
the toxicity of
TPP was
influenced by the
test media used.
72-hour
NOAEC: 1 mg/L
72-hour
LOAEC: 5 mg/L
The toxicity of
TPP to Chlorella
vulgaris was not
affected by test
medium.
Selected Study Design Parameters
Study
Type
Static
Static
Concentration
Range Tested
0.05-5 mg/L
0.05-5 mg/L
Analytical
Monitoring
No
No
Water
Chemistry
pH:NR
Temp: 22°C
DO:NR
Hardness: NR
pH:NR
Temp: 22°C
DO:NR
Hardness: NR
Solvent
Acetone
(<100 uL/L)
Acetone
(<100 uL/L)
Comments on
the Data
The 72-hour
LOAEC was
between 0.5 and
5 mg/L depending
on the test
medium. EC 50
values were not
determined. Test
substance purity
was not reported.
The 72-hour
LOAEC was 5
mg/L using three
different test
mediums. EC50
values were not
determined. Test
substance purity
was not reported.
1-42
-------
Table 1-3. Summary of available algal toxicity studies for triphenyl phosphate
Study
Reference
Mayeretal.,
1981
EG&G
Bionomics,
1978d
Species
Tested
Selenastrum
capricornutum
EC50,
NOAEC, and
LOAEC
96-hour: 2 mg/L
95% CI: 0.6-4
96-hour LOAEC:
0.6 mg/L
96-hour NOAEC:
Not observed
Selected Study Design Parameters
Study
Type
Static
Concentration
Range Tested
0.6-10 mg/L
Analytical
Monitoring
No
Water
Chemistry
pH: 7.0-8.2
Temp: 24±1°C
DO:NR
Hardness: NR
Solvent
Acetone: 0.05 mL
Comments on
the Data
The methods
reportedly
followed U.S.
EPA, 1971
guidelines.
Control growth
was not reported.
A NOAEC did not
appear to be
observed because
a 1 5% decrease in
chlorophyll a and
4% decrease in
cell number was
observed after 96
hours at the lowest
concentration of
0.6 mg/L. Test
substance purity
was not reported.
1-43
-------
Table 1-3. Summary of available algal toxicity studies for triphenyl phosphate
Study
Reference
Wong and
Chau, 1984
Species
Tested
Ankistrodesmus
falcatus
EC50,
NOAEC, and
LOAEC
22-day NOAEC:
0.1 mg/L
22-day LOAEC:
0.5 mg/L
Selected Study Design Parameters
Study
Type
Static
Concentration
Range Tested
0.05-5 mg/L
Analytical
Monitoring
No
Water
Chemistry
pH:NR
Temp: NR
DO:NR
Hardness: NR
Solvent
5 \j.L
Comments on
the Data
Use of standard
guidelines was not
indicated.
Duplicate cultures
were used.
Virtually no study
details were
included in the
published article,
precluding an
independent
evaluation of data
adequacy. Growth
of A falcatus was
determined
spectrophotometri
cally. Test
substance purity
was not reported.
1-44
-------
Chronic Toxicity to Fish (OPPT Harmonized Guideline 850.1400; OECD Guideline 210)
Conclusion:
The currently available data were judged adequate to meet the chronic toxicity endpoint
for freshwater fish.
The currently available data were judged inadequate to meet the chronic toxicity endpoint
for saltwater fish.
Basis for Conclusion:
Freshwater Fish
A confidential study for chronic toxicity to freshwater fish was submitted. The study results
indicated a Fish ChV of 0.140 mg/L. These data were judged adequate to meet this endpoint.
Publicly available data are summarized in Table 1-4. Two chronic studies in fish were located.
Both studies were published in Mayer et al. (1981). The study in fathead minnows reported a
NOAEC of 87 |J.g/L and a LOAEC of 230 |ig/L. The study used flow-through conditions and
analytically confirmed the test concentrations; however, the study is considered invalid due to
the large variation in measured concentrations (55-170 |ig/L at the NOAEC and 140-390 |ig/L at
the LOAEC). The study in rainbow trout is considered to be inadequate because the highest
concentration tested was 1.4 |ig/L, a concentration that did not elicit any effects. Also, the
measured concentrations were not given. Therefore, validity of the test could not be
independently evaluated.
Saltwater Fish
No chronic toxicity studies in saltwater fish species were located.
1-45
-------
Table 1-4. Summary of available chronic fish toxicity studies for triphenyl phosphate (115-86-6)
Study
Reference
Mayer etal.,
1981
Mayer etal.,
1981
EG&G
Bionomics,
1979
Species
Tested
Rainbow
trout
Fathead
minnow
NOAEC/
LOAEC
90-day
LOAEC:
>1.4|ig/L
30-day
NOAEC:
87|ig/L
LOAEC:
230 |ig/L
Selected Study Design Parameters
Study
Type
Flow-
through
(20
L/hour)
Flow-
through
(20
L/hour)
Concentration
Range Tested
Nominal: 0.22,
0.38, 0.44, 0.64,
0.91,1.2, and
1.4ng/L
Measured
concentrations
not reported
Mean measured:
0,2.8,12,36,87,
and 230 |ig/L
No. of
Fish/
Cone
NR, but at
least 10
based on
the number
of fish
subjected
to
vertebrae
pathology
exams.
60 eggs
40 fry
Analytical
Monitoring
Yes (mean
measured
concentrations
were within
62% of
nominal)
Yes
Water
Chemistry
pH: 7.2
Temp: 12±1°C
DO:NR
Hardness: 272
mg/L
pH: 6.8-7.6
Temp: 25±1°C
DO: >75%
saturation
Hardness: 38-44
mg/L
Solvent
Unidentified
solvent at
O.05 mL/L
TEG,
unspecified
concentration
Comments on the
Data
Measured concentrations
were not reported.
Endpoints evaluated
included mortality,
behavior, weight, length,
vertebrae pathology, and
eye pathology. Test
substance purity was not
reported.
Results based on fry
survival; other parameter
were not affected by
treatment.
Measured concentrations
varied substantially and
ranged from 55 to 170
Hg/L at the NOAEL and
from 140 to 390 ng/L at
theLOAEL. Test
substance purity was not
reported.
1-46
-------
Chronic Toxicity to Aquatic Invertebrates (OPPTS Harmonized Guidelines 850.1300 and
850.1350; OECD Guideline 211)
Conclusion:
No available chronic toxicity data for freshwater or saltwater invertebrates.
Basis for Conclusion:
Freshwater and Saltwater Species
No chronic toxicity studies in freshwater or saltwater invertebrate species were located.
Acute Oral, Acute Dietary, and Reproductive Toxicity in Birds (OPPTS Harmonized
Guidelines 850.2100, 850.2200, and 850.2300; OECD Guidelines 205 and 206)
Conclusion:
No available acute oral, acute dietary, and reproduction toxicity data.
Basis for Conclusion:
No toxicity studies in relevant bird species were located.
Earthworm Toxicity (OPPTS Harmonized Guideline 850.6200)
Conclusion:
No available earthworm toxicity data.
Basis for Conclusion:
No toxicity studies in earthworms were located.
1-47
-------
Physical/Chemical Properties
Triphenyl phosphate
CAS 115-86-6
MF C18H1504P
MW 326.29
SMILES c 1 ccccc 1 OP(=O)(Oc2ccccc2)Oc3 cccccS
Physical/Chemical Properties
Water Solubility (mg/L):
Conclusion: The available water solubility data are adequate.
Basis for Conclusion: The two best-documented studies, including one that followed an OECD-
guideline test, report solubilities of 1.9-2.1 ppm.
Solubility (mg/L)
Insoluble
1.90
2.1±0.1
1.4-1.6
0.2-0.3
0.73
0.714
Reference
Budavari, 2001 (The Merck Index); Lewis, 2000 (Sax's Dangerous Properties of
Industrial Materials); Lide and Milne, 1995 (CRC Handbook of Data on Common
Organic Compounds); Lewis, 1997 (Hawley's Condensed Chemical Dictionary)
Saeger et al., 1979 (shake-flask method using Milli-Q purified water); Huckins et al.,
1991; SRC, 2004 (PHYSPROP database)
Ofstad and Sletten, 1985 (OECD Guideline 105 (column-elution) from a mixture at
25°C)
Howard and Deo, 1979 (in buffered distilled water, pH 4.4-9.5 at 21°C)
Howard and Deo, 1979 (in filtered lake or river water, pH 7.8-8.2 at 21°C)
Hollifield, 1979
Kuhneetal., 1995
Log Kow:
Conclusion: The available log Kow data are adequate.
Basis for Conclusion: A variety of reputable studies report log Kow values in the range of 4.5-
4.7.
Log Kow
4.59
3.9
4.61
Reference
SRC, 2004 (PHYSPROP database); Hansch et al.,
1995
Unpublished data cited in Bengtsson et al., 1986
Mayer et al., 1981; Huckins et al., 1991
1-48
-------
Log Kow
4.63
4.67
4.58
4.62
Reference
Saeger, 1979 (shake-flask method)
FMC Industrial Chemical Division,
1979 (shake-flask method)
Ciba-Geigy, Ltd., 1982
Monsanto Chemical Co., 1982a
Monsanto Chemical Co., 1982b
Melting Point:
Conclusion: The available melting point data are adequate.
Basis for Conclusion: Melting point values within the range of 49-52°C are reported in a variety
of reputable secondary sources.
Melting Point (°C)
50
49-50
50.5
50.4
50-52
49.5-50
Reference
Lewis, 1997 (Hawley's Condensed
database)
Budavari, 2001 (The Merck Index)
Industrial Materials)
Chemical Dictionary); SRC, 2004 (PHYSPROP
Lewis, 2000 (Sax's Dangerous Properties of
Lide and Milne, 1995 (CRC Handbook of Data on Common Organic Compounds)
Ciba-Geigy, Ltd., 1982
Sigma-Aldrich, 2003-2004
Dorby and Keller, 1957
Boiling Point:
Conclusion: The available boiling point data are adequate.
Basis for Conclusion: Most sources report reduced-pressure boiling points of 244-245°C at 10
or 11 torr for triphenyl phosphate. Perry and Green (1984) report a boiling point of 413.5°C at
760 torr, which is consistent with the boiling point extrapolated using the Clausius-Clapeyron
Equation and the parameters measured by Dorby and Keller (1957). It has also been reported
that triphenyl phosphate decomposes at or near its boiling point (Dorby and Keller, 1957).
Boiling Point (°C/torr)
245/11
244/10
Reference
Lewis, 1997 (Hawley's Condensed Chemical Dictionary); SRC, 2004
(PHYSPROP database); Budavari, 2001 (The Merck Index); Lewis, 2000
(Sax's Dangerous Properties of Industrial Materials); Lide and Milne, 1995
(CRC Handbook of Data on Common Organic Compounds)
Sigma-Aldrich, 2003-2004
1-49
-------
Boiling Point (°C/torr)
413.5/760
414/760
dec. >410
Reference
Perry and Green, 1984
Dorby and Keller, 1957 (Extrapolated according to the Clausius-Clapeyron
Equation using experimentally -derived parameters: Log P(torr) = -A/T + C,
where T is in Kelvin, A= 4253, C=9.07)
The decomposition temperature was reported in this same paper.
Vapor Pressure (torr):
Conclusion: The available vapor pressure data are adequate.
Basis for Conclusion: Results from the Clausius-Clapeyron equation as measured by Dorby and
Keller (1957) are consistent with the vapor pressure data provided in Perry and Green (1984).
Vapor Pressure (torr/°C)
Reference
6.28xlO-6/25
0.90/193.5
8.6/249.8
84.7/322.5
354/379.2
SRC, 2004 (PHYSPROP database, extrapolated); Dorby and Keller, 1957
(Extrapolated according to the Clausius-Clapeyron Equation using
experimentally-derived parameters Log P (torr) = -A/T + C, where T is in
Kelvin, A= 4253, C=9.07)
1/193.5
Lewis, 2000 (Sax's Dangerous Properties of Industrial Materials)
1/193.5
5/230.4
10/249.8
20/269.7
40/290.3
60/305.2
100/322.5
200/349.8
400/379.2
760/413.5
Perry and Green, 1984
Odor:
Conclusion: The odor of this compound has been adequately characterized.
Odor
Odorless
Slight aromatic odor resembling
phenol
Phenol-like odor
Reference
Lewis, 2000 (Sax's
Dangerous Properties of Industrial Materials)
HSDB, 2004
1-50
-------
Oxidation/Reduction: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability:
Conclusion: The flammability (as the flash point) has been adequately characterized.
Basis for Conclusion: Similar values are reported in several reputable secondary sources.
Flash Point
435°F (223°C)
428°F (220°C)
428°F (cc)
Reference
Sigma- Aldrich, 2003-2004
Lewis, 1997 (Hawley's Condensed Chemical Dictionary)
Lewis, 2000 (Sax's Dangerous Properties of Industrial Materials)
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption:
Conclusion: The UV/VIS absorption of this compound has been adequately characterized.
Basis for Conclusion: Absorption maxima and coefficients are available for this compound in
three solvent systems, and are reported in reputable sources.
Wavelength
268 nm
262 nm
256 nm
288 nm
237 nm
268.5 nm
Absorption
Coefficient
912
1175
955
7.03xl03
1/mol-cm
2.62xl04
1/mol-cm
2.36xl03
1/mol-cm
Solvent
Hexane
Hexane
Hexane
MeOH,
KOH
MeOH,
KOH
MeOH
Reference
Lide and Milne, 1995 (CRC Handbook of Data on Common
Organic Compounds)
Lide and Milne, 1995 (CRC Handbook of Data on Common
Organic Compounds)
Lide and Milne, 1995 (CRC Handbook of Data on Common
Organic Compounds)
Sadtler Standard Spectra, no date
No absorption above 320 nm
Sadtler Standard Spectra, no date
No absorption above 320 nm
Sadtler Standard Spectra, no date
No absorption above 290 nm
1-51
-------
Wavelength
273. 5 run
218 nm
Absorption
Coefficient
2.36xl03
1/mol-cm
1.78xl04
1/mol-cm
Solvent
MeOH,
HC1
MeOH,
HC1
Reference
Sadtler Standard Spectra, no date
No absorption above 290 nm
Sadtler Standard Spectra, no date
No absorption above 290 nm
Viscosity: No data
Density/Relative Density/Bulk Density:
Conclusion: The density of this compound has been adequately characterized.
Basis for Conclusion: Similar values for density and relative density are available for this
material at different temperatures. Bulk density is also reported in a reputable source.
Density
1.268g/cc(60°C)
Bulk: 10.5 Ib/gal
1.2055g/cc(50°C)
Specific gravity, 25°C: 1.2
Reference
Lewis, 1997 (Hawley's Condensed Chemical Dictionary)
Lewis, 1997 (Hawley's Condensed Chemical Dictionary)
Lide and Milne, 1995 (CRC Handbook of Data on Common Organic
Compounds)
Cited from Midwest Research Institute, 1979 in Huckins et al., 1991
Dissociation Constant in Water:
Conclusion: This endpoint is adequately characterized
Basis for Conclusion: TPP is not expected to dissociate under environmentally important
conditions.
Henry's Law Constant:
Conclusion: The Henry's Law Constant has been adequately characterized for this compound.
Basis for Conclusion: One measured and one estimated value are reported in the literature, and
are in reasonable agreement with one another. The estimated value is based on measured vapor
pressure and water solubility data.
Henry's Law Constant
1.2xlO-5atm-m3/mole
3.31xlO-6atm-m3/mole
Reference
Cited from Mayer et al., 1981 in Huckins et al., 1991
SRC, 2004 (PHYSPROP database, estimated from vapor pressure
solubility)
and water
1-52
-------
Environmental Fate
Bioconcentration
Fish:
Conclusion: The bioconcentration of TPP has been adequately measured in rainbow trout,
goldfish, and killifish.
Basis for Conclusion: Similar BCFs are reported for rainbow trout in two key 90-day studies
(Monsanto Chemical Company, 1982c; Mayer, 1981). Other studies (Muir, 1984; Muir et al.,
1980) are available, but exhibit significant scatter in the data for rainbow trout. The data
reported by this author are based on uptake times of 24 hours or less, and may not represent
equilibrium conditions. The highest kinetic BCF value reported by this author, 18,960, may be
irrelevant because it was calculated based on a "slow" rate of elimination of residual
radioactivity by the fish. According to this study, the fish eliminated 98-99% of the initial load
of radioactivity (from the uptake of 14C-labeled TPP) in 9 days. The remaining 1-2% was
eliminated more slowly. Because only the total amount of radioactivity was measured without
identifying specific radioactive compounds present, it is not certain that the residual radioactivity
was due to unchanged TPP and not to metabolites.
Adequate studies are available for goldfish and killifish (Sasaki et al., 1981, 1982). In these two
studies, the authors measured BCFs under both static and flow-through conditions, with varying
TPP concentrations, and over differing lengths of time. The authors found that the measured
BCFs for killifish were largely independent of these parameters.
Reference
Monsanto
Chemical Co,
1982c
Mayer, 1981
Muir, 1984
Species
Rainbow
Trout
Rainbow
Trout
Rainbow
Trout
BCF
271
132-
364
573
931
1368
Key Design Parameters
Exp.
Type
Flow-
through
Static
Range
(ppb)
0.22,
1.4
3.1-
50.4
Study
Length
90 days
90 days
1-24
hours
T
(°C)
Comments
Elimination half life
0.54 days
1-53
-------
Reference
Muiretal.,
1980
Muir, 1984
Sasaki et al.,
1981
Sasaki et al.,
1981
Sasaki et al.,
1982
Species
Rainbow
trout
Fathead
minnow
Killifish
Goldfish
Killifish
BCF
2,590
(fast)
18,960
(slow)
218
561
1,743
250-
500
110-
150
189±90
193±79
84±32
Key Design Parameters
Exp.
Type
Static
Static
Static
Static
Flow-
through
(all)
Range
(ppb)
50
0.8-
34.9
250
initial
250
initial
30
20
10
Study
Length
6 hours
1-24
hours
2-3 days
2-3 days
35 days
32 days
18 days
T
(°C)
10
25
25
25
Comments
River water mixed with
dechlorinated tap water,
pH 8. 12-8.36. Fish were
exposed to TPP+water
for 6 hours then
transferred to clean
water. BCF expressed
as
k(uptake)/k(elimination) .
k(uptake) = 46.36/hour.
Elimination rate slows
down at about 9 days
with 98-99% eliminated.
k(fast)=0.0179/hour;
k(slow)=0.00245/hour.
BCF is independent of
concentration,
continuous (flow-
through) results correlate
to static results (Sasaki,
1981). BCF of
phosphate esters tested
correlate with Log Kow.
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
1-54
-------
Fish Metabolism:
Conclusion: The metabolism rate in fish has not been adequately characterized, and the
metabolites have not been adequately identified.
Basis for Conclusion: None of the studies summarized here identifies any metabolites. All of
the studies were designed to monitor the levels of TPP (as either the natural isotope or 14C
labeled) in fish to document the rates of uptake and elimination. Although these studies provide
information about the rate of elimination of TPP and/or its carbon-containing metabolites from
fish, none of these studies adequately describe how TPP is metabolized and what products are
formed.
Species
Rainbow trout
Rainbow trout
Killifish
Killifish
Goldfish
Rate
98-99% eliminated in 9 days
Rate constant = 0.0179/hour
Slower elimination after 9 days
Rate constant = 0.00245/hour
Elimination half-life is 0.54 days
Elimination half-life 1-2 hours
Apparent metabolism is much
faster in killifish than in goldfish.
Apparent metabolism is much
slower than in killifish.
Comment
Concentration of TPP in
water decreased in the
presence of fish. 0%
applied TPP remains in
the water after -11 hours.
Control (no fish) has no
change in TPP
concentration.
60-65% applied TPP
remains in the water after
100 hours in presence of
goldfish.
References
Muiretal., 1980
Mayeretal, 1981
Sasaki etal., 1982
Sasaki etal., 1981
Sasaki etal., 1981
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in water:
Conclusion: The available studies do not adequately describe the photolysis behavior of TPP in
water under normal environmental conditions. However, this endpoint appears to be adequately
characterized.
Basis for Conclusion: Since triphenyl phosphate does not absorb light at wavelengths above 290
nm, direct photolysis in sunlight is not expected. Three published photolysis studies were
located. Similar rate constants and half-lives are reported. For two of these studies, the light
1-55
-------
from the lamps was not filtered to block wavelengths <290 nm in either experiment (Hg lamps
emit at 254 nm), and the results are not environmentally relevant. For the third, the rate constant
for photolysis was found to be 34 times greater than phenol with a quantum yield of 0.290 at 254
nm (Wan et al., 1994).
Photolysis of Aqueous Triphenyl Phosphate Irradiated with Low-Pressure Hg Lamps
Initial concentration: 0. 1 ppm
pH: 3 and 10
Initial concentration: S.OxlO"4 M
pH: 3.4
Time: 6 hours
Initial concentration: S.OxlO"4 M
pH: 12
Time: 6 hours
Initial concentration: 1.0 ppm
Pseudo lst-order rate constant was >40/hour (t1/2
<1 .04 minutes) at both pH levels. Some
hydrolysis may occur at pH 10
TPP removed: 100%
PO43" detected: 60% of theoretical max.
Phenol detected: 0%
TPP removed: 100%
PO43" detected: 60% of theoretical max.
Phenol detected: 9% of theoretical max.
Rate constant: 1.9xlO"2/second
Half-life: 0.6 minutes
Ishikawaetal., 1992
Ishikawaetal., 1992
Ishikawaetal., 1992
Hicke and Thiemann,
1987
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion: The biodegradation of TPP under aerobic conditions has been adequately
characterized.
Basis for Conclusion: The key study was performed according to OECD guidelines. Additional
studies are available, in which TPP is degraded under a variety of conditions. TPP was also
found to be ready biodegradable in experimental studies.
Study Type/
Method
OECD 303A
SCAS
River die-
away
Innoculum
Activated
sludge
Activated
sludge
Acclim.
14 days
Degradation
93. 8% as DOC
removal
>95%
50%
Time
20
days
24
hours
2-4
days
Comments
Initial
concentration
5 ppm, emulsified
with octanol
Reference
Ciba-Geigy,
Ltd., 1983
Monsanto
Chemical Co.,
1980
Monsanto
Chemical Co.,
1980
1-56
-------
Study Type/
Method
C02
evolution
C02
evolution
Simulated
biological
treatment/
SCAS
Simulated
biological
treatment/
SCAS
River die-
away
River die-
away
River die-
away
MITI II
Innoculum
Activated
sludge
Activated
sludge
Activated
sludge w/
domestic
sewage feed
Activated
sludge w/
domestic
sewage feed
River/lake
water
Mississippi
River water
Mississippi
River water
Sewage
sludge
Acclim.
14 days
14 days
20-day
lag time
Degradation
82%
61.9%
81.8%
95%
93-96%
100%
as TPP removal
by GC analysis
50% primary
biodegradation
100%
83-94%
Time
27
days
7 days
28
days
24
hours
24
hours
7-8
days
2-4
days
1.75
days
28
days
Comments
Initial
concentration
22ppm
Initial
concentration
18.3 ppm
12-week test
duration,
acclimation time
not reported
Seneca River water
pH 8.2, Lake
Onondaga water
pH 7.8, Lake
Ontario water pH
8.2, all NY
sources; hydrolysis
may interfere with
measurement at
higher pH
Initial
concentration
0.05 ppm
Initial
concentration
1.0 ppm
Reference
Mayer et al.,
1981
Saeger et al.,
1979
Mayer et al.,
1981
Saeger et al.,
1979
Howard and
Deo, 1979
Mayer et al,
1981
Saeger et al.,
1979
Chemicals
Inspection &
Testing
Institute, 1992
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis:
Conclusion: The pyrolysis products of triphenyl phosphate have not been adequately described.
1-57
-------
Basis for Conclusion: No formal pyrolysis studies have been located in the literature.
Pyrolysis Products
Products include phosphorous oxide
Reference
Lewis, 2000 (Sax's Danj
Materials)
jerous Properties of Industrial
Hydrolysis as a Function of pH:
Conclusion: The hydrolysis data are adequate.
Basis for Conclusion: Triphenyl phosphate is rapidly hydrolyzed at high pHs, more slowly
hydrolyzed at neutral pH, and only very slowly hydrolyzed at acidic pHs. The rates measured
under alkaline conditions (pH ~9) are in good agreement with one another, and the rates
measured under acidic conditions (pH ~5 or lower) are in reasonable agreement with one
another. The results for hydrolysis at pH 7 have been reported to be 19 days, 1.3 years, and 406
days. There is no apparent reason for this discrepancy in values. It appears that the half-life of
19 days was measured once (Mayer et al., 1981) and has then been repeated in other sources.
The longer half-life (ca. 1.3 years) has been reported (within acceptable experimental error) in
two independent studies (Mabey and Mill, 1978), and is consistent with the observation in
Howard and Deo (1979) that the half-life at pH 6.7 was too slow for accurate measurement over
the course of the study (14 days).
Tw
19 days
3 days
7.5 days
1.3 days
1.3 years
>28 days
19 days
3 days
366 days
406 days
<5 days
630 days
1,125 days
<10 days
28 days
19 days
3 days
pH
7
9
8.2
9.5
7
5
7
9
3
7
9
3
7
9
5
7
9
Temp.
25°C
21°C
25°C
20°C
10°C
25°C
Comment
Half-life was too slow for accurate
measurement at pH 4.5 and 6.7.
Diphenyl phosphate was the only
hydrolysis product identified
Rate constant = 1.7xlO'9/sec at pH 7
Reference
Mayeretal., 1981
Howard and Deo, 1979
Mabey and Mill, 1978
Monsanto Chemical Co., 1980
Ciba-Geigy, Ltd., 1984
Ciba-Geigy, Ltd., 1984
Mayer et al., 1981, cited in
Anderson et al., 1993
1-58
-------
Sediment/Water Biodegradation:
Conclusion: The biodegradation of triphenyl phosphate in the presence of pond and/or river
sediment under various conditions has been adequately characterized.
Basis for Conclusion: Biodegradation of TPP has been studied under a variety of conditions and
temperatures in the presence of both river and pond sediment.
Sediment
Pond soil
Pond sediment
River
sediment
Pond sediment
River
sediment
Temp.
25
25
10
2
25
25
25
Tw
50-60 days
2.8 days
2.8 days
11. 9 days
7.0 days
56.7%,
3 days*
13.1%,
40 days*
68.9%,
3 days*
10.3%,
40 days*
Comments
Aerobic conditions.
Sediment is described to be hydrosoil from a
small pond.
Initial concentration, 0.05 ppm
Major product is diphenyl phosphate.
Static conditions (air/oxygen neither
excluded nor added during the test).
Sediment was collected from a eutrophic
farm pond near Winnipeg, Manitoba.
Initial TPP concentration 0. 10 ng/mL.
Sediment:water ratio 1:10.
Static conditions (air/oxygen neither
excluded nor added during the test).
Sediment was collected from the Red River
near Winnipeg, Manitoba.
Initial TPP concentration 0. 10 ng/mL.
Sediment:water ratio 1:10.
Aerobic conditions (respirometer, aerated).
Initial TPP concentration 0.05 ng/mL
Sediment:water ratio 1 :20
*Half-life not reported. Values are % TPP
remaining over time.
Anaerobic conditions (respirometer, under
N2).
Initial TPP concentration 0.05 ng/mL
Sediment:water ratio 1 :20
*Half-life not reported. Values are % TPP
remaining over time.
Reference
Muiretal., 1989
Muiretal., 1989
Muiretal., 1989
Muiretal., 1989
Muiretal., 1989
Soil Biodegradation with Product Identification:
Conclusion: The biodegradation rate of triphenyl phosphate in soil has been adequately
characterized under aerobic and anaerobic conditions. The biodegradation products have been
adequately characterized.
1-59
-------
Biodegradation of Triphenyl Phosphate in a Loamy Sand Soil at 20°C
Conditions
Aerobic
Anaerobic
Percent TPP Remaining Over Time, HPLC
13 Days
69.3
32 Days
46.6
50.2
60 Days
30.4
35.4
101 Days
20.2
31.4
Metabolites Identified
Diphenyl phosphate, CO2
Diphenyl phosphate, CO2, phenol
Reference: Anderson etal., 1993
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption:
Conclusion: The Koc has been adequately characterized in a variety of soil types.
KOC
2514
3561
2756
Soil Type
silry clay
loamy sand
silt loam
Reference
Anderson et al., 1993
All measurements were
made at 20°C.
1-60
-------
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Flame Retardant Alternatives
Tribromoneopentyl Alcohol
Hazard Review
2-1
-------
Tribromoneopentyl alcohol:
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
*
/
/
*
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
/
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
X
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
/
/
/
2-2
-------
Tribromoneopentyl alcohol:
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
/
/
/
/
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
/
/
/
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
-------
Chemical Identity
1-Propanol, 2,2-dimethyl-, tribromo derivative
Synonym Tribromoneopentyl alcohol
CAS 36483-57-5
MF C5H9Br3O
MW 324.84
SMILES BrC(C(CO)(C)C)(Br)Br
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401).
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
Several acute oral lethality studies were available in rats. One study summarized below as a
critical study (Ameribrom, Inc., 1982a) conformed to OPPTS and OECD guidelines, but did not
report the purity of the test substance. The other study summarized below (Norris et al., 1972a)
was performed on a test substance containing a high purity of tribromoneopentyl alcohol
(98.6%), but did not report all study details necessary for a full individual evaluation according
to OPPTS and OECD guidelines. A confidential study using the acute toxic class method (OECD
Guideline 423) provided lethality results for tribromoneopentyl alcohol (97% purity) that were
consistent with the published studies. Thus, all available acute oral toxicity data report similar
results for testing of tribromoneopentyl alcohol, and the quality of these studies, taken together,
is adequate to support the evaluation of acute oral toxicity.
Critical Studies:
Type: Acute oral toxicity
Species, strain, sex, number: Charles River CD rats, 5 animals/sex/dose
Dose: 2,575, 3,204, 3,289, 3,501, 3,769, and 4,117 mg/kg
Purity: Not reported, off-white crystals
Vehicle: Corn oil
Observation Period: 14 days
Method: Designed to conform to U.S. EPA, Pesticide Programs, Proposed Guidelines for
Registering Pesticides in the U.S., Hazard Evaluation: Humans and Domestic Animals, 163.81-1,
dated 22 August, 1978; preliminary test followed by main study
2-4
-------
Results: Male mortality was 2/5 at 2,575 and 3,204 mg/kg, 4/5 at 3,289, 3,501, 3,769, and 4,117
mg/kg. Female mortality was 2/5 at 2,575 and 3,501 mg/kg, 3/5 at 3,769 mg/kg, 4/5 at 3,204 and
3,289 mg/kg, and 5/5 at 4,117 mg/kg. LD50 (male) = 2,847 mg/kg (95% CI = 2,050-3,644).
LD50 (female) = 2,685 mg/kg (95% CI = 1,415-3,955). LD50 (combined) = 2,823 mg/kg (95%
CI = 2,217-3,429). Clinical signs noted included decreased motor activity, proneness, ataxia,
brady-pnoea, ptosis, irritability, hunching, reddening, urogenital wetting and bleeding,
lachrymation, salivation, haematuria, coat staining, piloerection, and ungroomed appearance.
Necropsy findings consisted of gastric mucosa congestion, ulceration, erosion, or hemorrhage,
associated with abnormal oily and yellow contents. The small intestine was usually distended
with hemorrhagic, pale, or yellow contents. One female at 3,769 mg/kg and one male at 4,117
mg/kg had congestion of the urinary bladder; the bladder contents were blood-stained in the male
with bladder congestion.
Reference: Ameribrom, Inc., 1982a
Type: Acute oral toxicity
Species, strain, sex, number: Sprague Dawley albino rat, 5 males/dose
Dose: 1,260, 1,580, 2,000, and 2,520 mg/kg
Purity: 98.6% tribromoneopentyl alcohol
Vehicle: Corn oil
Observation period: 13 days
Method: Test material administered as a 20% solution in corn oil to fasted rats by single dose
gavage. Animals were weighed before dosing, the day following dosing, and at weekly intervals
for 2 weeks thereafter. Clinical observations made "periodically" for signs of toxicity.
Results: LD50 = 1,630 mg/kg (95% CI = 1,370-1,950). Mortality was 0/5 at 1,260 mg/kg, 4/5 at
1,580 mg/kg, 3/5 at 2,000 mg/kg, and 4/5 at 2,520 mg/kg. Animals at all dose levels were noted
as having bloody urine. Necropsy revealed hemorrhagic appearance of the mucosa of the urinary
bladder at the highest dose level.
Reference: Norris et al., 1972a
Additional Studies and Information:
Other studies that were of lesser quality (such as a low percentage of tribromoneopentyl alcohol
in test substance) or that were reported in less detail are generally consistent with the above
studies (Biochemical Research Laboratory, no date; Norris et al., 1972b; Toxicology Research
Laboratory, 1976).
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
No available acute dermal toxicity data.
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Basis for Conclusion:
No studies of this type were located.
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The only available study of tribromoneopentyl alcohol (Norris et al., 1972a), summarized below,
did not fully conform to OPPTS and OECD guidelines. Study details to allow for a full
evaluation of study adequacy were missing, and the test atmosphere was not characterized. In
addition, only one concentration was tested, which did not produce mortality or toxicity, and was
lower than the currently recommended limit dose for single dose testing. An additional study,
conducted and reported in the same manner, was performed on a mixture containing only 11.3%
tribromoneopentyl alcohol (Norris et al., 1972b).
Type: Acute inhalation toxicity
Species, strain, sex, number: Sprague Dawley rats, 5 males
Doses: 0.714 mg/liter of air (nominal)
Purity: 98.6%
Vehicle: None
Duration: 7-hour exposure
Observation Period: 2 weeks
Method: The test substance (a solid at room temperature) was maintained at 100°C. Air was
metered through the test substance and into the 19 L glass exposure chamber at the rate of 1
liter/minute; according to the investigators, this procedure produced a vapor. Whether the
substance in the test chamber was exclusively a vapor, or whether aerosol or particulate was
formed, is uncertain. The exposure period was 7 hours. Clinical observations were made during
the exposure period and up to 2 weeks thereafter (no specification of frequency). Body weight
was measured before and after exposure and "periodically" for 2 weeks thereafter. Necropsy
was performed on 1 rat 1 day after exposure and on the remaining 4r rats at the end of the
observation period.
Results: No mortality, signs of toxicity, respiratory or nasal irritation, or abnormal body weight
changes were observed during the exposure or observation period. No abnormalities were noted
at necropsy.
Reference: Norris et al., 1972a
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Additional Study:
An acute inhalation toxicity study of a mixture containing only 11.3% tribromoneopentyl alcohol
(plus 81.1% dibromoneopentyl glycol and 7.6% monobromoneopentyl triol) (Morris et al.,
1972b) was performed in a similar manner as the above study. The nominal exposure
concentration of this mixture was 2.49 mg/L. The nominal exposure concentration of
tribromoneopentyl alcohol would have been 0.28 mg/L, a lower concentration than in the above
study of relatively pure tribromoneopentyl alcohol. There were no deaths, but labored breathing
and slight signs of nasal irritation were observed in the rats during exposure. The rats appeared
normal during the 2-week observation period and no pathological changes were observed during
necropsy. The apparent irritant effects in this study cannot be attributed solely to
tribromoneopentyl alcohol, which accounted for only a small percentage of the mixture, and
which caused no signs of irritation when tested alone at a higher concentration.
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available acute eye irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
The study summarized below as a critical study (Ameribrom, Inc., 1982b) conformed to OPPTS
and OECD guidelines, and observed mild eye irritation, but did not report the purity of the test
substance. A subsequent confidential (OPPTS and OECD guideline) study of tribromoneopentyl
alcohol (97% purity) in the rabbit reported moderate eye irritation. Other available data, though
inadequate for individual evaluation, reported similar results to these two studies and provide
support for the acute eye irritation evaluation.
Critical Studies:
Type: Acute eye irritation
Species, strain, sex, number: New Zealand White albino rabbits, 9/sex
Doses: 100 mg
Purity: Not reported; off-white crystals
Vehicle: None
Method: The study was designed to conform to the U.S. EPA, Pesticides Program, Proposed
Guidelines for Registering Pesticides in the U.S.; Hazard Evaluation: Human and Domestic
Animals 163.81-4, dated 22 August, 1978. Six rabbits were tested without any washing of test
substance from the eye. Three rabbits were tested with irrigation of the eye after 30 seconds of
exposure. Eyes were assessed at 24, 48, and 72 hours and 4, 7, 10, and 13 days after test
administration.
Results: Almost all animals of both groups (unwashed exposure and washed exposure) exhibited
diffuse opacity (Grade 1 on a scale of 1-4) on the cornea at 24 hours after exposure. One rabbit
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from the unwashed group exhibited Grade 2 opacity. Irridial congestion was also noted in most
animals in the unwashed exposure group. Conjunctival irritation, such as redness and discharge,
was observed in both the unwashed and washed exposure groups at varying degrees. All ocular
effects were fully reversible by the end of the observation period with many being fully resolved
a few days after exposure.
Reference: Ameribrom, Inc., 1982b
Additional Studies and Information:
Other studies that were of lesser quality (such as a low purity of tribromoneopentyl alcohol in
test substance) or were reported in less detail are generally consistent with the above study
(Keeler et al., 1974; Biochemical Research Laboratory, no date).
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available acute dermal irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
The study summarized below (Ameribrom, Inc., 1982c) generally conformed to OPPTS and
OECD guidelines with only slight derivations and detail omissions, except for the lack of
reporting of test substance purity. Although a summary table was also available for another
acute dermal irritation study (Biochemical Research Laboratory, no date) that reported similar
results to the above mentioned study, few study details were reported in the table.
Type: Acute dermal irritation
Species, strain, sex, number: New Zealand White albino rabbits, 3/sex
Doses: 0.5 g
Purity: Not reported, off-white crystals
Vehicle: Saline, enough to moisten test material
Method: The study was designed to conform with the U.S. EPA, Pesticides Programs, Proposed
Guidelines for Registering Pesticides in the U.S.; Hazard Evaluation: Humans and Domestic
Animals 163,82-5, dated 22 August 1978. Single application of slightly saline-moistened test
material to shaved skin under an occlusive wrap. The skin of one side of each animal was mildly
abraded and the skin of the other side was left intact. The test material was applied to both sides.
The dressings were removed 24 hours after dosing and residual test material was removed by
wiping with towels. Animals were regularly checked for clinical signs of toxicity during
exposure and were checked daily from day 2 of the study until study termination. Skin irritation
assessments were made 1 hour after removal of the wrap, as well as 72 hours and 4 and 5 days
after application of the test material.
Results: At 25 hours after application, very slight to well-defined erythema was displayed in
most animals and moderate-to-severe erythema was displayed in two animals. At 72 hours after
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application, four rabbits displayed very slight erythema and two rabbits displayed well-defined
erythema. One rabbit displayed a very slight edema. At 4 days after application, one rabbit
displayed very slight erythema. All skin responses were completely resolved by the final
assessment 5 days after application. Exfoliation was observed in three female rabbits from 72
hours after application until study termination. Incidence or severity of dermal irritation was not
affected by abrasion of skin before treatment. The authors concluded that the test substance was
a mild irritant to the skin.
Reference: Ameribrom, Inc., 1982c
Additional Studies:
Another study, reported with few details (Biochemical Research Laboratory, no date), was
generally consistent with the results of the above study. In this other study, undiluted
tribromoneopentyl alcohol was applied to the belly of rabbits for 10 applications (intact skin, no
irritation occurred) or 3 applications (abraded akin, slight hyperemia on abrasions after each of
the first two applications). Slight hyperemia and slight exfoliation occurred after similar
applications to intact and abraded belly skin of a 10% solution of tribromoneopentyl alcohol in
Dowanol DPM. There was no indication of absorption of acutely toxic amounts (not further
explained).
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The available skin sensitization data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available skin sensitization study was performed on a test substance mixture containing only
13.6 % tribromoneopentyl alcohol (plus 81% dibromoneopentyl glycol and 5.4%
monobromoneopentyl triol) (Keeler et al., 1974). Toxicological effects of the individual
component chemical, tribromoneopentyl alcohol, may differ from effects produced by the
combination of the chemicals in the mixture. The study also did not conform fully to OPPTS
and OECD guidelines. Results were negative for dermal sensitization in this study in guinea
pigs.
SUBCHRONIC TOXICITY
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Conclusion:
The available subchronic oral toxicity data were judged adequate to meet the endpoint.
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Basis for Conclusion:
The only available study for subchronic oral toxicity is a 30-day study in rats (Humiston et al,
1973), which was reasonably comprehensive, and conducted in a manner similar to the guideline
specifications. Differences from the guidelines are as follows: the frequency of clinical
observations was not reported; not all of the stipulated observations with regard to hematology,
clinical chemistry, organ weights, and histopathology were made; and a limited neurobehavioral
assessment was not performed. In these hazard reviews on the flame retardant alternatives,
however, the adequacy of neurotoxicity data is considered separately, so this data gap will be
noted under that topic. The 30-day study included urinalysis, which is not a guideline
requirement, but provides valuable information.
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
The only relevant available study is a 30-day repeated oral dose study, summarized below, which
was conducted in a manner similar to the guidelines for a 28-day oral toxicity study in rodents.
Type: Repeated-dose 30-day oral toxicity
Species, strain, sex, number: Sprague-Dawley rats, 5/sex/dose
Doses: 0, 10, 30, 100, and 300 mg/kg/day
Purity: 98.0%
Vehicle: None
Exposure period, frequency: 30 days, administered daily in diet (food constantly available)
Post Exposure Period: None
Method: The test substance was administered in the diet. The rats were weighed initially then
weekly throughout the study, and were observed for clinical signs, but frequency of this
observation was not reported. Food consumption was measured weekly, and dietary
concentrations were adjusted to maintain the target dosages. Hematologic evaluations (packed
cell volume, hemoglobin, total erythrocyte count, total and differential leukocyte counts) and
urinalysis (specific gravity, pH, sugar, proteins, occult blood, bilirubin) were performed on study
day 24 in the control and high dose groups. Clinical chemistry analyses [BUN, alkaline
phosphatase, SGPT (ALT)] were performed on blood samples collected from all the rats at the
termination of the study. A complete necropsy was performed, and heart, liver, kidney, testes,
and brain were weighed. A reasonably comprehensive selection of tissues was examined
histologically in high dose and control animals. Liver, kidney, and bladder were examined
histologically in the low- and mid-dose animals. Statistical analyses were performed on the
continuous variables.
Results: A statistically significant increase in BUN in male rats was noted at 300 mg/kg/day.
No significant changes were seen in the urinalysis results. Dose-related histopathologic changes
in kidney (degeneration and regeneration of renal cortical tubular epithelial cells) and urinary
bladder tissue (generalized hyperplasia of the transitional epithelium) were noted only in male
rats at > 100 mg/kg/day. Incidences of each of these effects were 0/5 in controls and in each of
the two lower dose groups, 2/5 in the 100 mg/kg/day group, and 5/5 in the 300 mg/kg/day group.
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Bladder effects were seen in some of the acute oral toxicity studies as well. Because the tissue
staining procedures may not have been optimal for visualizing hyaline droplets in renal tissue,
the possibility that the renal effects may have been related to alpha2u-globulin associated renal
toxicity cannot be ruled out. The OPPTS and OECD guidelines, however, do not address the
issue of staining techniques. No changes in any of the endpoints were noted in the female rats,
and no changes in endpoints other than those noted above were seen in the males. Although
alpha2u-globulin associated nephropathy is not considered relevant to humans (U.S. EPA, 1991),
not all chemically-induced male rat nephropathy is of this type. Therefore, in the absence of
additional information, the renal lesions are considered relevant. The NOAEL for bladder and
renal effects was 30 mg/kg/day and the LOAEL was 100 mg/kg/day.
Reference: Humiston et al., 1973
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
No studies of this type were located.
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
No studies of this type were located.
Subchronic Dermal Toxicity (21/28-day or 90-day)
Conclusion:
No available subchronic dermal toxicity data.
Basis for Conclusion:
No pertinent subchronic dermal toxicity studies were located that addressed the endpoints in the
guidelines listed below.
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD
Guideline 410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
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Subchronic Inhalation Toxicity: 90-Day Inhalation Toxicity (OPPTS Harmonized
Guideline 870.3465; OECD Guideline 413)
Conclusion:
No available subchronic inhalation toxicity data.
Basis for Conclusion:
No studies of this type were located.
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the reproductive toxicity endpoints in the
guidelines listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
No available developmental toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the developmental toxicity endpoints in the
guidelines listed below.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
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Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion:
No pertinent were located that addressed the chronic toxicity studies endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline
870.4300; OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline
870.4300; OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
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Basis for Conclusion:
No pertinent neurotoxicity studies were located that addressed the endpoints in the guidelines
listed below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Note this guideline is not relevant for tribromoneopentyl alcohol, which is not an
Organophosphorus substance.
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS Harmonized
Guideline 870.6300)
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat)
OPPTS Harmonized Guideline 870.6500
Peripheral Nerve Function (rodent)
OPPTS Harmonized Guideline 870.6850
Sensory Evoked Potentials (rat, pigmented strain preferred)
OPPTS Harmonized Guideline 870.6855
These studies may be indicated, for example, to follow up neurotoxic signs seen in other studies,
or because of structural similarity of the substance to neurotoxicants that affect these endpoints.
These studies may be combined with other toxicity studies.
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion:
No pertinent immunotoxicity studies were located that addressed the endpoints in the guideline
listed below.
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Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
The available genotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Adequate data were submitted for mutagenicity and chromosomal aberrations in vitro. Four
studies of reverse mutation in bacteria in vitro reported negative results without activation or
with activation using liver S9 from rat, rabbit, or monkey. These studies did not conform fully to
OPPTS and OECD guidelines or were missing vital study details, but reported similar results.
One study reported that activation with hamster S9 resulted in reverse mutation in bacteria. An
additional, confidential, OECD guideline study of reverse mutation in bacteria in vitro also
reported negative results without activation or with rat liver S9, and positive results with hamster
liver S9. Other confidential studies reported positive results, with metabolic activation, for
mutagenicity in cultured mouse lymphoma cells and chromosomal aberrations in cultured human
peripheral lymphocytes.
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA-1535, TA-100, TA-1538, TA-98, and TA-1537
Metabolic activation: Absence and presence of an activating system derived from rat liver (S-9
mix)
Concentrations: 50, 250, 1,250, 2,500, and 5,000 jig/plate
Purity: Not reported
Solvent: DMSO
Method: Procedures stated as complying with OECD Guideline 471 (1983); preliminary toxicity
test in strain TA-98. The assay utilized a plate incorporation method. The main study was
conducted in duplicate with a negative solvent control, positive controls, and plates devoid of
organisms to verify the sterility of the S-9 mix. Incubation at 37°C for 48 hours.
Results: No significant increases in revertant colony numbers over control counts were obtained
for trineopentyl alcohol with any of the tester strains, either in the presence or absence of
metabolic activation.
Reference: Ameribrom, Inc., 1990
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA-1535, TA-100, TA-1538, TA-98, and TA-1537
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Metabolic activation: With and without S-9 mix
Concentrations: 0, 50, 100, 500, and 1,000 jig/plate
Purity: Not reported
Solvent: DMSO
Method: The test was reported as having been performed in accordance with the methods
described in detail in the "Principles of the Ames Mutagenicity Test" by M. Green and E. Riklis
of 1979. Each compound was tested at least twice and in duplicates. Negative controls.
Positive controls, such as methylcholantrene, benzopyrene, and N-methyl-N-nitrosoguanidine
(MNNG).
Results: The compound was not mutagenic.
Reference: Ameribrom, Inc., 1982d
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA-1535, TA-1537, and TA-1538
Metabolic activation: With and without mammalian (rabbit, rat, and monkey) metabolic
activation
Concentrations: 0.05% (plate tests); 0.025%, 0.050%, and 0.100% (suspension tests)
Purity: >99%, "pure" tribromoneopentyl alcohol
Solvent: DMSO or saline
Method: Cytotoxicity testing performed. Positive and negative controls used. Plate incubation
at 37°C for 4 days, with each compound done in duplicate. Suspension tests were conducted
with metabolic activation at 37°C for 1 hour in an oxygen atmosphere, or without metabolic
activation at 37°C for 1 hour, with all flasks shaken during treatment. Suspension tests were
scored after plating and incubation for 48 hours at 37°C.
Results: The test substance did not exhibit genetic activity under any of the testing conditions
(plate tests, with and without activation; suspension tests, with and without activation) employed
in this study.
Reference: Litton Bionetics, Inc., 1975a
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA-1535, TA-1537, and TA-1538
Metabolic activation: With and without mammalian (rabbit, rat, and monkey) metabolic
activation
Concentrations: 0.150% (plate tests); 0.075%, 0.150%, and 0.300% (suspension tests)
Purity: Not reported, "plant" tribromoneopentyl alcohol
Solvent: DMSO or saline
Method: Cytotoxicity testing performed. Positive and negative controls used. Plate incubation
at 37°C for 4 days, with each compound done in duplicate. Suspension tests were conducted
with metabolic activation at 37°C for 1 hour in an oxygen atmosphere, or without metabolic
activation at 37°C for 1 hour, with all flasks shaken during treatment. Suspension tests were
scored after plating and incubation for 48 hours at 37°C.
Results: The test substance did not exhibit genetic activity when all test data were considered.
The negative assessment was based on combined test results for both rat and rabbit activation
assays and non-activation assays, as two sets of original test data with TA-1535 (one with rat
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tissue, one with rabbit tissue) suggested mutagenic activity, but repeat tests with this strain did
not indicate mutagenic activity.
Reference: Litton Bionetics, Inc., 1975b
Additional Information
Results of a 1983 preincubation assay in Salmonella typhimurium, listed on the NTP (2004)
online database, confirm the negative results of other studies in TA100, TA98, TA1535, and
TA1537 without activation or with activation by rat liver S9. Activation using S9 from hamster
liver resulted in positive results in TA100 and TA1535, but negative results in the two other
strains. A more recent confidential study of 98% pure tribromoneopentyl alcohol, conducted
according to OECD guideline 471 (May 1983 version) in S. typhimurium (TA98, TA100,
TA1535, TA1537), also reported negative results without an activating system or with rat liver
S9 in all four strains, and positive results with hamster liver S9 in TA100 and TA1535 only.
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
A confidential study reported dose-related mutagenicity in cultured L5178Y mouse lymphoma
cells treated with tribromoneopentyl alcohol with, but not without metabolic activation.
Chromosomal Aberrations in vitro:
In Vitro Mammalian Chromosome Aberration Test (OPPTS Harmonized Guideline
870.5375; OECD Guideline 473)
A confidential study reported that, with, but not without metabolic activation, tribromoneopentyl
alcohol increased the frequency of chromosomal aberrations in human peripheral lymphocytes in
vitro.
Other
Mitotic Gene Conversion in Saccharomyces cerevisiae (OPPTS Harmonized
Guideline 870.5575)
The two available studies, conducted by the same laboratory at about the same time, appear
marginally adequate.
Type: Mitotic gene conversion
Species, strain: Saccharomyces cerevisiae D4
Metabolic activation: With and without mammalian (rabbit, rat, and monkey) metabolic
activation
Concentrations: 0.5%, 1.0%, and 2.0%
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Purity: >99%, "pure" tribromoneopentyl alcohol
Solvent: DMSO or saline
Method: Cytotoxicity testing performed. Suspension tests were conducted with metabolic
activation at 37°C in an oxygen atmosphere for 4 hours, and without metabolic activation at
30°C for 4 hours, with all flasks shaken during treatment. Scoring was done after plating and
incubation for 3-5 days at 30°C. Concurrent negative controls, positive controls run
concurrently with the non-activation assay. Study authors state (without reporting the data) that
the positive controls for activation assay were run on a different day, but cell culture was the
same. The authors may be referring to the positive control data reported in the appendix of the
following report on "plant" tribromoneopentyl alcohol.
Results: The test substance did not exhibit genetic activity either with or without metabolic
activation.
Reference: Litton Bionetics, Inc., 1975a
Type: Mitotic gene conversion
Species, strain: Saccharomyces cerevisiae D4
Metabolic activation: With and without mammalian (rabbit, rat, and monkey) metabolic
activation
Concentrations: 0.375%, 0.750%, and 1.500%
Purity: Not reported, "plant" tribromoneopentyl alcohol
Solvent: DMSO or saline
Method: Cytotoxicity testing performed. Suspension tests were conducted with metabolic
activation at 37°C in an oxygen atmosphere for 4 hours, and without metabolic activation at
30°C for 4 hours, with all flasks shaken during treatment. Scoring was done after plating and
incubation for 3-5 days at 30°C. Concurrent negative controls. Concurrent positive controls for
the activation assays. Positive control data for the non-activation assay were not reported, but
may have been those in the above mitotic gene conversion study with pure tribromoneopentyl
alcohol.
Results: The test substance did not exhibit significant genetic activity either with or without
metabolic activation.
Reference: Litton Bionetics, Inc., 1975b
No studies were available on the genotoxicity of tribromoneopentyl alcohol in the following
types of types of tests:
Gene Mutation in Vivo
Chromosomal Aberrations in Vivo
DNA Damage and Repair
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Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available acute toxicity data for fish, aquatic invertebrates, and algae were judged adequate
to meet the endpoints. The acute marine/estuary toxicity endpoints for fish, aquatic invertebrates
were judged inadequate to meet the endpoints.
Basis for Conclusion:
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
A confidential study in Cyprinus carpio (carp), with a 96-hour LC50 of 32 mg/L, conducted
under static test conditions, was submitted. The LCO was 18 mg/L. A 14-day study in Cyprinus
carpio (carp), conducted under semi-static test conditions, was also submitted. The 14-day LC50
was >32 mg/L. The NOEC and LOEC for sublethal effects were 5.6 and 10 mg/L, respectively.
The available data were judged adequate to meet this endpoint.
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1010; OECD Guideline 202)
A confidential study in Daphnia magna was submitted. The 48-hour EC50 for immobility was
64 mg/L under static test conditions. The NOEC was 32 mg/L. The available data were judged
adequate to meet this endpoint.
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
A confidential study in Selenastrum capricornutum was submitted. The 72-hour EC50 values for
cell growth inhibition (biomass) and growth rate reduction were 28 and >100 mg/L, respectively,
under static test conditions. The 72-hour NOEC was 2.2 mg/L. The available data were judged
adequate to meet this endpoint.
No additional acute toxicity studies with freshwater or saltwater fish, aquatic invertebrates, or
algae were located that followed or were similar to the guideline protocol listed below.
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
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Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that
addressed the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized
Guideline 850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no
subchronic toxicity studies with earthworms were located that addressed the endpoints in the
guidelines listed below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
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Physical/Chemical Properties
1-Propanol, 2,2-dimethyl-, tribromo derivative
Synonym Tribromoneopentyl alcohol
CAS 36483-57-5
MF C5H9Br3O
MW 324.84
SMILES BrC(C(CO)(C)C)(Br)Br
Water Solubility (mg/L):
Conclusion:
The available water solubility data are adequate.
Basis for Conclusion:
A confidential experimental study for the water solubility of tribromoneopentyl was submitted.
Using OECD Guideline 105, a water solubility of 1,930 mg/L at 20.1°C was measured.
LogKow:
Conclusion:
The available log Kow data are adequate.
Basis for Conclusion:
A confidential experimental study for the log Kow of tribromoneopentyl was submitted. Using
OECD Guideline 117, a log Kow of 2.6 was measured using the HPLC method.
Oxidation/Reduction: No data
Melting Point:
Conclusion:
The available melting point data are adequate.
Basis for Conclusion:
The melting point of tribromoneopentyl has been reported as 62-67°C in confidential EPA
databases.
2-21
-------
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity:
Conclusion:
The available explosivity data are adequate.
Basis for Conclusion:
A confidential study was submitted indicating that tribromoneopentyl alcohol has a low
explosion severity potential in a 20 litre sphere test.
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
2-22
-------
Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion: The available aerobic biodegradation data are adequate.
Basis for Conclusion. Submitted confidential studies indicate that tribromoneopentyl alcohol
underwent 2.5% CC>2 evolution over 28 days in an OECD 310 test and 77% removal as DOC
using OECD 302B in 36 days after a 10-day lag period (MC). In addition, a submitted
confidential study indicates that tribromoneopentyl alcohol is not ready biodegradable.
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
2-23
-------
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
2-24
-------
References
AmeriBrom, Inc. 1982a. Acute oral toxicity in the rat. Final Report. TSCA 8D submission by
AmeriBrom, Inc., 1990, OTS0530263.
AmeriBrom, Inc. 1982b. Primary eye irritation study in rabbits. Final Report. TSCA 8D
submission by AmeriBrom, Inc., 1990, OTS0530264.
AmeriBrom, Inc. 1982c. Primary dermal irritation study in rabbits. Final Report. TSCA 8D
submission by AmeriBrom, Inc., 1990, OTS0530265.
AmeriBrom, Inc. 1982d. Mutagenicity test according to "The Ames" method. TSCA 8D
submission by AmeriBrom, Inc., 1990, OTS0530266.
AmeriBrom, Inc. 1990. Assessment of mutagenic potential in histidine autotrophs of
Salmonella typhimurium (The Ames Test). Final Report. TSCA 8D submission by AmeriBrom,
Inc., 1990, OTS0530270.
Biochemical Research Laboratory, no date. Toxicological properties and industrial handling
hazards of tribromoneopentyl glycerol alcohol. TSCA 8D submission by The Dow Chemical
Company, 1990, OTS0528750.
Humiston, CG; Kociba, RJ; Wade, CE. 1973. Results of a 30-day dietary feeding study in rats
maintained on diets containing tribromoneopentyl alcohol, FR-1360. Halogen Research
Laboratory, Chemical Biology Research, Dow Chemical USA, Midland, Michigan. TSCA 8D
submission by The Dow Chemical Company, 1990, OTS0528744. TSCA 8D submission by
Ethyl Corporation, 1990, OTS0528518.
Keeler, PA; Yakel, HO; Rampy, LW. 1974. Eye irritation and skin sensitization properties of a
sample of FR-1138 (dibromoneopentyl glycol). Toxicology Research Laboratory, Dow
Chemical USA. TSCA 8D submission by Dow Chemical Company, no date of receipt,
OTS0516120.
Litton Bionetics, Inc. 1975a. Mutagenic evaluation of compound 236-2-60 B, "pure"
tribromoneopentyl alcohol >99%. Kensington, Maryland. TSCA 8D submission by The Dow
Chemical Company, 1990, OTS0530089.
Litton Bionetics, Inc. 1975b. Mutagenic evaluation of compound 236-2-60 D, "plant"
tribromoneopentyl alcohol. Kensington, Maryland. TSCA 8D submission by The Dow
Chemical Company, 1990, OTS0530090.
2-25
-------
Norris, JM; Kociba, R; Leong, BK. 1972a. Single dose oral lethality and acute vapor inhalation
toxicity of FR-1360 (tribromoneopentyl alcohol) in rats. Dow Chemical USA, Midland,
Michigan. TSCA 8D submission by The Dow Chemical Company, 1990, OTS0528751. TSCA
8D submission by Ethyl Corporation, 1990, OTS0528517.
Norris, JM; Kociba, R; Pernell, H. 1972b. Acute oral lethality and acute vapor inhalation
toxicity of FR-1138 (dibromoneopentyl glycerol). TSCA 8D submission by Chemical Biology
Research, Dow Chemical USA, 1972, OTS0516117.
NTP (National Toxicology Program). 2004. NTP studies on 3-bromo-2,2-bis(bromomethyl)
propanol: 1983 Salmonella study details. Online at http://ntp-apps.niehs.hih.gov/.
Toxicology Research Laboratory. 1976. Toxicological properties and industrial handling
hazards of: tribromoneopentyl alcohol. TSCA 8D submission by The Dow Chemical Company,
1990, OTS0530138.
U.S. EPA. 1991. Alpha2u-globulin: Association with chemically induced renal toxicity and
neoplasia in the male rat. Prepared for the Risk Assessment Forum, Washington, DC.
EPA/625/3-91/019F.
2-26
-------
Flame Retardant Alternatives
Tris(l,3-dichloro-2-propyl) Phosphate
Hazard Review
5-1
-------
Tris(l,3-dichloro-2-propyl) phosphate:
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
/
*
/
/
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
*
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
*
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
/
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
/
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
/
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
/
*
X
Immunotoxicity
Immunotoxicity
*
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
/
/
/
*
/
5-2
-------
Tris(l,3-dichloro-2-propyl) phosphate:
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
/
/
/
/
*
/
/
X
/
/
/
X
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
/
*
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
*
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic NOAEC,
LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
*
*
*
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
*
-------
Chemical Identity
2-Propanol, 1,3-dichloro, phosphate (3:1)
CAS 13674-87-8
MF C9H15C16O4P
MW 430.91
SMILES C1CC(CC1)OP(=O)(OC(CC1)CC1)OC(CC1)CC1
Synonyms Tris(l,3-dichloro-2-propyl) phosphate, TDCPP, Fyrol FR-2
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401).
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
Several acute oral lethality studies were available in a variety of species: rabbits, rats, and mice.
These studies were from the older (pre 1980) literature, did not report substance purity, and do
not fully conform to OPPTS or OECD guidelines, but given the magnitude of the LD50 values
the data are adequate for the evaluation of acute oral toxicity. Acute oral LD50 values generally
exceeded the current limit dose of 2,000 mg/kg. Reports that specified a 14-day observation
period are presented in detail.
Critical Studies:
Type: Acute oral toxicity
Species, strain, sex, number: Rabbit, Dutch-belted, 5 males/group
Doses: 0, 5,000, 7,500, and 10,000 mg/kg
Purity: Fyrol FR-2; purity not specifically reported
Vehicle: Not reported by Akzo-Nobel
Method: 14-Day post-dosing observation period; observations limited to mortality, clinical
signs, and necropsy. LD50 calculated according to Litchfield and Wilcoxon.
Results: Clinical signs shortly after dosing included ataxia, weakness, and diarrhea; survivors
normal by day 9. Necropsy revealed no abnormalities. Acute oral male rabbit LD50 = 6,800
mg/kg (95% CI 5,615-8,234 mg/kg).
Reference: Robust summary from Akzo-Nobel, 200la, unpublished study conducted 1982
Type: Acute oral toxicity
3-4
-------
Species, strain, sex, number: Rat, Sprague-Dawley, 5 males/group
Dose: 1,000, 2,150, 5,640, or 10,000 mg/kg
Purity: Fyrol FR-2; purity not specifically reported
Vehicle: None
Observation period: 14 days post dosing
Method: 14-Day post-dosing observation period; observations limited to mortality, clinical
signs, and necropsy; LD50 calculated according to Litchfield and Wilcoxon; not specified
whether fed or fasted at time of dosing.
Results: No effects at 1,000 mg/kg. Dose-related depression at or above 2,160 mg/kg; survivors
normal by day 5. No gross lesions in survivors; fatalities had congestion of heart, lung, and
liver. Acute rat oral LD50 = 3,160 mg/kg (95% CI 2,050-4,800 mg/kg)
Reference: Stauffer, 1972d; robust summary from Akzo-Nobel, 200la
Type: Acute oral toxicity
Species, strain, sex, number: Mouse, Slc/ddY, 10/sex/dose
Purity: Not reported
Doses: For males: 0, 2,210, 2,380, 2,570, 2,780, 3,000, 3,240, and 3,500 mg/kg. For females: 0,
2,890, 2,040, 2,210, 2,380, 2,570, and 2,780 mg/kg.
Vehicle: Olive oil
Method: Observed for mortality and clinical signs for!4 days. No body weight or gross
necropsy examination.
Results: Treated animals exhibited ataxic gait, hyperactivity, convulsion and death. No
mortality was observed in controls or in males at 2,210 mg/kg or females at 1,890 mg/kg. The
LD50 values were 2,670 mg/kg (2,520-2,830 mg/kg) for male mice and 2,250 (2,120-2,380
mg/kg) for female mice.
Reference: Kamata et al., 1989
Additional Studies and Information:
Other studies available only in secondary sources reported similar results. An oral LD50 of
>2,000 mg/kg was reported in male and female rats exposed to Tolgard TDCP MKl(Cuthbert,
1989a as reported in WHO, 1998); clinical signs observed during the first 5 days after dosing
included hypokinesia, piloerection, soiled coats, ataxia, chromodacryorrhea, rhinorrhea, and
salivation.
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged adequate to meet the endpoint.
5-5
-------
Basis for Conclusion:
The available studies predate the preferred study guidelines, and did not report purity, but
together indicated no mortality at the guideline limit dose of 2,000 mg/kg. The report specifying
a 14-day observation period is presented in more detail.
Type: Acute dermal toxicity
Species, strain, sex, number: Rabbit, New Zealand albino, sex not specified, 4
Dose: 4,640 mg/kg
Purity: Fyrol FR-2; Stauffer, no data
Vehicle: None
Exposure period: 24 Hour
Method: 4 Rabbits tested occluded; 14-day observation period. Gross necropsy.
Results: Mortality after 14 days = 0/4. No overt signs of toxicity and no gross necropsy
findings. Therefore, dermal acute LD50 >4,640 mg/kg.
Reference: Stauffer, 1973a; additional information from robust summary in Akzo-Nobel, 200la
Additional Studies and Information:
Other studies available only in secondary sources with minimal detail. A dermal LD50 of
>2,000 mg/kg was reported in male and female Sprague-Dawley rats exposed to Tolgard TDCP
MK1 (Cuthbert, 1989b as reported in WHO, 1998). No deaths and no clinical signs were noted
24 hours after treatment.
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300; OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available study on TDCPP predates the preferred guidelines. The duration was shorter than
currently recommended and no deaths were observed. Analysis of aerosol particle size,
however, was not mentioned so it is not known whether the size was respirable. Necropsies
were not performed.
Type: Acute inhalation toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 5 males and 5 females
Doses: 9.8 mg/L (9,800 mg/m3)
Purity: No data
Vehicle: None
Duration: 1 hour
Method: Observation period = 14 days. Observed daily for signs of toxicity and for mortality.
3-6
-------
Results: No mortality after 14 days; initial signs of moderate depression
Reference: Stauffer, 1973b
Additional Studies and Information:
Other studies available only in secondary sources reported similar results. An acute inhalation
LC50 of >5,220 mg/m3 was reported for Sprague-Dawley rats exposed to aerosol of TDCPP
(Amgard TDCP) (Anderson, 1990 as reported in WHO, 1998).
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available eye irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Two reasonably adequate studies report similar results in rabbits: mild reversible irritation of the
conjunctiva. The studies are summarized below.
Type: Acute eye irritation
Species, strain, sex, number: Rabbit, New Zealand White, sex not specified; 6
Doses: 0.1 mL
Purity: No data, Stauffer Fyrol FR-2
Vehicle: None
Method: Cited CFR [U.S. Federal Hazardous Substances Labelling Act] Section 191.12,
chapter 1, title 21. Following instillation of TDCPP, eyes were examined at 24, 48, and 72
hours.
Results: Mild conjunctival effects in 3/6 that cleared by 48 hours.
Reference: Stauffer, 1972c
Type: Acute (24-hour) eye irritation
Species, strain, sex, number: Rabbit, New Zealand White, male and female; 9 total
Doses: 0.1 mL
Purity: No data
Vehicle: None
Method: U.S. EPA Hazard Evaluation. 1978. Fed. Reg. 43: 163: pp. 37331-37402. Thirty
seconds following instillation of TDCPP, the treated eyes of three rabbits were washed, treated
eyes were not washed in 6 rabbits. The untreated eye of each animal served as a control. The
cornea, iris and conjunctiva of each eye were examined at 24, 48, and 72 hours, and at 4 and 7
days after instillation of TDCPP using the Draize scoring method.
Results: No signs of eye irritation were observed (average total Draize score of zero).
Reference: Stauffer, 1979; robust summary from Akzo-Nobel, 200la for study dated 1979
5-7
-------
Additional Studies and Information:
One hour following application of Tolgard TDCP MK1 to the eyes of New Zealand White
rabbits, slight conjunctival redness and slight discharge were noted (Cuthbert and Jackson, 1990
as reported in WHO, 1998); effects cleared by 24 hours.
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available dermal irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Two reasonably adequate studies, patterned after guidelines in effect at the time, provide similar
results, indicating that TDCPP was a non-irritant when applied for 4 hours (consistent with
current guidelines) and a mild irritant when applied for 24 hours to rabbit skin. Additional
studies provide support. The studies are summarized below.
Critical Studies:
Type: Acute (24-hour) dermal irritation
Species, strain, sex, number: Rabbit, New Zealand, sex not specified, 6
Doses: 0.5 mL
Purity: Not reported; Stauffer Fyrol FR-2
Vehicle: None
Method: Cites "EPA protocol". Back hair was shaved, each rabbit tested on intact and abraded
skin, occlusive dressing removed after 24 hours, observations at 24 and 72 hours.
Results: No edema on intact or abraded skin in any of the 6 rabbits. Mild erythema was visible
at 24 hours but cleared by 72 hours, resulting in a score of 0.63. The report classified TDCPP as
a mild irritant.
Reference: Stauffer, 1979
Type: Acute (4-hour) dermal irritation
Species, strain, sex, number: Rabbit, not specified (but New Zealand white rabbits were used in
an eye irritation test conducted at the same time)
Doses: 0.5 mL
Purity: Not reported; Stauffer Fyrol FR-2
Vehicle: None
Method: Back hair shaved, each rabbit tested on intact and abraded skin, occlusive dressing
removed after 4 hours, observations at 4, 24 and 48 hours.
Results: No erythema or edema on intact or abraded skin in any of the 6 rabbits.
Reference: Stauffer, 1972c
-------
Additional Studies:
Another study, on Tolgard TDCPP MK1, reported well-defined (score 2) erythema in 2 New
Zealand White rabbits and slight erythema in a third rabbit 1 hour after patch removal, but
duration of exposure was not specified (Cuthbert, 1989c as reported in WHO, 1998). Effects
cleared by 48 hours. The substance was classified as a skin irritant.
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The available skin sensitization data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential study that reported negative results in a skin sensitization study in guinea pigs
was submitted that allows this endpoint to be adequately characterized.
A robust summary in a submission to the HPV Challenge program was located for an
unpublished industrial study stated to have been conducted under guideline. The summary
probably has not been reviewed by EPA, since this endpoint is not required for the HPV
program. Furthermore, the summary omits information necessary to determine study adequacy,
such as: the strain, sex, group size, substance purity, and dose levels. The summary claimed that
the doses were selected according to guideline, but the exact levels are not stipulated in the
guideline. Without the additional information, this study cannot be evaluated for adequacy.
Critical Studies:
Type: Dermal sensitization study
Species, strain, sex, number: Guinea pig, strain and sex not reported
Doses: Stated as according to guideline, but exact doses are not stipulated in guideline.
Purity: Not reported; Fyrol FR-2
Vehicle: Water
Method: Three pairs of intradermal injections into shaved shoulder: 1:1 Freunds Complete
Adjuvent (FCA) and saline, the test material, and 1:1 FCA and test material. Controls received
water in place of the test material. On day 6, 24 hours before topical induction application,
sodium lauryl sulfate was applied to sites to enhance local irritation. On day 7, test substance
was applied to sites (water for controls). On day 21, animals received challenge dose by dermal
application, occluded for 24 hours. Sites observed for irritation and sensitization (Grade 0-4).
Results: The sensitization score for Fyrol FR-2 was zero, indicating the substance is not a
chemical sensitizer.
Reference: Robust summary in Akzo-Nobel, 200Ib for unpublished and unidentified study
dated 2001
5-9
-------
SUBCHRONIC TOXICITY
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Conclusion.
The available subchronic oral toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A Japanese 90-day dietary study in mice (Kamata et al. 1989) provides limited relevant
information in the English abstract and data tables. The study was not adequate to characterize
this endpoint because histopathological analysis was apparently limited to the liver. A fertility
study by Wilczynski et al. (1983), discussed under the Reproductive Toxicity endpoint,
evaluated male rabbits exposed by oral gavage for 12 weeks, but did not involve treated females.
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
No study of this type was located.
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
Type: 90-Day repeated oral
Species, strain, sex, number: Mouse, Slc/ddY, 12/sex/dose
Doses: TDCPP at dietary concentrations of 0, 0.01, 0.04, 0.13, 0.42, and 1.33% in the diet,
resulting in reported average daily doses of 0, 13.2, 47.3, 171.0, 576.0, and 1,792.3 mg/kg/day in
males and 0, 15.3, 62.5, 213.6, 598.0, and 1,973.1 mg/kg/day in female mice
Purity: Not reported
Vehicle: None; added to diet
Exposure period, frequency: 90 days, ad lib
Method: Body weight, food consumption measured weekly. At 1 and 3 months in half the
animals, hematologic (erythrocyte, hemoglobin, hematocrit, and leukocyte counts) and clinical
chemistry parameters (total protein, albumin, albumin/globulin ratio, blood urea nitrogen,
glucose, total cholesterol, alkaline phosphatase, aspartate aminotransferase, alanine
aminotransferase). At 1 and 3 months, half the animals were necropsied and absolute and
relative organ weights were determined for brain, heart, lung, liver, kidney, and spleen. The
liver was examined for microscopic histopathology; the English text does not mention whether
other tissues were examined.
Results: At the highest dietary level, 1.33%, all mice exhibited emaciation, rough hair, and
tremor and died within 1 month. At 1.33%, food consumption was reduced and body weight loss
occurred in both sexes. Mean body weight gain was reduced by about 10% (estimated from
graph) in males at 0.42% throughout the study. The following statistically significant changes
3-10
-------
occurred in treated groups compared to controls. Slight anemia (reduced hemoglobin; p<0.05) in
males at 0.42% after 3 months. Anemia (reduced hemoglobin at >0.13% after 1 month and at
0.42% at 3 months, erythrocyte and hematocrit at 0.42% at 1 and 3 months) in females (3-month
values p<0.01). Albumin/globulin ratios elevated in all treated male groups at 3 months.
Alkaline phosphatase elevated in females at 0.42% at 1 month but not later. Dose-related organ
weight elevations compared to controls observed at 3 months in males included relative liver
weight (+32-51%) at >0.13% and relative kidney weight (+39%) at 0.42%. Significant
elevations in organ weights in females at 3 months included relative liver weight (+16-51%) at
>0.04%, absolute (+30%) and relative (+34-40%) kidney weights at >0.13%, and absolute liver
weight (+40%) at 0.42%. The statistical significance of these organ weight elevations was
p<0.01 for rats exposed at >0.13% and p<0.05 for rats exposed at 0.04.%. Histopathology of the
liver (slight focal necrosis) was observed in only two females at 0.42%. The dietary level of
0.01% is aNOAEL of 15.3 mg/kg/day and the dietary level of 0.04% is a LOAEL of 62.5
mg/kg/day for liver and kidney weight elevations in female mice.
Reference: Kamata et al., 1989
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
No studies of this type were located.
Subchronic Dermal Toxicity (21/28-day or 90-day)
Conclusion.
No available subchronic dermal toxicity data.
Basis for Conclusion:
No data exist for the subchronic dermal toxicity endpoint.
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD
Guideline 410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
No studies of either type were located.
3-11
-------
Subchronic Inhalation Toxicity (90-day)
Conclusion:
No available subchronic inhalation toxicity data.
Basis for Conclusion:
No repeated-exposure inhalation toxicity studies were located.
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD
Guideline 413)
No studies of this type were located.
REPRODUCTIVE TOXICITY
Conclusion:
The available reproductive toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A fertility assay in male rabbits exposed by oral gavage for 12 weeks prior to mating
(Wilczynski et al., 1983) partially characterizes this endpoint, but is not sufficient to satisfy the
reproductive toxicity endpoint since it was described only in an abstract and females were not
tested. Other studies (Hazleton, 1978; Tanaka et al., 1981) described below under
Developmental Toxicity reported that in pregnant female rats exposed orally to TDCPP, adverse
reproductive effects occurred only at maternally lethal doses. However, no study evaluated
reproductive function in females treated prior to mating.
The 2-year feeding bioassay in rats by Freudenthal and Henrich (2000; Bio/Dynamics, 1980,
1981), discussed below under Chronic Toxicity, provides reproductive histopathology data that
are, however, insufficient to satisfy the reproductive toxicity endpoint. This study provided
histopathology results for the testis, epididymis, seminal vesicle, ovary, and uterus for the
control and high-dose groups (0 and 80 mg/kg/day) after 1 year (10 scheduled
sacrifices/sex/group) and for survivors in all groups after 2 years; unscheduled sacrifices (rats
killed in a moribund state) were also examined. The 2-year exposure is too long to represent
reproductive toxicity, because of the confounding effects of aging; the results pointed to dose-
related effects in male reproductive organs (at >5 mg/kg/day, atrophy and decreased secretory
product of the seminal vesicles; at >20 mg/kg/day, testicular germinal atrophy with
oligospermia; and at 80 mg/kg/day, oligospermia and luminal accumulation of degenerated
seminal products in the epididymis). No significant effect was observed in females. The tested
doses, which were considerably lower than the guideline limit dose of 1,000 mg/kg/day, were not
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high enough to induce significant reproductive histopathology after one year of exposure; 1/10
high-dose males had oligospermia. Thus, a LOAEL for reproductive effects following
subchronic (90-day) exposure is not available and cannot be extrapolated from the existing data,
but the chronic data indicate a LOAEL of 5 mg/kg/day for atrophy and decreased secretory
product of the seminal vesicles.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
No studies were available that met the specific designs of the three protocols listed above.
Additional Studies:
A study described in an abstract by Wilczynski et al. (1983) addresses fertility in male rabbits
exposed by oral gavage for 12 weeks prior to mating.
Type: Fertility
Species, strain, sex, number: Rabbit, strain not specified, 10 males/dose
Purity: Not reported
Doses: 0, 2, 20, or 200 mg/kg/day
Vehicle: Not reported
Exposure duration, frequency: 12 weeks, once by oral gavage daily
Method: Males treated for 12 weeks, then mated with untreated females. Body weight, clinical
signs, clinical chemistry, hematology, mating behavior, male fertility, sperm quantity and
quality, kidney and liver weights, gross and microscopic pathology (range of organs examined
not specified).
Results: High-dose animals had significantly increased absolute kidney weight and relative liver
weight. TDCPP had no effect on male reproductive parameters; there was no histopathology in
kidneys, liver, pituitaries, testes, or epididymides.
Reference: Wilczynski et al., 1983
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged adequate to meet the endpoint.
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Basis for Conclusion:
Developmental toxicity studies in two strains of rats exposed to Fyrol FR-2 by oral gavage
followed methods consistent with OECD Guideline 414 (one study pre-dated the guideline).
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700; OECD
Guideline 414)
Type: Prenatal developmental toxicity
Species, strain, sex, number: Rat, Wistar, 15 pregnant females at the highest dose, 23-24
pregnant females in controls and other dose groups.
Purity: not reported
Doses: 0, 25, 50, 100, 200, and 400 mg/kg/day
Vehicle: Olive oil
Exposure duration, frequency: Once by oral gavage daily on gestational days (GD) 7-19.
Method: Body weight, food consumption, clinical signs, pregnancy rates, and necropsy of dams,
kidney weight; uterine contents (including implants and resorption) at day 20 of gestation,
corpora lutea; fetal viability, sex ratio and weight, crown-rump length, and external and skeletal
abnormalities.
Seven dams from each of the control and <200 mg/kg/day groups were permitted to litter
normally and evaluated for implantation sites, delivery index, number of live offspring at birth
and survival on PND 4, at 4th week, and at 10th week. Litters were culled to 10 offspring on
postnatal day 4 (PND 4) and subjected to behavioral tests (open field, water maze, rota rod,
inclined screen, pain reflex and Preyer's reflex). Absolute organ weights of 10 organs plus
testis, uterus and ovary were measured in offspring.
Results: Maternal mortality occurred only at 400 mg/kg/day: 11/15 died. Food consumption
was suppressed at 400 mg/kg/day and slightly at 200 mg/kg/day. At 400 mg/kg/day, mean body
weight loss occurred during GD 7-15, resulting in significantly (p<0.05) reduced terminal body
weight on GD20: -17% lower than control group. Absolute and relative kidney weights were
significantly increased at 200 and 400 mg/kg/day. TDCPP at <200 mg/kg/day had no effect on
corpora lutea or mean numbers of implants, fetal body weight, fetal sex ratio, or the number of
dead or live fetuses. The numbers of dead fetuses and live fetuses were significantly (p<0.01)
changed compared to controls by the loss of one whole litter at 400 mg/kg/day. No increase in
malformations was observed in treated groups. For maternal toxicity, the NOAEL was 100
mg/kg/day and the LOAEL was 200 mg/kg/day for increased kidney weight. For fetal toxicity,
the NOAEL was 200 mg/kg/day and the LOAEL was 400 mg/kg/day for increased fetal death;
the highest dose of 400 mg/kg/day was a NOAEL for teratogenicity.
Postnatal observations: TDCPP at <200 mg/kg/day had no effect on implantation, delivery,
postnatal survival, behavior, functional test results, or absolute organ weights of offspring.
Reference: Tanaka et al., 1981
Type: Prenatal developmental toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 20 pregnant females/dose
Purity: not reported
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Doses: 0, 25, 100, and 400 mg/kg/day
Vehicle: Corn oil
Exposure duration, frequency: Once by oral gavage daily on gestational days 6-15
Method: Body weight, food consumption, clinical signs, pregnancy rates, and necropsy of dams;
uterine contents (including implants and resorption) at day 19 of gestation, corpora lutea; fetal
viability and weight, crown-rump length, external, visceral (1/3 fetuses), and skeletal
abnormalities; extensive statistical analyses.
Results: High-dose dams exhibited clinical signs (urine stains, hunched appearance, and
alopecia); sporadic signs of urine stains and hunched appearance occurred in a few mid-dose
dams, but not at the low-dose. Food consumption was statistically lower in mid-dose dams on
days 7-11 and in high-dose group throughout (days 7-15). During Days 6-11, significant
(p<0.05) reductions in body weight gain in mid-dose dams and mean body weight loss at the
high dose; on days 11-15, only high-dose dams showed reduced body weight gain. Overall body
weights reduced in high-dose dams. TDCPP had no effect on implantation efficiency or mean
number of corpora lutea. Treatment at the high dose significantly (p<0.05) increased the number
of resorptions (to 14.4% compared to 6.7% in controls) and reduced fetal viability (to 85.6%
compared to 93.3% for controls). Decreased skeletal development in the high-dose groups is
related to growth retardation and decreased fetal size. The incidence of malformations was not
related to treatment. The study indicates a NOAEL of 25 mg/kg/day and a LOAEL of 100
mg/kg/day for maternal toxicity (clinical signs and transient reduction in body weight gain) and a
NOAEL of 100 mg/kg/day and a LOAEL of 400 mg/kg/day for developmental toxicity
(increased resorptions and fetal mortality).
Reference: Hazleton, 1978
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
No studies with the specific designs of the two tests listed above were available.
CHRONIC TOXICITY
Conclusion:
The available chronic toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The combined chronic toxicity/carcinogenicity assay in dietarily exposed rats is consistent with
the guideline (Freudenthal and Henrich, 2000; Bio/Dynamics, 1980).
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Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
No studies of this type were located.
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
The protocol of a 2-year feeding bioassay in rats was consistent with this guideline (Freudenthal
and Henrich, 2000; Bio/Dynamics, 1980). The published article focused on tumor results rather
than non-neoplastic effects.
Type: Combined oral chronic toxicity and carcinogenicity assay
Species, strain, sex, number: Rat, Sprague-Dawley, 60/sex/group
Purity: 95%
Doses: 0, 5, 20, and 80 mg/kg body weight/day
Vehicle: None other than feed
Route: In feed; diets blended weekly to achieve target doses
Exposure duration, frequency: 2 years, ad lib
Method: Examined twice daily for mortality and clinical signs, weekly physical examination.
Body weights and food consumption weekly for the first 13 weeks and biweekly thereafter.
Ophthalmoscopic examinations every 6 months. Extensive hematology, clinical chemistry and
urinalysis parameters at 3, 6, 12, 18, and 24 months. Ten/sex/dose randomly chosen for
termination at 12 months; the remainder at 24 months. Gross necropsy including organ weights
(8 organs plus gonads); histopathology of more than 30 tissues in control and high-dose rats; at
low- and mid-doses, histopathology limited to liver, kidneys, testes, and adrenals. Statistical
analyses.
Results: The following changes compared to controls were statistically significant (p<0.05).
Mortality increased in high-dose males (to 61.7% vs 43.3% for controls). Lower body weights
in high-dose males and females. Treatment had no effect on feed consumption. Signs of anemia
(lower hemoglobin, hematocrit, erythrocyte counts) in high-dose rats. At the mid-dose,
increased absolute and relative kidney weight males and females, absolute liver weight and
relative thyroid weight in males, and relative liver weight in females. At the high dose,
increased relative liver weight in males and absolute and relative thyroid weights in females.
Increases in the incidences of the following nonneoplastic lesions were statistically significant
(p<0.05) in treated groups compared to the control groups; changes were not strictly dose-related
in that incidences were depressed in high-dose groups. Kidney lesions (convoluted tubule
hyperplasia) in males at >20 mg/kg/day and in females at 80 mg/kg/day. Other systemic lesions
at 80 mg/kg/day involved the parathyroid (hyperplasia) in males and the liver (foci) and spleen
(erythroid/myeloid hyperplasia) in females. Reproductive system lesions in males involved
seminal vesicles (atrophy, decreased secretory product) at >5 mg/kg/day, testes (eosinophilic
material in lumen, periarteritis nodosa) at >20 mg/kg/day, and epididymis (oligospermia and
degenerated seminal product) at 80 mg/kg/day. (Tumor incidences are reported below under
Carcinogenicity.) The authors reported the lowest dose of 5 mg/kg/day as a NOAEL and the
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mid-dose of 20 mg/kg/day as a LOAEL. However, as evaluated in NRC (2000), the lowest dose
of 5 mg/kg/day was a LOAEL for atrophy and decreased secretory product of the seminal
vesicle.
Reference: Freudenthal and Henrich, 2000; also Bio/Dynamics (1980), fiche 27 of 32 and
Bio/Dynamics (1981) fiche 6 of 6.
CARCINOGENICITY
Conclusion:
The available carcinogenicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Increased tumor incidences were observed in a combined chronic toxicity/carcinogenicity assay
in rats exposed to TDCPP in the diet (Freudenthal and Henrich, 2000).
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
No studies of this type were located.
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
A 2-year feeding bioassay by Freudenthal and Henrich (2000) was consistent with this guideline.
Type: Combined oral chronic toxicity and carcinogenicity assay
Species, strain, sex, number: Rat, Sprague-Dawley, 60/sex/group
Purity: 95%
Doses: 0, 5, 20, and 80 mg/kg body weight/day
Vehicle: None other than feed
Route: In feed; diets blended weekly to achieve target doses
Exposure duration, frequency: 2, ad lib
Method: See description above under Chronic Toxicity
Results: The following neoplastic changes compared to controls were statistically significant
(p<0.05). Dose-related increased incidences at >20 mg/kg/day of renal cortical adenomas in
both sexes and testicular interstitial tumors in males, and at 80 mg/kg/day, of hepatocellular
adenomas and carcinomas combined in both sexes and adrenal cortical adenomas in females.
The NRC (2000) concluded that this study provides sufficient evidence of carcinogenicity of
TDCPP in rats following chronic oral exposure.
Reference: Freudenthal and Henrich, 2000; also Bio/Dynamics (1980, 1981)
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NEUROTOXICITY
Conclusion:
The available neurotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The delayed neurotoxicity component is satisfied by the existing data, but a developmental
toxicity study by Tanaka et al. (1981) that included postnatal behavioral examinations did not
fully satisfy the developmental neurotoxicity component. TDCPP gave negative results in single
acute and subchronic oral delayed neurotoxicity studies in hens and in limited postnatal testing
in rats exposed during gestation. A 2-year feeding bioassay in rats by Freudenthal and Henrich,
2000; Bio/Dynamics, 1980), discussed above under the Chronic Toxicity and Carcinogenicity
endpoints, reported no lesions of the cervical spinal cord, but a slight (not statistically
significant) increase in the incidence of gliomas of the brain in rats exposed to TDCPP at 80
mg/kg/day. The study authors could not determine whether this effect was related to exposure.
Delayed Neurotoxicity
Conclusion:
The available delayed neurotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Several acute studies and one subchronic study for delayed neurotoxicity in the hen, summarized
below, give no evidence of acute cholinergic toxicity, inhibition of neurotoxic esterase (NTE)
activity, or delayed neurotoxicity for TDCPP. These studies, performed prior to the existence of
the guidelines, do not entirely conform to current guidelines, and may lack detail such as the
purity of the TDCPP sample. The lack of significant NTE inhibition following dosing with
10,000 mg/kg suggests that no additional testing for delayed neurotoxicity is needed for TDCPP.
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Unpublished industrial acute (1- or 5-day) and subchronic (90-day) delayed neurotoxicity assays,
which pre-date the guideline, are missing some details. One acute study employed a gavage dose
5 times higher than now specified under the guideline. The subchronic assay had a longer
duration and a larger group size than specified under the guideline.
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Critical Studies
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, White Leghorn, 4/dose
Purity: Fyrol FR-2, purity not reported, clear colorless liquid
Doses: 420 mg/kg (highest dose specified in protocol)
Vehicle: test substance diluted 50% in corn oil
Positive control: 90 or 120 mg/kg/day tri-ortho-tylol phosphate (TOCP)
Route: Gavage
Exposure duration, frequency: Once daily on five consecutive days
Method: Navy MIL-H-19457B (SHIPS) protocol. Hens were weighed and graded on days 7, 9,
11, 14, 16, 18, 21, and 23 after the first dose for no signs, doubtful/minor signs, positive paralytic
signs, advanced paralytic signs, or death. Scores on the 21st day were compared with results for
TOCP. Necropsy not performed.
Results: No overt signs of neurotoxicity in with TDCPP treatment. Positive control caused
inability to walk, hypertension, ataxia, and prostration.
Reference: Bullock and Kamienski, 1972 as described in WHO, 1998; Stauffer 1972a
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, White Leghorn, 4/dose for TDCPP, 3/dose for controls
Purity: Fyrol FR-2, clear colorless liquid; one part of the report stated that the purity was not
reported, whereas another part of the report indicated purity >99%.
Doses: 10,000 mg/kg
Vehicle: None
Positive control: 500 mg/kg tri-ortho-cresyl phosphate (TOCP)
Negative control: 15 mg/kg tetraethyl pyrophosphate (TEPP)
Route: Oral gavage
Exposure duration, frequency: Once
Method: Twenty minutes before dosing, hens received atropine and 2-PAM to protect against
cholinergic effects. Hens were observed for toxic signs at 2-hour intervals for the first 8 hours.
Mortalities were recorded after 24 hours. Brains were harvested 24 hours after dosing and
analyzed for neurotoxic esterase (NTE) activity.
Results: Toxic signs were not reported specifically for TDCPP, but for all compounds tested at
the maximum tolerated dose, signs included listlessness and ataxia. Inhibition of NTE activity
was 7% for TDCPP and the negative control TEPP, but 85% for the positive control (TOCP).
The current guideline specifies that testing is not necessary at doses above 2,000 mg/kg.
Reference: Stauffer, 1978
Type: Subchronic oral delayed neurotoxicity
Species, strain, sex, number: Hen, adult, White Leghorn, 10/dose
Purity: Not reported
Doses: 0, 4, 20, and 100 mg/kg/day
Vehicle: Not reported
Route: Oral Gavage
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Exposure duration, frequency: 90 days, daily
Method: Body weight. Daily observations for mortality and behavioral changes; evaluated for
signs of motor weakness 3 times per week. At termination, hens were necropsied and brain
(multiple sections), sciatic nerve, and spinal cord (cervical, thoracic and lumbar) were examined
histopathologically. TOCP was the positive control.
Results: Hens treated with TDCPP at the high dose exhibited mean reductions in body weight
during the latter part of the study, but no overt signs of neurotoxicity and no histopathological
effects in the nervous tissues. Conversely, the positive control hens exhibited consistently lower
body weight gain, clinical signs of toxicity (locomotor impairment and ataxia) that became more
severe with time. Histopathology results were not reported for the positive control.
Reference: Robust summary from Akzo-Nobel, 200la; unpublished, unidentified study dated
1979
Neurotoxicity (Adult)
Conclusion:
The available adult neurotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The chronic oral bioassay by Freudenthal and Henrich (2000; Bio/Dynamics, 1980, 1981)
reported no lesions of the brain or spinal cord in rats exposed to TDCPP at doses as high as 80
mg/kg/day for 2 years, but no functional tests of neurotoxicity were performed.
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
No studies of this type were located.
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS Harmonized
Guideline 870.6300)
Conclusion:
The available developmental neurotoxicity data were judged inadequate to meet the endpoint,
although the available tests suggest that TDCPP is not a developmental neurotoxin.
Basis for Conclusion:
No studies of this specific design were located. A Japanese-language gavage study by Tanaka et
al. (1981), described above under Developmental Toxicity, included postnatal neurobehavioral
tests (open field, water maze, rota rod, inclined screen, pain reflex, and Preyer's reflex) of
sensory and motor function in rats. Full descriptions of these tests were not available in the
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English summary and therefore could not be compared to the guideline protocol. The study
reported no adverse effect in these tests for offspring of dams that were exposed on gestational
days 7-15 at doses as high as 200 mg/kg/day (the highest tested non-lethal dose that was a
LOAEL for increased kidney weight). This study does not fully satisfy the developmental
neurotoxicity endpoint because it omitted some parameters specified under the guideline:
developmental landmarks for sexual maturity, auditory startle test, and neurohistopathological
examinations.
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat)
OPPTS Harmonized Guideline 870.6500
Peripheral Nerve Function (rodent)
OPPTS Harmonized Guideline 870.6850
Sensory Evoked Potentials (rat, pigmented strain preferred)
OPPTS Harmonized Guideline 870.6855
These studies may be indicated, for example, to follow up neurotoxic signs seen in other studies,
or because of structural similarity of the substance to neurotoxicants that affect these endpoints.
These studies may be combined with other toxicity studies.
Conclusion: These endpoints do not appear to be applicable to TDCPP.
Basis for Conclusion: Although there are no studies addressing these endpoints, there are no
reliable data for TDCPP, and no structure-activity considerations, that indicate a need for these
follow-up studies.
Other Neurotoxicity Data
Cholinesterase inhibition
Fyrol FR-2 administered at 0, 2,000, or 3,980 mg/kg in corn oil was administered to groups of 10
male Sprague-Dawley rats by oral gavage had no effect on plasma or erythrocyte cholinesterase
levels measured 4 or 14 hours after dosing (Stauffer, 1972b).
IMMUNOTOXICITY
Conclusion:
The available immunotoxicity data were judged inadequate to meet the endpoint.
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Basis for Conclusion:
The only study evaluating the potential immunotoxicity of TDCPP (Luster et al., 1981) predates
the guideline for immunotoxicity (note that the OPPTS guideline cites other works by this
author). There is some uncertainty as the test material, reported as Fyrol FR2, but mis-identified
by the authors as tris(2,3-dichloropropyl) phosphate. The study methods differed from the
guideline in the short exposure period (4 rather than 28 days), parenteral administration (rather
than oral or inhalation route), measurement of serum immunoglobulins in non-immunized rather
than immunized mice, and the omission of some tests (enumeration of immunological cell
subpopulations, test for NK-cell activity). The results do not provide dose-response information
as to immunotoxicity of TDCPP following subchronic exposure by oral or inhalation routes of
exposure.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
Critical study
Type: Immunotoxicity, subcutaneous, acute
Species, strain, sex, number: Mouse, B6C3FJ, 6-8 females/dose
Doses: 0, 0.25, 2.5, or 25 mg/kg/day (Total cumulative doses of 0, 1, 10, or 100 mg/kg)
Identity: Stauffer Fyrol FR-2, lot 4670-3-23. This is the same lot as TDCPP tested in the 2-year
oral assay by Freudenthal and Henrich (2000)
Purity: Stauffer, purity >95%
Vehicle: Corn oil
Route: Subcutaneous injection
Exposure duration, frequency: 4 days, once daily
Method: Observations included body weight, hematology, clinical chemistry (5 parameters)
terminal necropsy, organ weights (liver, spleen and thymus), histopathology of spleen, thymus,
and eight other organs, plaque-forming assay response to sheep red blood cells, and serum
immunoglobulin quantification (non-immunized mice only). Non-guideline tests included
proliferative capacity of granulocyte-macrophage progenitor cells (bone marrow), in vitro
lymphoproliferative (LP) responses to mitogens, delayed hypersensitivity response to keyhole
limpet hemocyanin. Extensive statistical analysis.
Results: Twenty percent of high-dose mice exhibited lymphoid depletion of the thymus.
Statistically significant decreases in vitro lipopolysaccharide (B-cell antigen) at 2.5 mg/kg/day
and concanavalin A (T-cell antigen) at 25 mg/kg/day.
Reference: Luster et al., 1981
GENOTOXICITY
Conclusion: The available genotoxicity data were judged adequate to meet the endpoint.
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Basis for Conclusion:
TDCPP has been tested in in vitro and in vivo genotoxicity assays conducted in prokaryotic and
eukaryotic cells under methods similar to guidelines. Results of in vivo tests (mutation in
Drosophila, chromosomal aberration in mice) were negative, but positive results were reported
in several in vitro assays (mutagenicity in bacterial and mammalian cells, chromosomal
aberration).
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA97, TA98, TA100, TA1535, TA1537
Metabolic activation: Tested with and without S9 from livers of Aroclor-induced male
Sprague-Dawley rats or male Hamsters
Concentrations: 0, five concentrations between 10 and 10,000 jig/plate.
Purity: 94.4%
Method: Preincubation (20 minutes) and plate incorporation (48 hours) at 37°C. Positive
controls were used; DMSO was the solvent. Triplicate plates per concentration. All assays
repeated within 1 week.
Results: In three different laboratories, TDCPP tested positive in strains TA97 and TA100 in the
presence of S9 from Aroclor-induced hamster liver and in strain TA1535 in the presence of S9
from Aroclor-induced rat or hamster liver. Positive controls gave expected increases. Solvent
control and all other test combinations were negative.
Reference: Mortelmans et al., 1986
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538
Metabolic activation: Tested with and without Kanechlor 500 (PCB)-induced liver S9 from
male Wistar rats
Concentrations: 0, 10, 30, 100, and 300 jig/plate.
Purity: Assayed as -94% TDCPP, plus -6% bis(l-chloromethyl-2-chloroethyl)(2,3-
dichloropropyl) phosphate.
Method: Plate incorporation, 48-hour incubation at 37°C. Cited Ames protocol, which
presumes the use of replicates and positive controls.
Results: No increase in revertants in any strain without activation or in strains TA98, TA1537,
or TA1538 with activation. Weak increases in TA100 and TA1535 at the highest concentrations
with S9.
Reference: Nakamura et al., 1979
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Additional Studies
Other S. typhimurium assays in which S9 was prepared from phenobarbital-induced rat liver
reported mutagenicity of TDCPP in strain TA98 by liquid preincubation assay (Abe and Urano,
1994) and in TA100 by plate incorporation assay (Gold et al., 1978; Soederlund et al., 1985).
Majeska and Matheson (1983) reported dose-related positive results for TDCPP and its
metabolite l,3-dichloro-2-propanol in TA100 with S9 (phenobarbital-induced) in standard plate
assays at concentrations up to 500 jig/plate. In a liquid preincubation quantitative assay, results
for TDCPP were essentially negativeonly increasing mutation frequencies at cytotoxic
concentrations (survival <3%). However, its metabolites increased mutant frequencies with less
cytotoxicity: l,3-dichloro-2-propanone positive at <80% survival and l,3-dichloro-2-propanol
positive at <30% survival.
TDCPP was not mutagenic in S. typhimurium strains TA100, TA1535, or TA1538 without
activation or when Aroclor-induction was used to prepare the S9 fraction (Prival et al., 1977);
the highest exposure level was 10 |j,L per plate.
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
Type: Mammalian Cell Gene Mutation Test: Forward Mutation
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: Tested with and without phenobarbital-induced liver S9 from male mice
Concentrations: 0, and five concentrations up to -32 nL/mL without S9, and six concentrations
up to 70 nL/mL with S9. Test conditions chosen based on preliminary assays so that 50%
growth reduction occurred at highest concentration.
Purity: Not reported
Method: Selection of forward mutation from TK+/- to TK-/- genotype. Activity compared to
tris(2,3-dibromopropyl)phosphate (TBPP).
Results: TDCPP yielded negative results with or without activation. TBPP was negative
without, but positive with activation.
Reference: Brusick et al., 1979; also Litton Bionetics, Inc., 1977
Type: Mammalian Cell Gene Mutation Test: Forward Mutation
Species, strain: V79 Chinese hamster lung cells
Metabolic activation: Tested with phenobarbital-induced liver S9 from male rats
Concentrations: 0, 0.02 mM TDCPP. Test conditions chosen based on preliminary assays.
Purity: Not reported
Method: In two experiments, selection of 6-thioguanine-resistant colonies. Activity compared
to tris(2,3-dibromopropyl)phosphate (TBPP).
Results: TDCPP with S9 did not increase mutation frequency. TBPP yielded positive results.
Reference: Soederlund et al., 1985
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Gene Mutation in Vivo:
Sex-linked Recessive Lethal test in Drosophila melanogaster (OPPTS Harmonized
Guideline 870.5275)
Type: Sex-linked Recessive Lethal test
Species, strain: Drosophila melanogaster, 100 males/concentration
Metabolic activation: None
Concentrations: 2.5 and 25% in feed (1% gum tragacanth in 3% sucrose)
Purity: Technical-grade Fyrol FR-2, purity not reported
Method: TDCPP added to feed of males for 24 hours, subsequently mated with virgin
unexposed females
Results: No evidence of toxicity or increase in the percentage of sex-linked recessive lethal
mutations.
Reference: Brusick and Jagannath, 1977 as described in WHO, 1998; also Litton Bionetics, Inc.,
1976
Chromosomal Aberration in Vitro:
In Vitro Mammalian Chromosome Aberration Test (OPPTS Harmonized Guideline
870.5375)
Type: In vitro chromosome aberration assay
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: None, phenobarbital-induced or PCB-induced
Concentrations: 0, 0.01 to 0.1 |j,L/mL for non-induced, phenobarbital-induced or PCB-induced
mouse
Purity: Not reported
Method: 4-hour exposure to TDCPP with or without activation. Chromosomal aberrations
scored in 50 metaphase spreads per concentration.
Results: TDCPP caused increases chromosomal aberrations (up to 40%) with PCB- or
phenobarbital-induction compared to noninduced S9.
Reference: Brusick et al., 1979; also Litton Bionetics, Inc., 1977
Additional Information
One confidential study reported negative results for TDCPP in cultured Chinese hamster ovary
cells with or without metabolic activation. Another confidential study reported positive results
in human lymphocytes with metabolic activation.
In vitro Sister Chromatid Exchange Assay (OPPTS Harmonized Guideline
870.5900)
Type: In vitro sister chromatid exchange assay
3-25
-------
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: None, phenobarbital-induced or PCB-induced
Concentrations: 0, 0.005-0.03 |j,L/mL for phenobarbital-induced (4 concentrations), and 6
concentrations up to 0.070 |j,L/mL for non-induced or PCB-induced mouse
Purity: Not reported
Method: Ten cells per concentration were analyzed.
Results: TDCPP increased the incidence of sister chromatid exchanges in mouse lymphocytes
under all three test conditions.
Reference: Brusick et al., 1979; also Litton Bionetics, Inc., 1977
Additional Information
One submitted confidential study reported negative results in a sister chromatid exchange assay.
The data for this study are not adequate because the cell line was not identified. Fyrol FR-2 did
not induce sister chromatid exchanges when applied to 3- to 4-day-old chicken embryos (Bloom,
1984).
Chromosomal Aberration in Vivo:
Mammalian Bone Marrow Chromosomal Aberration Test (OPPTS Harmonized
Guideline 870.5385)
The available study provides sufficient evidence that TDCPP did not induce chromosomal
aberrations in mice exposed at the maximum tolerated dose of 760 mg/kg.
Type: Bone marrow chromosomal aberration in vivo
Species, strain: Mouse, CD-I, 4-8 males/group
Metabolic activation: None
Concentrations: 0, 0.05, 0.17, and 0.5 mL/kg; using the specific gravity of 1.52, the doses were
0, 76, 260, or 760 mg/kg. The highest dose was the maximum tolerated dose. Negative control
was DMSO
Exposure duration, frequency: By oral gavage in once or daily on 5 consecutive days.
Purity: Technical grade; Not reported
Method: Mice were sacrificed at 6, 24, and 48 hours after single dose or 6 hours after the last of
5 doses. Between 233 and 400 cells were scored, rather than 500/animal. Triethylenemelamine
was positive control.
Results: No evidence of increased frequency of chromosomal aberrations with TDCPP. TBPP
was also negative at doses up to 1,000 mg/kg. Positive control produce expected large increase
in micronucleated polychromatic erythrocytes.
Reference: Brusick et al., 1979; Litton Bionetics, Inc., 1978
Mammalian erythrocyte micronucleus test (OPPTS Harmonized Guideline
870.5395)
3-26
-------
TDCPP administered as 2,000 mg/kg by an unspecified route to mice did not induce micronuclei
in bone marrow erythrocytes (Thomas and Collier, 1985 as reported in WHO, 1998).
DNA Damage and Repair
Unscheduled DNA synthesis in mammalian cells in culture (OPPTS Harmonized
Guideline 870.5550)
Type: Unscheduled DNA synthesis in mammalian cells (hepatocytes) in culture
Species, strain: Rat, Wistar, male
Metabolic activation: With or without phenobarbital-induction
Concentrations: 0, 0.05, and 0.1 mM
Purity: Not reported
Vehicle: DMSO
Method: Cultured hepatocytes exposed to TDCPP or TBPP for 18-19 hours. Incorporation of
radiothymidine into DNA.
Results: TDCPP was not genotoxic at 0.05 mM, but at 0.1 mM, a moderate response was
observed in hepatocytes from untreated rats, but not phenobarbital-treated rats. TBPP, the
positive control, yielded positive results in induced and non-induced hepatocytes.
Reference: Soederlund et al., 1985
Additional Information
A confidential study reported negative results for TDCPP and its metabolites (not identified) in
cultured primary hepatocytes from male Sprague-Dawley rats.
3-27
-------
Ecotoxicity
Aquatic Organism Toxicity
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline 850.1075;
OECD Guideline 203)
Conclusion:
The available acute toxicity data for freshwater fish (cold- and warm-water species) and
saltwater fish were judged inadequate to meet the endpoint. The available acute fish toxicity
studies are summarized in Table 3-1. However, if the results of the SafePharm study (1993a),
cited by IPCS (1998) (see below), are confirmed independently, the acute toxicity data for cold
freshwater fish species might meet the endpoint given the high degree of agreement of the two
available studies in rainbow trout.
Basis for Conclusion:
Freshwater Fish
Ahrens et al. (1979) tested the toxicity to goldfish (Carassius auratus) of tris (l,3-dichloro-2-
propyl) phosphate (TDCPP) released from fabric treated with the flame retardant. Laundered or
unlaundered sections of garment that had been treated with Fyrol FR-2, were placed in tanks
with six goldfish. Fish in the tank with the unlaundered section became sluggish and all died
within 3 hours. The concentration of Fyrol FR-2 in the test water reached 30 mg/L. Fish
exposed for 96 hours to the laundered section of garment did not exhibit signs of toxicity. In
another study, TDCPP in water at 1 mg/L was not toxic to goldfish after 168 hours, but 5 mg/L
of TDCPP killed all (6/6) goldfish within 24 hours (Eldefrawi et al., 1977). The studies by
Ahrens et al. (1979) and Eldefrawi et al. (1977) did not evaluate toxicity using a range of
concentrations of TDCPP in water and, thus, cannot be used to derive an LC50.
Sasaki et al. (1981) estimated that the 96-hour LC50 values for killifish (Oryzias latipes) and
goldfish were 3.6 mg/L and 5.1 mg/L, respectively. It appears that mortality was not evaluated
in a control group offish. It is unclear if the TDCPP concentrations in water reported by Sasaki
et al. (1981) are measured or nominal values. The latter point is important because a parallel
study indicated that the amount of TDCPP added to test water declines rapidly and less than 40%
of the original amount of TDCPP remains in the test water after 96 hours (Sasaki et al., 1981).
Thus, the lethal concentrations of TDCPP could be lower than the reported LC50 values.
Sasaki et al. (1981) reported deformation of the spine in 7/10 killifish exposed to 3.5 mg/L
TDCPP for 24 hours. However, Sasaki et al. (1981) do not provide sufficient information
regarding the spine deformation in killifish to make meaningful use of these observations. It is
unclear whether the deformations were observed in the acute toxicity study or in a separate assay
using killifish only. It appears that deformation was tested at only one concentration and a
control group offish was not evaluated.
3-28
-------
Another study showed that the 96-hour LC50 of TDCPP in rainbow trout (currently classified as
Oncorhynchus mykiss) was 1.4 mg/L (95% CI: 0.9-1.9 mg/L) (Unpublished study conducted in
1990, summarized in Akzo-Nobel, Inc., 2001a,b). ANOEC was not observed since one fish
died at 0.63 mg/L, the lowest concentration tested. Compound purity was not provided in the
summary and the reported concentrations of TDCPP in the test water appear to be nominal
values. The guideline for acute toxicity in fish (OPPTS 850.1075) indicates that test
concentrations must be measured during the test if, as was the case in this study, aeration is used.
Thus, the study reported by Akzo-Nobel, Inc. (2001a,b) does not meet the criteria established by
the guideline. The studies by Sasaki et al. (1981) and Akzo-Nobel, Inc. (2001a,b) suggest that
the 96-hour LC50 for TDCPP in fish is in the range of 1 to 5 mg/L, making it moderately toxic to
fish. However, the data are inadequate to satisfy the acute toxicity endpoint for freshwater fish.
A 96-hour LC50 of 1.1 mg/L and a NOEC of 0.56 mg/L for TDCPP in rainbow trout
(SafePharm, 1993a) were reported in IPCS (1998). Although the results of the study by
SafePharm (1993a) are in agreement with those of Akzo-Nobel, Inc. (2001a,b), the study by
SafePharm (1993a), or a study summary, was not available to allow for an independent
evaluation of these data. Confirmation of the results of the study by SafePharm (1993a) might
allow the acute toxicity endpoint for freshwater fish to be satisfied.
Marine Fish
No acute toxicity studies in saltwater fish species were located.
3-29
-------
Table 3-1. Summary of available acute fish toxicity studies for tris(l,3-dichloro-2-propyl)phosphate [TDCPP] (CASRN: 13674-87-8)"
Study
Reference
Ahrens et
al., 1979
Species
Tested
Goldfish
(Carassius
auratus)
96-Hour
T C
Aj*-'50
None
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
None
No. of
Fish/
Cone
6
Analytical
Monitoring
Yes. The
concentration
ofFyrolFR-2
in water was
determined
by gas
chromatograp
by.
Water Chemistry
pH:NR
Temp: 20°C
DO:NR
Hardness: NR
Water volume: 20 L
Electrical
conductivity: 290
micromhos/cm
Solvent
None
Comments on the Data
A laundered or
unlaundered 38 cm x 64
cm section of garment
(0.24 square meter area;
227 g/m3), which had been
treated with Fyrol FR-2,
was placed in tanks with
six goldfish.
Fish in the tank became
progressively more
sluggish and all died within
3 hours. The measured
concentration of Fyrol FR-
2 in the test water was 30
mg/L.
Fish exposed for 96 hours
to the same section of
fabric after it had been
laundered did not die.
Data for mortality in
control fish were not
presented in the study.
Goldfish are not a
designated test species, as
per OPPTS 850. 1075 (Fish
Acute Toxicity Test,
Freshwater and Marine).
The study cannot be used
J-J
-------
Table 3-1. Summary of available acute fish toxicity studies for tris(l,3-dichloro-2-propyl)phosphate [TDCPP] (CASRN: 13674-87-8)"
Study
Reference
Akzo-
Nobel,
Inc.,
2001a,b
(Study
conducted
in 1990)
Species
Tested
Rainbow
trout
(Salmo
gairdneri)
96-Hour
T C
Aj*-'50
1.4mg/L
(95% CI:
0.9-1.9
mg/L)
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
Controls, 0.63,
1.25,2.5,5,10
mg/L
No. of
Fish/
Cone
10
Analytical
Monitoring
No
Water Chemistry
pH: 7.14-7.78
Temp: 11. 8-14.8 °C.
DO: 92- 100% of air
saturation value
Hardness: 218-228
mg/L as CaCO3
Solvent
None reported
Comments on the Data
All mortalities occurred
within the first 24 hours.
Mortality was dose related.
One fish died in the lowest
dose group (0.63 mg/L).
All fish died in the 5 and
10 mg/L groups.
A NOEC was not observed.
-------
Table 3-1. Summary of available acute fish toxicity studies for tris(l,3-dichloro-2-propyl)phosphate [TDCPP] (CASRN: 13674-87-8)"
Study
Reference
Eldefrawi
etal, 1977
Species
Tested
Goldfish
(Carassius
auratus)
96-Hour
None
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
1 and 5 mg/L in
water
No. of
Fish/
Cone
6
Analytical
Monitoring
None
reported
Water Chemistry
pH:NR
Temp: 20°C
DO:NR
Hardness: NR
Electrical
conductivity: 290
micromhos/cm
Solvent
Water or
acetone
Comments on the Data
Fish were exposed to 1 or 5
mg/L TDCPP in water or
acetone. None of the fish
in the 1 mg/L treatment
had died after 168 hours.
All fish in the 5 mg/L
treatment died within 24
hours.
The most conspicuous
signs of toxicity were
sluggishness and
disoriented swimming prior
to death.
Mortality in control fish
was not reported.
Goldfish are not a
designated test species, as
per OPPTS 850.1075 (Fish
Acute Toxicity Test,
Freshwater and Marine).
The study cannot be used
to establish an LC50 value.
-------
Table 3-1. Summary of available acute fish toxicity studies for tris(l,3-dichloro-2-propyl)phosphate [TDCPP] (CASRN: 13674-87-8)"
Study
Reference
Sasaki et
al., 1981
Species
Tested
Killifish
(Oryzias
latipes)
Goldfish
(Carassius
auratus)
96-Hour
T C
Aj*-'50
Killifish:
3.6mg/L
Goldfish:
5.1 mg/L
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
NR
No. of
Fish/
Cone
7 to 9
Analytical
Monitoring
Unclear if
conducted
Water Chemistry
pH:NR
Temp: 25°C.
DO:NR
Hardness: NR
Electrical
conductivity: NR
Solvent
NR
Comments on the Data
Fish were acclimated at
least for 10 days at 25 °C
The test concentrations
used were not reported. A
control group was not
tested.
Killifish, but not goldfish,
are a designated test
species, as per OPPTS
850. 1075 (Fish Acute
Toxicity Test, Freshwater
and Marine).
Deformation of the spine
was observed in 7/10
killifish exposed to 3.5
mg/L TDCPP for 24 hours.
"Studies that were either published in a foreign language or that were not readily and that were not critical to the hazard assessment were not retrieved.
bNR: Not reported
-------
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD 202)
Conclusion:
The available acute toxicity data for freshwater invertebrates were judged inadequate to meet the
endpoint. However, if the results of the study cited by IPCS (1998) (see below) are confirmed
independently, the data might meet the endpoint given the high degree of agreement of the two
available studies in freshwater invertebrates.
Basis for Conclusion:
The available data are summarized in Table 3-2. A flow-through study revealed a 48-hour LC50
of TDCPP with Daphnia magna of 3.8 mg/L (95% CI: 3.5-4.2 mg/L) and a NOEC of 1.6 mg/L
(Unpublished study conducted in 1999, summarized in Akzo-Nobel, Inc., 2001a,b). Although
some of the conditions of the study design (such as number of organisms, and water temperature
and chemistry) appear to meet OPPTS Harmonized Guideline 850.1010, other aspects of the
study, including compound purity and condition and fertility of the organisms in culture, were
not reported in the summary. The amount of solvent used in the control group and the TDCPP
treatments might have exceeded the recommended maximum solvent concentration, as per the
OPPTS Guideline (100 mg/L), but this does not appear to have affected the study results. A 48-
hour LC50 of 4.6 mg/L and a NOEC of 1.8 mg/L were reported for daphnia in a study by
SafePharm (1993b), as cited in IPCS (1998). Although the results of the study by SafePharm
(1993b) are in agreement with those of Akzo-Nobel, Inc. (2001a,b), the study by SafePharm
(1993b), or a study summary, was not available to allow for an independent evaluation of these
data. Confirmation of the results of the study by SafePharm (1993b) might allow the acute
freshwater invertebrate toxicity endpoint to be satisfied.
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Conclusion:
No available acute marine/estuarine invertebrate toxicity data.
Basis for Conclusion:
No acute toxicity studies in marine/estuarine invertebrate species were located.
3-34
-------
Table 3-2. Summary of available acute invertebrate toxicity studies for tris(l,3-dichloro-2-propyl)phosphate [TDCPP] (CASRN: 13674-87-8)"
Study
Reference
Akzo-
Nobel, Inc.,
2001a,b
(Study
conducted in
1999)
Species
Tested
Daphnia
magna
48-Hour
LC50
3.8
mg/L
(95%
CI: 3.5-
4.2
mg/L)
Selected Study Design Parameters
Study
Type
Flow-
through
Concentrations
Tested
Negative control,
solvent control
(dimethyl-
formamide),0.98,
1.6,2.8,3.8,5.1
mg/L
No. of
Organisms/
Concentration
10
Analytical
Monitoring
Yes
Water
Chemistry
pH: 8.3
Temp:
20±2°C
DO: >8 5
mg/L (94%
of air
saturation
value)
Hardness:
126 mg/L as
CaCO3.
Solvent
Dimethyl-
formamide
Comments on the Data
Daphnids in the negative and
solvent control groups appeared
normal, as did the organisms in
the 0.98 and 1.6 mg/L groups.
Mortality in the 2.8, 3.8, and 5. 1
mg/L groups was 0, 70, and
80%, respectively. Daphnids
(15%) in the 2.8 mg/L group
were lethargic at study
termination.
The amount of solvent used in
the control group and the
TDCPP treatments is estimated
to be approximately 300 mg/L.
This exceeds the recommended
maximum solvent concentration
of 100 mg/L. The estimate is
based on a reported
dimethylformamide volume of
0.1 ml, a test chamber volume
of 300 ml and a specific gravity
ofO.95.
aStudies that were either published in a foreign language or that were not readily and that were not critical to the hazard assessment were not retrieved.
-------
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Conclusion:
No available chronic toxicity data for freshwater and marine fish.
Basis for Conclusion:
No chronic toxicity studies in freshwater and marine fish were located.
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1300;
OECD 211) and Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized
Guideline 850.1350)
Conclusion:
No available chronic toxicity data for freshwater and marine/estuarine invertebrates.
Basis for Conclusion:
No chronic toxicity studies in freshwater and marine/estuarine invertebrates were located.
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Conclusion:
The available algal toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are summarized in Table 3-3. The summary of a 96-hour algal toxicity study
(Unpublished study conducted in 1992, summarized in Akzo-Nobel, Inc., 2001a,b) indicates that
the study does not meet the OPPTS Harmonized Guideline 850.5400. The pH and temperature
of the test water during the study were outside of the acceptable ranges for Selenastrum
capricornutum, as per Guideline 850.5400. Moreover, the two highest concentrations tested
exceed the estimated water solubility of TDCPP (42 mg/L) and the concentrations tested were
apparently not verified analytically. Additional information, including test substance purity,
hardness, DO, TOC, TSS, exposure vessel size and head space, and measured chemical
concentrations, were not provided in the summary. Also, there is no evidence that positive
controls were used in order to establish that the algae were responding in the expected manner to
a known chemical. The deviations from the OPPTS Guideline indicate that the study is
inadequate to satisfy the algal toxicity endpoint. Another study indicates that TDCPP at 10 mg/L
had no effect on growth or biomass of the algal species Scenedesmus subspicatus exposed for 72
3-36
-------
hours (Unpublished study conducted by SafePharm, 1994, cited in IPCS, 1998). The study, or a
study summary, was not available for the study by SafePharm (1994) to allow for an independent
evaluation of these data.
3-37
-------
Table 3-3. Summary of available algal toxicity studies for tris(l,3-dichloro-2-propyl)phosphate [TDCPP] (CASRN: 13674-87-8)a
Study
Reference
Akzo-
Nobel, Inc.,
2001a,b
(Study
conducted in
1992)
Species
Tested
Selenastrum
capricornutum
EC50, NOAEC,
and LOAEC
96-hour EbC50
(biomass)
= 12 mg/L (95%
CI: 10-15 mg/L).
96-hour ErC50
(growth rate) = 39
mg/L (95% CI:
3 1-50 mg/L).
96-hour NOAEC:
6 mg/L.
Selected Study Design Parametersb
Study
Type
Static
Concentration
Range Tested
0 (negative
control), 2, 6, 18,
54, or 162 mg/L
Analytical
Monitoring
No
Water
Chemistry
Temp: 21°C
pH: 6.7-7.9
DO:NR
Hardness: NR
Solvent
None
reported
Comments on the
Data
A number of problems
are evident with this
study, namely the pH
changed markedly
during the study, and the
reported pH and water
temperature were outside
of the recommended
values for this algal
species.
"Studies that were either published in a foreign language or that were not readily and that were not critical to the hazard assessment were not retrieved.
b NR: Not reported.
-------
Terrestrial Organism Toxicity
Acute Oral (OPPTS Harmonized Guideline 850.2100), Dietary (OPPTS Harmonized
Guideline 850.2200; OECD Guideline 205), or Reproductive Toxicity (OPPTS Harmonized
Guideline 850.2300; OECD Guideline 206) in Birds
Conclusion:
No available acute oral, dietary, and reproductive toxicity data.
Basis for Conclusion:
No acute oral, dietary, or reproductive toxicity studies in birds were located.
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
Conclusion:
The available earthworm subchronic toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No earthworm subchronic toxicity studies were located. An acute (14-hour) LC50 of 130 mg/kg
soil and aNOEC of 100 mg/kg soil with the earthworm, Eisenia fetida (SafePharm, 1996), were
reported in IPCS 1998. However, the study has also been reported to be a 14-day subchronic
toxicity study (NICNAS, 2001). The study, or a study summary, was not available for an
independent evaluation of the study and the results.
3-39
-------
Physical/Chemical Properties
Tris(l,3-dichloro-2-propyl) phosphate
CAS 13674-87-8
MF C9H15C16O4P
MW 430.91
SMILES C1CC(CC1)OP(=O)(OC(CC1)CC1)OC(CC1)CC1
Physical/Chemical Properties
Water Solubility:
Conclusion: The available water solubility data are adequate.
Basis for Conclusion: The key study (highlighted) was performed according to a reliable
method, and is in reasonable agreement with other values reported in the literature.
Solubility (mg/L)
42
7
100
110
18.1
References
Akzo Nobel, 2001a,b: Water Solubility determination according to OECD Guideline
105 (shake-flask method)
Aston et al., 1996 (24°C); Hollifield, 1979; SRC, 2004 (PHYSPROP Database, 24°C);
HSDB, 2003 (24°C)
Eldefrawi et al., 1977; WHO, 1998 (30°C); Budavari, 2001 (The Merck Index); Lewis,
2000 (Sax's Dangerous Properties of Industrial Materials)
CERI, 1999
Confidential submitted study using shake flask method
Log K^:
Conclusion: The available log Kow data are adequate.
Basis for Conclusion: The key study (highlighted) was performed according to a reliable
method.
LogK,,w
2.4
3.8
3.65
3.75
3.69
Reference
Akzo Nobel, 2001a,b: Determination of Octanol- Water Partition Coefficient
According to OECD Guideline 1 17 (HPLC Method)
WHO, 1998
SRC, 2004 (PHYSPROP Database); HSDB, 2003
Shake-flask method, Sasaki et al., 1981
Confidential submitted study using the HPLC method
3-40
-------
Oxidation/Reduction: No data
Melting Point:
Conclusion: The available melting point data for TDCPP are adequate.
Basis for Conclusion: The key study (highlighted) was performed according to a reliable
method. It is noted that the other literature data do not agree with the key study; however, the
methods used to measure the melting points are not provided in any of the sources. As an
OECD-guideline compliant method, the key study is better described and better supported.
Melting Point (°C)
-58
27
26.66
References
Akzo Nobel, 2001a,b: melting
Guideline 102), freezing point
point determination by DSC (compliant with OECD
was determined to be -40°C, melting point -58°C
CERI, 1999
Akzo Nobel, 2003
Boiling Point:
Conclusion: The boiling point data are adequate.
Basis for Conclusion: A variety of literature sources report the same value for the boiling point,
although there is some indication that the compound may decompose at or near the boiling point.
Since experimental details are not provided in any of the sources, it is not possible to determine
whether the temperatures reported are decomposition or boiling temperatures. Nevertheless,
given the high boiling point reported for this material, the available data are adequate to
characterize its potential volatility.
Boiling Point (°C/torr)
236-237/5
200/4
Dec. >200/4
Gradual Dec. >200
References
SRC, 2004 (PHYSPROP database); Budavari, 2001 (The Merck Index);
Lewis, 2000 (Sax's Dangerous Properties of Industrial Materials);
WHO, 1998
Akzo Nobel, 2003
WHO, 1998
HSDB, 2003
Vapor Pressure:
Conclusion: The available vapor pressure data are not adequate
Basis for Conclusion: Although this measured vapor pressure is reported in two sources, it
appears to be very high relative to the boiling points reported for this chemical. For comparison,
an estimated vapor pressure (EPIWIN) is also included in the table below. The vapor pressure
remains a data need.
3-41
-------
Vapor Pressure (torr/°C)
0.01/30
2.98 xlO'7
Reference
WHO, 1998; Akzo Nobel, 2001a,b
EPIWIN, 2000; v. 3.11 estimate
Odor:
Conclusion: The odor of this compound has been adequately characterized.
Basis for Conclusion: Although no standardized tests are available for characterizing chemical
odors, the two descriptions found are similar, and are consistent with the low volatility expected
for this chemical.
Odor
Mild Odor
Bland Odor
Reference
HSDB, 2003
Akzo Nobel, 2003
Oxidation/Reduction Chemical Incompatibility: No data
Flammability:
Conclusion: The flammability (as the flash point and autoignition temperature) has been
adequately characterized.
Basis for Conclusion: Studies on the flash point and autoingition temperature of this chemical
were located and appear reasonable given the other physical/chemical properties available for
this compound.
Flash Point
252° C (coc)
>107.22°C (Seta closed cup)
Reference
WHO, 1998; HSDB, 2003
Akzo Nobel, 2003
Autoignition Temperature
512.77°C
Reference
Akzo Nobel, 2003
Explosivity: No data
Corrosion Characteristics: No data
3-42
-------
pH:
This chemical does not contain functional groups expected to influence the pH of aqueous
solutions. Data for this endpoint are therefore not applicable.
UV/Visible Adsorption: No data
Viscosity:
Conclusion: The viscosity of this chemical at various temperatures has been adequately
characterized.
Basis for Conclusion: Studies on the viscosity of this chemical were located and appear
reasonable given the other physical/chemical properties available for this compound.
Viscosity (cP)
1,800 at 25°C
2,200 at 0°C
540 at 40°C
Reference
WHO, 1998; Akzo Nobel,
2003
Akzo Nobel, 2003
Akzo Nobel, 2003
Density/Relative Density/Bulk Density:
Conclusion: The density of this compound has been adequately characterized.
Basis for Conclusion: Consistent data are provided in several reputable sources.
Density
1.52at25°C
1.5022 at 20°C
1.48kg/Lat25°C
Reference
Specific gravity. WHO, 1998
Specific gravity. Budavari, 2001 (The Merck Index);
Properties of Industrial Materials)
Lewis, 2000 (Sax's Dangerous
Bulk density. HSDB, 2003
Dissociation Constant in Water:
This compound does not have functional groups that are expected to dissociate in water. This
endpoint is therefore not applicable.
Henry's Law Constant: No data
3-43
-------
Environmental Fate
Bioconcentration
Fish:
Conclusion: The bioconcentration factor has been adequately characterized.
Basis for Conclusion: The two studies cited in the table below provide consistent information
for killifish under both static and flow-through conditions, over a variety of observation times,
and with varying initial concentrations of test substance. The BCF was also measured in
goldfish; the reported BCFs are independent of study length.
Reference
Sasaki et
al., 1981
Sasaki et
al., 1981
Sasaki et
al., 1982
Species
Killifish
Goldfish
Killifish
BCF
113
110
77
5
3
46±5
32±4
31±6
59±16
49±12
Key Design Parameters
Exp.
type
Static
Static
Flow-
through
(all)
Range
(ppb)
1,000
initial
1,000
initial
400
300
40
40
80
Study
length
24 hours
55 hours
96 hours
24 hours
96 hours
3 days
4 days
6 days
30 days
32 days
T(°C)
25
25
25
Comments
Half-life for elimination
of the test compound in
water + fish =31 hours.
Half-life for elimination
of the test compound in
water + fish = 42 hours.
BCF is independent of
concentration; continuous
(flow-through) results
correlate to static results
(Sasaki et al., 1981).
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism:
Conclusion: The metabolism of TDCPP in fish is not adequately characterized in the literature.
Basis for Conclusion: The depuration rate is adequately described in killifish, however, the
metabolite distribution is not addressed.
3-44
-------
Species
Killifish
Killifish
Goldfish
Rate
Elimination half-life, 1.65 hours
Apparent metabolism is much
faster in killifish than in goldfish.
(Quantitative data are not
provided.)
Apparent metabolism is much
slower than in killifish.
(Quantitative data are not
provided.)
Comment
Depuration rate -
elimination of TDCPP
when exposed fish are
moved to clean water.
-10% of applied TDCPP
remains in the water in
the presence of killifish
after 96 hours. Control
(no fish) has no change in
TPP concentration.
-25% of applied TDCPP
remains in the water after
96 hours in presence of
goldfish.
Reference
Sasaki etal, 1982
Sasaki etal., 1981
Sasaki etal., 1981
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion: The biodegradation of TDCPP under aerobic conditions has been adequately
characterized.
Basis for Conclusion: The key study (highlighted) was performed according to a GLP-
compliant OECD guideline test. The other data located in the literature are generally in
agreement with the key study.
Study type/
Method
OECD
Guideline
301B
Modified
Sturm Test
Innoculum
Activated
sludge
Acclim
Degradation
0%byCO2
evolution.
DOC red. not
calculated
due to
solubility
issues.
Time
28 days
Comments
Initial concentrations
2, 10 mg/L. GLP-
compliant.
Also reported:
1) Closed bottle test
(OECD Guideline
30 ID) showed no
inhibition of bacterial
cultures in 10 days.
Reference
Akzo Nobel,
2001a,b; Akzo
Chemicals
Incorporated,
1990
3-45
-------
Study type/
Method
Japanese
MITI test
OECD 302C
River Die-
Away
Innoculum
Activated
sludge
Water from
Oh River
(Osaka,
Japan)
Neya River
(Osaka,
Japan)
Seawater
(Osaka Bay)
Acclim
Degradation
avg. l%by
BOD
0%byO2
uptake
12.5%
18.5%
0%
5.4%
0%
22%
Time
28 days
28 days
7 days
14 days
7 days
14 days
7 days
14 days
Comments
Initial concentrations
100 mg/L (test
substance), 30 mg/L
(sludge).
Initial concentrations
20 mg/L in Oh River
water and 1 mg/L in
Neya River water.
Concentration in
seawater not
reported.
Analysis by
Molybdenum Blue
calorimetric assay for
increase in phosphate
ion.
Reference
CERI, 1999;
HSDB, 2003;
Chemicals
Inspection and
Testing
Institute, 1992
WHO, 1998
WHO, 1998
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis:
Conclusion: The available pyrolysis data are not adequate.
Basis for Conclusion: Although a semi-quantitative description of the pyrolysis products is
given in the Choudry and Hutzinger paper, the list of degradates provided accounts for only 60%
of the total mass expected and doesn't contain any oxygenated or phosphorus-containing
compounds. Therefore, this study does not provide a complete profile of the pyrolysis of
TDCPP.
Pyrolysis Products
Relative mol.% degradates, 0.1 mole TDCPP heated at 250-260°C under
reduced pressure (3 mm Hg), overall yield 60 wt%: trans-1,3-
dichloropropene 26.7%, c/'s-l,3-dichloropropene 36.0%, 1,2,3-
trichloropropane 34.4%, l-chloro-2-propene 2.9%.
Thermal oxidative degradation in air at 370°C: Hydrogen halides,
halogenated C2 and C3 species, acrolein
Reference
Choudhry and Hutzinj
?er, 1982
HSDB, 2003
3-46
-------
Pyrolysis Products
When heated to decomposition, it emits toxic fumes of Cl+ and POX
Reference
Lewis, 2000 (Sax's Dangerous
Properties of Industrial Materials)
Hydrolysis as a Function of pH:
Conclusion: The hydrolysis rate data are adequate. The hydrolysis products are not described.
Basis for Conclusion: The studies cited below were GLP-compliant tests run according to
accepted guidelines.
Tw
>1 year
>1 year
14.7
days
28 days
128
days
pH
4
7
9
9
9
Temp.
50°C
40°C
20°C
Comment
OECD 111; EPA Ser. 835 OPPTS No. 835.2110.
GLP-compliant.
Initial concentration, 10 mg/L. Study length, 5
days. Preliminary study.
OECD 111; EPA Ser. 835 OPPTS No. 835.2110.
GLP-compliant.
Definitive 30-day study.
OECD 111; EPA Ser. 835 OPPTS No. 835.2110.
GLP-compliant.
Definitive 30-day study.
Reference
Akzo Nobel, 200 la,b
Akzo Nobel, 200 la,b
Akzo Nobel, 200 la,b
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
3-47
-------
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Jackson (1990a).
Eldefrawi, AT; Mansour, NA; Brattsten, LB; et al. 1977. Further toxicological studies with
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EPIWIN. 2000. v. 3.11. Downloadable at
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Freudenthal, RI; Henrich, RT. 2000. Chronic toxicity and carcinogenic potential of Tris(l,3-
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Bio/Dynamics, 1980]
3-49
-------
Gold, MD; Blum, A; Ames, BN. 1978. Another flame retardant, tris-(l,3-dichloro-2-propyl)-
phosphate, and its expected metabolites are mutagens. Science. 200: 785-787.
Hazleton (Hazleton Laboratories America, Inc.). 1978. Teratology study in rats. FR-2 (Fyrol).
(Final report). TSCA 8e submission by Stauffer Chemical Corporation (1981) Toxicological
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NRC, 2000 as Stauffer Chem. Co., 1977-1978).
Hollifield, HC. 1979. Rapid nephelometric estimate of water solubility of highly insoluble
organic chemicals of environmental interest. Bull. Environ. Contam. Toxicol. 23: 579-586.
HSDB. 2003. Tris(l,3-dichloro-2-propyl) phosphate. Hazardous Substances Data Bank. The
National Library of Medicine. Available on-line at http://toxnet.nlm.nih.gov/cgi-bin/sis/.
Accessed July 2004.
IPCS. 1998. Environmental Health Criteria, Vol. 209. Flame retardants. Tris(chloropropyl)
phosphate and tris(2-chloroethyl) phosphate. International Programme on Chemical Safety.
Geneva, World Health Organization.
Kamata, E; Naito, K; Nakaji, Y; et al. 1989. Acute and subacute toxicity studies of tris (1,3-
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Lewis, R. 2000. Fyrol FR 2. Sax's dangerous properties of industrial materials. 10th Ed. New
York, NY: John Wiley & Sons, Inc., p732.
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Drosophila.. Report T-6355. TSCA 8e submission by Stauffer Chemical Corp., 1981,
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Litton Bionetics, Inc. 1977. Mutagenicity evaluation of Fyrol FR-2 (Final Report). Reports T-
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3-50
-------
Majeska, JB; Matheson, DW. 1983. Quantitative estimate of mutagenicity of tris-(l,3-dichloro-
2-propyl) phosphate (TCPP) and its possible metabolites in Salmonella. Environ. Mutagen. 5:
478-479.
Mortelmans, K; Haworth, S; Lawlor, T; et al. 1986. Salmonella mutagenicity tests: II. Results
from the testing of 270 chemicals. Environ. Mutagen. 8(Suppl. 7): 1-119.
Nakamura, A; Tateno, N; Kojima, S; et al. 1979. Mutagenicity of halogenated alkanols and
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3-51
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3-53
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Flame Retardant Alternatives
Proprietary A: Chloroalkyl phosphate (1)
Hazard Review
4-1
-------
Proprietary A: Chloroalkyl phosphate (1)
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
/
*
/
/
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
*
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
*
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
/
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
/
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
/
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
/
*
X
Immunotoxicity
Immunotoxicity
*
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
/
/
/
*
/
4-2
-------
Proprietary A: Chloroalkyl phosphate (1)
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
/
/
/
/
*
/
/
X
/
/
/
X
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
/
*
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
*
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic NOAEC,
LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
*
*
*
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
*
-------
Chemical Identity
Proprietary A: Chloroalkyl phosphate (1)
CAS
MF
MW
SMILES
Synonyms
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401).
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
Several acute oral lethality studies were available in a variety of species: rabbits, rats, and mice.
These studies were from the older (pre 1980) literature, did not report substance purity, and do
not fully conform to OPPTS or OECD guidelines, but given the magnitude of the LD50 values
the data are adequate for the evaluation of acute oral toxicity. Acute oral LD50 values generally
exceeded the current limit dose of 2,000 mg/kg. Reports that specified a 14-day observation
period are presented in detail.
Critical Studies:
Type: Acute oral toxicity
Species, strain, sex, number: Rabbit, Dutch-belted, 5 males/group
Doses: 0, 5,000, 7,500, and 10,000 mg/kg
Purity: [Formulation 2]; purity not specifically reported
Vehicle: Not reported
Method: 14-Day post-dosing observation period; observations limited to mortality, clinical
signs, and necropsy. LD50 calculated according to Litchfield and Wilcoxon.
Results: Clinical signs shortly after dosing included ataxia, weakness, and diarrhea; survivors
normal by day 9. Necropsy revealed no abnormalities. Acute oral male rabbit LD50 = 6,800
mg/kg (95% CI 5,615-8,234 mg/kg).
Reference: Robust summary from Ref. 4
Type: Acute oral toxicity
4-4
-------
Species, strain, sex, number: Rat, Sprague-Dawley, 5 males/group
Dose: 1,000, 2,150, 5,640, or 10,000 mg/kg
Purity: [Formulation 2]; purity not specifically reported
Vehicle: None
Observation period: 14 days post dosing
Method: 14-Day post-dosing observation period; observations limited to mortality, clinical
signs, and necropsy; LD50 calculated according to Litchfield and Wilcoxon; not specified
whether fed or fasted at time of dosing.
Results: No effects at 1,000 mg/kg. Dose-related depression at or above 2,160 mg/kg; survivors
normal by day 5. No gross lesions in survivors; fatalities had congestion of heart, lung, and
liver. Acute rat oral LD50 = 3,160 mg/kg (95% CI 2,050-4,800 mg/kg)
Reference: Ref 53; robust summary from Ref. 4
Type: Acute oral toxicity
Species, strain, sex, number: Mouse, Slc/ddY, 10/sex/dose
Purity: Not reported
Doses: For males: 0, 2,210, 2,380, 2,570, 2,780, 3,000, 3,240, and 3,500 mg/kg. For females: 0,
2,890, 2,040, 2,210, 2,380, 2,570, and 2,780 mg/kg.
Vehicle: Olive oil
Method: Observed for mortality and clinical signs for!4 days. No body weight or gross
necropsy examination.
Results: Treated animals exhibited ataxic gait, hyperactivity, convulsion and death. No
mortality was observed in controls or in males at 2,210 mg/kg or females at 1,890 mg/kg. The
LD50 values were 2,670 mg/kg (2,520-2,830 mg/kg) for male mice and 2,250 (2,120-2,380
mg/kg) for female mice.
Reference: Ref. 30
Additional Studies and Information:
Other studies available only in secondary sources reported similar results. An oral LD50 of
>2,000 mg/kg was reported in male and female rats exposed to [Formulation 3] (Ref. 18 as
reported in Ref. 61); clinical signs observed during the first 5 days after dosing included
hypokinesia, piloerection, soiled coats, ataxia, chromodacryorrhea, rhinorrhea, and salivation.
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged adequate to meet the endpoint.
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Basis for Conclusion:
The available studies predate the preferred study guidelines, and did not report purity, but
together indicated no mortality at the guideline limit dose of 2,000 mg/kg. The report specifying
a 14-day observation period is presented in more detail.
Type: Acute dermal toxicity
Species, strain, sex, number: Rabbit, New Zealand albino, sex not specified, 4
Dose: 4,640 mg/kg
Purity: [Formulation 2], no data
Vehicle: None
Exposure period: 24 Hour
Method: 4 Rabbits tested occluded; 14-day observation period. Gross necropsy.
Results: Mortality after 14 days = 0/4. No overt signs of toxicity and no gross necropsy
findings. Therefore, dermal acute LD50 >4,640 mg/kg.
Reference: Ref. 54; additional information from robust summary in Ref. 4
Additional Studies and Information:
Other studies available only in secondary sources with minimal detail. A dermal LD50 of
>2,000 mg/kg was reported in male and female Sprague-Dawley rats exposed to [Formulation 3]
(Ref. 19 as reported in Ref. 61). No deaths and no clinical signs were noted 24 hours after
treatment.
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300; OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available study on Proprietary A predates the preferred guidelines. The duration was shorter
than currently recommended and no deaths were observed. Analysis of aerosol particle size,
however, was not mentioned so it is not known whether the size was respirable. Necropsies
were not performed.
Type: Acute inhalation toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 5 males and 5 females
Doses: 9.8 mg/L (9,800 mg/m3)
Purity: No data
Vehicle: None
Duration: 1 hour
Method: Observation period = 14 days. Observed daily for signs of toxicity and for mortality.
4-6
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Results: No mortality after 14 days; initial signs of moderate depression
Reference: Ref 55
Additional Studies and Information:
Other studies available only in secondary sources reported similar results. An acute inhalation
LC50 of >5,220 mg/m3 was reported for Sprague-Dawley rats exposed to aerosol of Proprietary
A [Formulation 1] (Ref. 7 as reported in Ref. 61).
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available eye irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Two reasonably adequate studies report similar results in rabbits: mild reversible irritation of the
conjunctiva. The studies are summarized below.
Type: Acute eye irritation
Species, strain, sex, number: Rabbit, New Zealand White, sex not specified; 6
Doses: 0.1 mL
Purity: No data, [Formulation 2]
Vehicle: None
Method: Cited CFR [U.S. Federal Hazardous Substances Labelling Act] Section 191.12,
chapter 1, title 21. Following instillation of Proprietary A, eyes were examined at 24, 48, and 72
hours.
Results: Mild conjunctival effects in 3/6 that cleared by 48 hours.
Reference: Ref. 52
Type: Acute (24-hour) eye irritation
Species, strain, sex, number: Rabbit, New Zealand White, male and female; 9 total
Doses: 0.1 mL
Purity: No data
Vehicle: None
Method: U.S. EPA Hazard Evaluation. 1978. Fed. Reg. 43: 163: pp. 37331-37402. Thirty
seconds following instillation of Proprietary A, the treated eyes of three rabbits were washed,
treated eyes were not washed in 6 rabbits. The untreated eye of each animal served as a control.
The cornea, iris and conjunctiva of each eye were examined at 24, 48, and 72 hours, and at 4 and
7 days after instillation of Proprietary A using the Draize scoring method.
Results: No signs of eye irritation were observed (average total Draize score of zero).
Reference: Ref. 57; robust summary from Ref. 4
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Additional Studies and Information:
One hour following application of [Formulation 3] to the eyes of New Zealand White rabbits,
slight conjunctival redness and slight discharge were noted (Ref. 21 as reported in Ref 61);
effects cleared by 24 hours.
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available dermal irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Two reasonably adequate studies, patterned after guidelines in effect at the time, provide similar
results, indicating that Proprietary A was a non-irritant when applied for 4 hours (consistent with
current guidelines) and a mild irritant when applied for 24 hours to rabbit skin. Additional
studies provide support. The studies are summarized below.
Critical Studies:
Type: Acute (24-hour) dermal irritation
Species, strain, sex, number: Rabbit, New Zealand, sex not specified, 6
Doses: 0.5 mL
Purity: Not reported; [Formulation 2]
Vehicle: None
Method: Cites "EPA protocol". Back hair was shaved, each rabbit tested on intact and abraded
skin, occlusive dressing removed after 24 hours, observations at 24 and 72 hours.
Results: No edema on intact or abraded skin in any of the 6 rabbits. Mild erythema was visible
at 24 hours but cleared by 72 hours, resulting in a score of 0.63. The report classified
Proprietary A as a mild irritant.
Reference: Ref. 57
Type: Acute (4-hour) dermal irritation
Species, strain, sex, number: Rabbit, not specified (but New Zealand white rabbits were used in
an eye irritation test conducted at the same time)
Doses: 0.5 mL
Purity: Not reported; [Formulation 2]
Vehicle: None
Method: Back hair shaved, each rabbit tested on intact and abraded skin, occlusive dressing
removed after 4 hours, observations at 4, 24 and 48 hours.
Results: No erythema or edema on intact or abraded skin in any of the 6 rabbits.
Reference: Ref. 52
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Additional Studies:
Another study, on [Formulation 3], reported well-defined (score 2) erythema in 2 New Zealand
White rabbits and slight erythema in a third rabbit 1 hour after patch removal, but duration of
exposure was not specified (Ref 20 as reported in Ref. 61). Effects cleared by 48 hours. The
substance was classified as a skin irritant.
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The available skin sensitization data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential negative study of skin sensitization in guinea pigs was submitted that meets the
requirements for the endpoint.
A robust summary was located for an unpublished industrial study stated to have been conducted
under guideline. The summary omits information necessary to determine study adequacy, such
as: the strain, sex, group size, substance purity, and dose levels. The summary claimed that the
doses were selected according to guideline, but the exact levels are not stipulated in the
guideline. Without the additional information, the study cannot be evaluated for adequacy.
Critical Studies:
Type: Dermal sensitization study
Species, strain, sex, number: Guinea pig, strain and sex not reported
Doses: Stated as according to guideline, but exact doses are not stipulated in guideline.
Purity: Not reported; [Formulation 2]
Vehicle: Water
Method: Three pairs of intradermal injections into shaved shoulder: 1:1 Freunds Complete
Adjuvent (FCA) and saline, the test material, and 1:1 FCA and test material. Controls received
water in place of the test material. On day 6, 24 hours before topical induction application,
sodium lauryl sulfate was applied to sites to enhance local irritation. On day 7, test substance
was applied to sites (water for controls). On day 21, animals received challenge dose by dermal
application, occluded for 24 hours. Sites observed for irritation and sensitization (Grade 0-4).
Results: The sensitization score for [Formulation 2] was zero, indicating the substance is not a
chemical sensitizer.
Reference: Robust summary in Ref. 5
SUBCHRONIC TOXICITY
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
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Conclusion:
The available subchronic oral toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A Japanese 90-day dietary study in mice (Ref. 30) provides limited relevant information in the
English abstract and data tables. The study was not adequate to characterize this endpoint
because histopathological analysis was apparently limited to the liver. A fertility study by Ref.
62, discussed under the Reproductive Toxicity endpoint, evaluated male rabbits exposed by oral
gavage for 12 weeks, but did not involve treated females.
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
No study of this type was located.
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
Type: 90-Day repeated oral
Species, strain, sex, number: Mouse, Slc/ddY, 12/sex/dose
Doses: Proprietary A at dietary concentrations of 0, 0.01, 0.04, 0.13, 0.42, and 1.33% in the diet,
resulting in reported average daily doses of 0, 13.2, 47.3, 171.0, 576.0, and 1,792.3 mg/kg/day in
males and 0, 15.3, 62.5, 213.6, 598.0, and 1,973.1 mg/kg/day in female mice
Purity: Not reported
Vehicle: None; added to diet
Exposure period, frequency: 90 days, ad lib
Method: Body weight, food consumption measured weekly. At 1 and 3 months in half the
animals, hematologic (erythrocyte, hemoglobin, hematocrit, and leukocyte counts) and clinical
chemistry parameters (total protein, albumin, albumin/globulin ratio, blood urea nitrogen,
glucose, total cholesterol, alkaline phosphatase, aspartate aminotransferase, alanine
aminotransferase). At 1 and 3 months, half the animals were necropsied and absolute and
relative organ weights were determined for brain, heart, lung, liver, kidney, and spleen. The
liver was examined for microscopic histopathology; the English text does not mention whether
other tissues were examined.
Results: At the highest dietary level, 1.33%, all mice exhibited emaciation, rough hair, and
tremor and died within 1 month. At 1.33%, food consumption was reduced and body weight loss
occurred in both sexes. Mean body weight gain was reduced by about 10% (estimated from
graph) in males at 0.42% throughout the study. The following statistically significant changes
occurred in treated groups compared to controls. Slight anemia (reduced hemoglobin; p<0.05) in
males at 0.42% after 3 months. Anemia (reduced hemoglobin at >0.13% after 1 month and at
0.42% at 3 months, erythrocyte and hematocrit at 0.42% at 1 and 3 months) in females (3-month
values p<0.01). Albumin/globulin ratios elevated in all treated male groups at 3 months.
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Alkaline phosphatase elevated in females at 0.42% at 1 month but not later. Dose-related organ
weight elevations compared to controls observed at 3 months in males included relative liver
weight (+32-51%) at >0.13% and relative kidney weight (+39%) at 0.42%. Significant
elevations in organ weights in females at 3 months included relative liver weight (+16-51%) at
>0.04%, absolute (+30%) and relative (+34-40%) kidney weights at >0.13%, and absolute liver
weight (+40%) at 0.42%. The statistical significance of these organ weight elevations was
p<0.01 for rats exposed at >0.13% and p<0.05 for rats exposed at 0.04.%. Histopathology of the
liver (slight focal necrosis) was observed in only two females at 0.42%. The dietary level of
0.01% is aNOAEL of 15.3 mg/kg/day and the dietary level of 0.04% is a LOAEL of 62.5
mg/kg/day for liver and kidney weight elevations in female mice.
Reference: Ref. 30
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
No studies of this type were located.
Subchronic Dermal Toxicity (21/28-day or 90-day)
Conclusion:
No available subchronic dermal toxicity data.
Basis for Conclusion:
No data exist for the subchronic dermal toxicity endpoint.
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD
Guideline 410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
No studies of either type were located.
Subchronic Inhalation Toxicity (90-day)
Conclusion:
No available subchronic inhalation toxicity data.
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Basis for Conclusion:
No repeated-exposure inhalation toxicity studies were located.
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD
Guideline 413)
No studies of this type were located.
REPRODUCTIVE TOXICITY
Conclusion:
The available reproductive toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A fertility assay in male rabbits exposed by oral gavage for 12 weeks prior to mating (Ref 62)
partially characterizes this endpoint, but is not sufficient to satisfy the reproductive toxicity
endpoint since it was described only in an abstract and females were not tested. Other studies
(Ref. 26, 59) described below under Developmental Toxicity reported that in pregnant female
rats exposed orally to Proprietary A, adverse reproductive effects occurred only at maternally
lethal doses. However, no study evaluated reproductive function in females treated prior to
mating.
The 2-year feeding bioassay in rats by Ref. 24 (Ref. 9, 9a), discussed below under Chronic
Toxicity, provides reproductive histopathology data that are, however, insufficient to satisfy the
reproductive toxicity endpoint. This study provided histopathology results for the testis,
epididymis, seminal vesicle, ovary, and uterus for the control and high-dose groups (0 and 80
mg/kg/day) after 1 year (10 scheduled sacrifices/sex/group) and for survivors in all groups after
2 years; unscheduled sacrifices (rats killed in a moribund state) were also examined. The 2-year
exposure is too long to represent reproductive toxicity, because of the confounding effects of
aging; the results pointed to dose-related effects in male reproductive organs (at >5 mg/kg/day,
atrophy and decreased secretory product of the seminal vesicles; at >20 mg/kg/day, testicular
germinal atrophy with oligospermia, and at 80 mg/kg/day, atrophy and decreased secretory
product of the seminal vesicles and oligospermia and luminal accumulation of degenerated
seminal products in the epididymis). No significant effect was observed in females. The tested
doses, which were considerably lower than the guideline limit dose of 1,000 mg/kg/day, were not
high enough to induce significant reproductive histopathology after one year of exposure; 1/10
high-dose males had oligospermia. Thus, a LOAEL for reproductive effects following
subchronic (90-day) exposure is not available and cannot be extrapolated from the existing data,
but the chronic data indicate a LOAEL of 5 mg/kg/day for atrophy and decreased secretory
product of the seminal vesicles.
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Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
No studies were available that met the specific designs of the three protocols listed above.
Additional Studies:
A study described in an abstract by Ref 62 addresses fertility in male rabbits exposed by oral
gavage for 12 weeks prior to mating.
Type: Fertility
Species, strain, sex, number: Rabbit, strain not specified, 10 males/dose
Purity: Not reported
Doses: 0, 2, 20, or 200 mg/kg/day
Vehicle: Not reported
Exposure duration, frequency: 12 weeks, once by oral gavage daily
Method: Males treated for 12 weeks, then mated with untreated females. Body weight, clinical
signs, clinical chemistry, hematology, mating behavior, male fertility, sperm quantity and
quality, kidney and liver weights, gross and microscopic pathology (range of organs examined
not specified).
Results: High-dose animals had significantly increased absolute kidney weight and relative liver
weight. Proprietary A had no effect on male reproductive parameters; there was no
histopathology in kidneys, liver, pituitaries, testes, or epididymides.
Reference: Ref. 62
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Developmental toxicity studies in two strains of rats exposed to [Formulation 2] by oral gavage
followed methods consistent with OECD Guideline 414 (one study pre-dated the guideline).
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Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700; OECD
Guideline 414)
Type: Prenatal developmental toxicity
Species, strain, sex, number: Rat, Wistar, 15 pregnant females at the highest dose, 23-24
pregnant females in controls and other dose groups.
Purity: not reported
Doses: 0, 25, 50, 100, 200, and 400 mg/kg/day
Vehicle: Olive oil
Exposure duration, frequency: Once by oral gavage daily on gestational days (GD) 7-19.
Method: Body weight, food consumption, clinical signs, pregnancy rates, and necropsy of dams,
kidney weight; uterine contents (including implants and resorption) at day 20 of gestation,
corpora lutea; fetal viability, sex ratio and weight, crown-rump length, and external and skeletal
abnormalities.
Seven dams from each of the control and <200 mg/kg/day groups were permitted to litter
normally and evaluated for implantation sites, delivery index, number of live offspring at birth
and survival on PND 4, at 4th week, and at 10th week. Litters were culled to 10 offspring on
postnatal day 4 (PND 4) and subjected to behavioral tests (open field, water maze, rota rod,
inclined screen, pain reflex and Preyer's reflex). Absolute organ weights of 10 organs plus
testis, uterus and ovary were measured in offspring.
Results: Maternal mortality occurred only at 400 mg/kg/day: 11/15 died. Food consumption
was suppressed at 400 mg/kg/day and slightly at 200 mg/kg/day. At 400 mg/kg/day, mean body
weight loss occurred during GD 7-15, resulting in significantly (p<0.05) reduced terminal body
weight on GD20: -17% lower than control group. Absolute and relative kidney weights were
significantly increased at 200 and 400 mg/kg/day. Proprietary A at <200 mg/kg/day had no
effect on corpora lutea or mean numbers of implants, fetal body weight, fetal sex ratio, or the
number of dead or live fetuses. The numbers of dead fetuses and live fetuses were significantly
(p<0.01) changed compared to controls by the loss of one whole litter at 400 mg/kg/day. No
increase in malformations was observed in treated groups. For maternal toxicity, the NOAEL
was 100 mg/kg/day and the LOAEL was 200 mg/kg/day for increased kidney weight. For fetal
toxicity, the NOAEL was 200 mg/kg/day and the LOAEL was 400 mg/kg/day for increased fetal
death; the highest dose of 400 mg/kg/day was a NOAEL for teratogenicity.
Postnatal observations: Proprietary A at <200 mg/kg/day had no effect on implantation,
delivery, postnatal survival, behavior, functional test results, or absolute organ weights of
offspring.
Reference: Ref 59
Type: Prenatal developmental toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 20 pregnant females/dose
Purity: not reported
Doses: 0, 25, 100, and 400 mg/kg/day
Vehicle: Corn oil
Exposure duration, frequency: Once by oral gavage daily on gestational days 6-15
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Method: Body weight, food consumption, clinical signs, pregnancy rates, and necropsy of dams;
uterine contents (including implants and resorption) at day 19 of gestation, corpora lutea; fetal
viability and weight, crown-rump length, external, visceral (1/3 fetuses), and skeletal
abnormalities; extensive statistical analyses.
Results: High-dose dams exhibited clinical signs (urine stains, hunched appearance, and
alopecia); sporadic signs of urine stains and hunched appearance occurred in a few mid-dose
dams, but not at the low-dose. Food consumption was statistically lower in mid-dose dams on
days 7-11 and in high-dose group throughout (days 7-15). During Days 6-11, significant
(p<0.05) reductions in body weight gain in mid-dose dams and mean body weight loss at the
high dose; on days 11-15, only high-dose dams showed reduced body weight gain. Overall body
weights reduced in high-dose dams. Proprietary A had no effect on implantation efficiency or
mean number of corpora lutea. Treatment at the high dose significantly (p<0.05) increased the
number of resorptions (to 14.4% compared to 6.7% in controls) and reduced fetal viability (to
85.6% compared to 93.3% for controls). Decreased skeletal development in the high-dose
groups is related to growth retardation and decreased fetal size. The incidence of malformations
was not related to treatment. The study indicates a NOAEL of 25 mg/kg/day and a LOAEL of
100 mg/kg/day for maternal toxicity (clinical signs and transient reduction in body weight gain)
and a NOAEL of 100 mg/kg/day and a LOAEL of 400 mg/kg/day for developmental toxicity
(increased resorptions and fetal mortality).
Reference: Ref 26
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
No studies with the specific designs of the two tests listed above were available.
CHRONIC TOXICITY
Conclusion:
The available chronic toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The combined chronic toxicity/carcinogenicity assay in dietarily exposed rats is consistent with
the guideline (Ref. 9, 24).
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
No studies of this type were located.
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Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
The protocol of a 2-year feeding bioassay in rats was consistent with this guideline (Ref. 9, 24).
The published article focused on tumor results rather than non-neoplastic effects.
Type: Combined oral chronic toxicity and carcinogenicity assay
Species, strain, sex, number: Rat, Sprague-Dawley, 60/sex/group
Purity: 95%
Doses: 0, 5, 20, and 80 mg/kg body weight/day
Vehicle: None other than feed
Route: In feed; diets blended weekly to achieve target doses
Exposure duration, frequency: 2 years, ad lib
Method: Examined twice daily for mortality and clinical signs, weekly physical examination.
Body weights and food consumption weekly for the first 13 weeks and biweekly thereafter.
Ophthalmoscopic examinations every 6 months. Extensive hematology, clinical chemistry and
urinalysis parameters at 3, 6, 12, 18, and 24 months. Ten/sex/dose randomly chosen for
termination at 12 months; the remainder at 24 months. Gross necropsy including organ weights
(8 organs plus gonads); histopathology of more than 30 tissues in control and high-dose rats; at
low- and mid-doses, histopathology limited to liver, kidneys, testes, and adrenals. Statistical
analyses.
Results: The following changes compared to controls were statistically significant (p<0.05).
Mortality increased in high-dose males (to 61.7% vs 43.3% for controls). Lower body weights
in high-dose males and females. Treatment had no effect on feed consumption. Signs of anemia
(lower hemoglobin, hematocrit, erythrocyte counts) in high-dose rats. At the mid-dose,
increased absolute and relative kidney weight males and females, absolute liver weight and
relative thyroid weight in males, and relative liver weight in females. At the high dose,
increased relative liver weight in males and absolute and relative thyroid weights in females.
Increases in the incidences of the following nonneoplastic lesions were statistically significant
(p<0.05) in treated groups compared to the control groups; changes were not strictly dose-related
in that incidences were depressed in high-dose groups. Kidney lesions (convoluted tubule
hyperplasia) in males at >20 mg/kg/day and in females at 80 mg/kg/day. Other systemic lesions
at 80 mg/kg/day involved the parathyroid (hyperplasia) in males and the liver (foci) and spleen
(erythroid/myeloid hyperplasia) in females. Reproductive system lesions in males involved
seminal vesicles (atrophy, decreased secretory product) at >5 mg/kg/day, testes (eosinophilic
material in lumen, periarteritis nodosa) at >20 mg/kg/day, and epididymis (oligospermia and
degenerated seminal product) at 80 mg/kg/day. (Tumor incidences are reported below under
Carcinogenicity.) The authors reported the lowest dose of 5 mg/kg/day as a NOAEL and the
mid-dose of 20 mg/kg/day as a LOAEL. However, as evaluated in NRC (2000), the lowest dose
of 5 mg/kg/day was a LOAEL for atrophy and decreased secretory product of the seminal
vesicle.
Reference: Ref. 24; also Ref. 9 and 9a.
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CARCINOGENICITY
Conclusion:
The available carcinogenicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Increased tumor incidences were observed in a combined chronic toxicity/carcinogenicity assay
in rats exposed to Proprietary A in the diet (Ref. 24).
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
No studies of this type were located.
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
A 2-year feeding bioassay by Ref. 24 was consistent with this guideline.
Type: Combined oral chronic toxicity and carcinogenicity assay
Species, strain, sex, number: Rat, Sprague-Dawley, 60/sex/group
Purity: 95%
Doses: 0, 5, 20, and 80 mg/kg body weight/day
Vehicle: None other than feed
Route: In feed; diets blended weekly to achieve target doses
Exposure duration, frequency: 2, ad lib
Method: See description above under Chronic Toxicity
Results: The following neoplastic changes compared to controls were statistically significant
(p<0.05). Dose-related increased incidences at >20 mg/kg/day of renal cortical adenomas in
both sexes and testicular interstitial tumors in males, and at 80 mg/kg/day, of hepatocellular
adenomas and carcinomas combined in both sexes and adrenal cortical adenomas in females.
Ref. 40 concluded that this study provides sufficient evidence of carcinogenicity of Proprietary
A in rats following chronic oral exposure.
Reference: Ref. 24; also Ref. 9, 9a
NEUROTOXICITY
Conclusion:
The available neurotoxicity data were judged inadequate to meet the endpoint.
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Basis for Conclusion:
The delayed neurotoxicity component is satisfied by the existing data, but a developmental
toxicity study by Ref. 59 that included postnatal behavioral examinations did not fully satisfy the
developmental neurotoxicity component. Proprietary A gave negative results in single acute and
subchronic oral delayed neurotoxicity studies in hens and in limited postnatal testing in rats
exposed during gestation. A 2-year feeding bioassay in rats by Ref. 24, discussed above under
the Chronic Toxicity and Carcinogenicity endpoints, reported no lesions of the cervical spinal
cord, but a slight (not statistically significant) increase in the incidence of gliomas of the brain in
rats exposed to Proprietary A at 80 mg/kg/day. The study authors could not determine whether
this effect was related to exposure.
Delayed Neurotoxicity
Conclusion:
The available delayed neurotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Several acute studies and one subchronic study for delayed neurotoxicity in the hen, summarized
below, give no evidence of acute cholinergic toxicity, inhibition of neurotoxic esterase (NTE)
activity, or delayed neurotoxicity for Proprietary A. These studies, performed prior to the
existence of the guidelines, do not entirely conform to current guidelines, and may lack detail
such as the purity of the Proprietary A sample. The lack of significant NTE inhibition following
dosing with 10,000 mg/kg suggests that no additional testing for delayed neurotoxicity is needed
for Proprietary A.
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Unpublished industrial acute (1- or 5-day) and subchronic (90-day) delayed neurotoxicity assays,
which pre-date the guideline, are missing some details. One acute study employed a gavage dose
5 times higher than now specified under the guideline. The subchronic assay had a longer
duration and a larger group size than specified under the guideline.
Critical Studies
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, White Leghorn, 4/dose
Purity: [Formulation 2], purity not reported, clear colorless liquid
Doses: 420 mg/kg (highest dose specified in protocol)
Vehicle: test substance diluted 50% in corn oil
Positive control: 90 or 120 mg/kg/day tri-ortho-tylol phosphate (TOCP)
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Route: Gavage
Exposure duration, frequency: Once daily on five consecutive days
Method: Navy MIL-H-19457B (SHIPS) protocol. Hens were weighed and graded on days 7, 9,
11, 14, 16, 18, 21, and 23 after the first dose for no signs, doubtful/minor signs, positive paralytic
signs, advanced paralytic signs, or death. Scores on the 21st day were compared with results for
TOCP. Necropsy not performed.
Results: No overt signs of neurotoxicity in with Proprietary A treatment. Positive control
caused inability to walk, hypertension, ataxia, and prostration.
Reference: Ref 14 as described in Ref 61; Ref 50
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, White Leghorn, 4/dose for Proprietary A, 3/dose for controls
Purity: [Formulation 2], clear colorless liquid; one part of the report stated that the purity was
not reported, whereas another part of the report indicated purity >99%.
Doses: 10,000 mg/kg
Vehicle: None
Positive control: 500 mg/kg tri-ortho-cresyl phosphate (TOCP)
Negative control: 15 mg/kg tetraethyl pyrophosphate (TEPP)
Route: Oral gavage
Exposure duration, frequency: Once
Method: Twenty minutes before dosing, hens received atropine and 2-PAM to protect against
cholinergic effects. Hens were observed for toxic signs at 2-hour intervals for the first 8 hours.
Mortalities were recorded after 24 hours. Brains were harvested 24 hours after dosing and
analyzed for neurotoxic esterase (NTE) activity.
Results: Toxic signs were not reported specifically for Proprietary A, but for all compounds
tested at the maximum tolerated dose, signs included listlessness and ataxia. Inhibition of NTE
activity was 7% for Proprietary A and the negative control tetraethyl pyrophosphate, but 85% for
the positive control (TOCP). The current guideline specifies that testing is not necessary at
doses above 2,000 mg/kg.
Reference: Ref. 56
Type: Subchronic oral delayed neurotoxicity
Species, strain, sex, number: Hen, adult, White Leghorn, 10/dose
Purity: Not reported
Doses: 0, 4, 20, and 100 mg/kg/day
Vehicle: Not reported
Route: Oral Gavage
Exposure duration, frequency: 90 days, daily
Method: Body weight. Daily observations for mortality and behavioral changes; evaluated for
signs of motor weakness 3 times per week. At termination, hens were necropsied and brain
(multiple sections), sciatic nerve, and spinal cord (cervical, thoracic and lumbar) were examined
histopathologically. TOCP was the positive control.
Results: Hens treated with Proprietary A at the high dose exhibited mean reductions in body
weight during the latter part of the study, but no overt signs of neurotoxicity and no
4-19
-------
histopathological effects in the nervous tissues. Conversely, the positive control hens exhibited
consistently lower body weight gain, clinical signs of toxicity (locomotor impairment and ataxia)
that became more severe with time. Histopathology results were not reported for the positive
control.
Reference: Robust summary from Ref. 4
Neurotoxicity (Adult)
Conclusion:
The available adult neurotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The chronic oral bioassay by (Ref. 9, 9a, 24) reported no lesions of the brain or spinal cord in
rats exposed to TDCPP at doses as high as 80 mg/kg/day for 2 years, but no functional tests of
neurotoxicity were performed.
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
No studies of this type were located.
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS Harmonized
Guideline 870.6300)
Conclusion:
The available developmental neurotoxicity data were judged inadequate to meet the endpoint,
although the available tests suggest that Proprietary A is not a developmental neurotoxin.
Basis for Conclusion:
No studies of this specific design were located. A Japanese-language gavage study by Ref. 59,
described above under Developmental Toxicity, included postnatal neurobehavioral tests (open
field, water maze, rota rod, inclined screen, pain reflex, and Preyer's reflex) of sensory and
motor function in rats. Full descriptions of these tests were not available in the English summary
and therefore could not be compared to the guideline protocol. The study reported no adverse
effect in these tests for offspring of dams that were exposed on gestational days 7-15 at doses as
high as 200 mg/kg/day (the highest tested non-lethal dose that was a LOAEL for increased
kidney weight). This study does not fully satisfy the developmental neurotoxicity endpoint
because it omitted some parameters specified under the guideline: developmental landmarks for
sexual maturity, auditory startle test, and neurohistopathological examinations.
4-20
-------
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat)
OPPTS Harmonized Guideline 870.6500
Peripheral Nerve Function (rodent)
OPPTS Harmonized Guideline 870.6850
Sensory Evoked Potentials (rat, pigmented strain preferred)
OPPTS Harmonized Guideline 870.6855
These studies may be indicated, for example, to follow up neurotoxic signs seen in other studies,
or because of structural similarity of the substance to neurotoxicants that affect these endpoints.
These studies may be combined with other toxicity studies.
Conclusion: These endpoints do not appear to be applicable to Proprietary A.
Basis for Conclusion: Although there are no studies addressing these endpoints, there are no
reliable data for Proprietary A, and no structure-activity considerations, that indicate a need for
these follow-up studies.
Other Neurotoxicity Data
Cholinesterase inhibition
[Formulation 2] administered at 0, 2,000, or 3,980 mg/kg in corn oil was administered to groups
of 10 male Sprague-Dawley rats by oral gavage had no effect on plasma or erythrocyte
cholinesterase levels measured 4 or 14 hours after dosing (Ref. 51).
IMMUNOTOXICITY
Conclusion:
The available immunotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The only study evaluating the potential immunotoxicity of Proprietary A (Ref. 35) predates the
guideline for immunotoxicity (note that the OPPTS guideline cites other works by this author).
There is some uncertainty as the test material, reported as [Formulation 2], but mis-identified by
the authors as [Chemical 1]. The study methods differed from the guideline in the short
exposure period (4 rather than 28 days), parenteral administration (rather than oral or inhalation
route), measurement of serum immunoglobulins in non-immunized rather than immunized mice,
and the omission of some tests (enumeration of immunological cell subpopulations, test for NK-
cell activity). The results do not provide dose-response information as to immunotoxicity of
Proprietary A following subchronic exposure by oral or inhalation routes of exposure.
4-21
-------
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
Critical study
Type: Immunotoxicity, subcutaneous, acute
Species, strain, sex, number: Mouse, B6C3Fb 6-8 females/dose
Doses: 0, 0.25, 2.5, or 25 mg/kg/day (Total cumulative doses of 0, 1, 10, or 100 mg/kg)
Identity: [Formulation 2]; this is the same as Proprietary A tested in the 2-year oral assay by
Ref. 24
Purity: purity >95%
Vehicle: Corn oil
Route: Subcutaneous injection
Exposure duration, frequency: 4 days, once daily
Method: Observations included body weight, hematology, clinical chemistry (5 parameters)
terminal necropsy, organ weights (liver, spleen and thymus), histopathology of spleen, thymus,
and eight other organs, plaque-forming assay response to sheep red blood cells, and serum
immunoglobulin quantification (non-immunized mice only). Non-guideline tests included
proliferative capacity of granulocyte-macrophage progenitor cells (bone marrow), in vitro
lymphoproliferative (LP) responses to mitogens, delayed hypersensitivity response to keyhole
limpet hemocyanin. Extensive statistical analysis.
Results: Twenty percent of high-dose mice exhibited lymphoid depletion of the thymus.
Statistically significant decreases in vitro lipopolysaccharide (B-cell antigen) at 2.5 mg/kg/day
and concanavalin A (T-cell antigen) at 25 mg/kg/day.
Reference: Ref. 35
GENOTOXICITY
Conclusion:
The available genotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Proprietary A has been tested in in vitro and in vivo genotoxicity assays conducted in prokaryotic
and eukaryotic cells under methods similar to guidelines. Results of in vivo tests (mutation in
Drosophila., chromosomal aberration in mice) were negative, but positive results were reported
in several in vitro assays (mutagenicity in bacterial and mammalian cells, chromosomal
aberration).
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
4-22
-------
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA97, TA98, TA100, TA1535, TA1537
Metabolic activation: Tested with and without S9 from livers of Aroclor-induced male
Sprague-Dawley rats or male Hamsters
Concentrations: 0, five concentrations between 10 and 10,000 |ig/plate.
Purity: 94.4%
Method: Preincubation (20 minutes) and plate incorporation (48 hours) at 37°C. Positive
controls were used; DMSO was the solvent. Triplicate plates per concentration. All assays
repeated within 1 week.
Results: In three different laboratories, Proprietary A tested positive in strains TA97 and TA100
in the presence of S9 from Aroclor-induced hamster liver and in strain TA1535 in the presence
of S9 from Aroclor-induced rat or hamster liver. Positive controls gave expected increases.
Solvent control and all other test combinations were negative.
Reference: Ref 37
Type: Bacterial reverse mutation
Species, strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538
Metabolic activation: Tested with and without Kanechlor 500 (PCB)-induced liver S9 from
male Wistar rats
Concentrations: 0, 10, 30, 100, and 300 [ig/plate.
Purity: Assayed as -94% Proprietary A, plus -6% [Chemical 7]
Method: Plate incorporation, 48-hour incubation at 37°C. Cited Ames protocol, which
presumes the use of replicates and positive controls.
Results: No increase in revertants in any strain without activation or in strains TA98, TA1537,
or TA1538 with activation. Weak increases in TA100 and TA1535 at the highest concentrations
with S9.
Reference: Ref. 38
Additional Studies
Other S. typhimurium assays in which S9 was prepared from phenobarbital-induced rat liver
reported mutagenicity of Proprietary A in strain TA98 by liquid preincubation assay (Ref. 1) and
in TA100 by plate incorporation assay (Ref. 25, 48). Ref. 36 reported dose-related positive
results for Proprietary A and its metabolite [Chemical 8] in TA100 with S9 (phenobarbital-
induced) in standard plate assays at concentrations up to 500 jig/plate. In a liquid preincubation
quantitative assay, results for Proprietary A were essentially negativeonly increasing mutation
frequencies at cytotoxic concentrations (survival <3%). However, its metabolites increased
mutant frequencies with less cytotoxicity: [Chemical 9] positive at <80% survival and [Chemical
8] positive at <30% survival.
Proprietary A was not mutagenic in S. typhimurium strains TA100, TA1535, or TA1538 without
activation or when Aroclor-induction was used to prepare the S9 fraction (Ref. 41); the highest
exposure level was 10 |j,L per plate.
4-23
-------
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
Type: Mammalian Cell Gene Mutation Test: Forward Mutation
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: Tested with and without phenobarbital-induced liver S9 from male mice
Concentrations: 0, and five concentrations up to -32 nL/mL without S9, and six concentrations
up to 70 nL/mL with S9. Test conditions chosen based on preliminary assays so that 50%
growth reduction occurred at highest concentration.
Purity: Not reported
Method: Selection of forward mutation from TK+/- to TK-/- genotype. Activity compared to
[Chemical 2].
Results: Proprietary A yielded negative results with or without activation. [Chemical 2] was
negative without, but positive with activation.
Reference: Ref. 12; also Ref. 33
Type: Mammalian Cell Gene Mutation Test: Forward Mutation
Species, strain: V79 Chinese hamster lung cells
Metabolic activation: Tested with phenobarbital-induced liver S9 from male rats
Concentrations: 0, 0.02 mM Proprietary A. Test conditions chosen based on preliminary
assays.
Purity: Not reported
Method: In two experiments, selection of 6-thioguanine-resistant colonies. Activity compared
to [Chemical 2].
Results: Proprietary A with S9 did not increase mutation frequency. [Chemical 2] yielded
positive results.
Reference: Ref 48
Gene Mutation in Vivo:
Sex-linked Recessive Lethal test in Drosophila melanogaster (OPPTS Harmonized
Guideline 870.5275)
Type: Sex-linked Recessive Lethal test
Species, strain: Drosophila melanogaster, 100 males/concentration
Metabolic activation: None
Concentrations: 2.5 and 25% in feed (1% gum tragacanth in 3% sucrose)
Purity: Technical-grade [Formulation 2], purity not reported
Method: Proprietary A added to feed of males for 24 hours, subsequently mated with virgin
unexposed females
Results: No evidence of toxicity or increase in the percentage of sex-linked recessive lethal
mutations.
Reference: Ref. 11 as described in Ref. 61; also Ref. 32
4-24
-------
Chromosomal Aberration in Vitro:
In Vitro Mammalian Chromosome Aberration Test (OPPTS Harmonized Guideline
870.5375)
Type: In vitro chromosome aberration assay
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: None, phenobarbital-induced or PCB-induced
Concentrations: 0, 0.01 to 0.1 |j,L/mL for non-induced, phenobarbital-induced or PCB-induced
mouse
Purity: Not reported
Method: 4-hour exposure to Proprietary A with or without activation. Chromosomal aberrations
scored in 50 metaphase spreads per concentration.
Results: Proprietary A caused increases chromosomal aberrations (up to 40%) with PCB- or
phenobarbital-induction compared to noninduced S9.
Reference: Ref. 12; also Ref. 33
Additional Information
Two confidential studies were submitted. One reported negative results in cultured Chinese
hamster ovary cells with or without metabolic activation. Another reported positive results in
human lymphocytes with metabolic activation.
In vitro Sister Chromatid Exchange Assay (OPPTS Harmonized Guideline
870.5900)
Type: In vitro sister chromatid exchange assay
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: None, phenobarbital-induced or PCB-induced
Concentrations: 0, 0.005-0.03 :L/mL for phenobarbital-induced (4 concentrations), and 6
concentrations up to 0.070 :L/mL for non-induced or PCB-induced mouse
Purity: Not reported
Method: Ten cells per concentration were analyzed.
Results: Proprietary A increased the incidence of sister chromatid exchanges in mouse
lymphocytes under all three test conditions.
Reference: Ref. 12; also Ref. 33
Additional Information
One submitted confidential study reported negative results in a sister chromatid exchange assay.
[Formulation 2] did not induce sister chromatid exchanges when applied to 3- to 4-day-old
chicken embryos (Ref. 10).
4-25
-------
Chromosomal Aberration in Vivo:
Mammalian Bone Marrow Chromosomal Aberration Test (OPPTS Harmonized
Guideline 870.5385)
The available study provides sufficient evidence that Proprietary A did not induce chromosomal
aberrations in mice exposed at the maximum tolerated dose of 760 mg/kg.
Type: Bone marrow chromosomal aberration in vivo
Species, strain: Mouse, CD-I, 4-8 males/group
Metabolic activation: None
Concentrations: 0, 0.05, 0.17, and 0.5 mL/kg; using the specific gravity of 1.52, the doses were
0, 76, 260, or 760 mg/kg. The highest dose was the maximum tolerated dose. Negative control
was DMSO
Exposure duration, frequency: By oral gavage in once or daily on 5 consecutive days.
Purity: Technical grade; Not reported
Method: Mice were sacrificed at 6, 24, and 48 hours after single dose or 6 hours after the last of
5 doses. Between 233 and 400 cells were scored, rather than 500/animal. Triethylenemelamine
was positive control.
Results: No evidence of increased frequency of chromosomal aberrations with Proprietary A.
[Chemical 2] was also negative at doses up to 1,000 mg/kg. Positive control produce expected
large increase in micronucleated polychromatic erythrocytes.
Reference: Ref 12; Ref. 34
Mammalian erythrocyte micronucleus test (OPPTS Harmonized Guideline
870.5395)
Proprietary A administered as 2,000 mg/kg by an unspecified route to mice did not induce
micronuclei in bone marrow erythrocytes (Ref. 60 as reported in Ref. 61).
DNA Damage and Repair:
Unscheduled DNA synthesis in mammalian cells in culture (OPPTS Harmonized
Guideline 870.5550)
Type: Unscheduled DNA synthesis in mammalian cells (hepatocytes) in culture
Species, strain: Rat, Wistar, male
Metabolic activation: With or without phenobarbital-induction
Concentrations: 0, 0.05, and 0.1 mM
Purity: Not reported
Vehicle: DMSO
Method: Cultured hepatocytes exposed to Proprietary A or [Chemical 2] for 18-19 hours.
Incorporation of radiothymidine into DNA.
4-26
-------
Results: Proprietary A was not genotoxic at 0.05 mM, but at 0.1 mM, a moderate response was
observed in hepatocytes from untreated rats, but not phenobarbital-treated rats. [Chemical 2],
the positive control, yielded positive results in induced and non-induced hepatocytes.
Reference: Ref 48
Additional Information
A submitted confidential study reported negative results for Proprietary A in cultured primary
hepatocytes from male Sprague-Dawley rats.
4-27
-------
Ecotoxicity
Aquatic Organism Toxicity
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline 850.1075;
OECD Guideline 203)
Conclusion:
The available acute toxicity data for freshwater fish (cold- and warm-water species) and
saltwater fish were judged inadequate to meet the endpoints. The available acute fish toxicity
studies are summarized in Table 4-1. However, if the results of Ref. 42, cited by Ref 29 (see
below), are confirmed independently, the acute toxicity endpoint for cold freshwater fish species
might be satisfied given the high degree of agreement of the two available studies in rainbow
trout.
Basis for Conclusion:
Freshwater Fish
Ref. 2 tested the toxicity to goldfish (Carassius auratus) of Proprietary A released from fabric
treated with the flame retardant. Laundered or unlaundered sections of garment that had been
treated with [Formulation 2], were placed in tanks with six goldfish. Fish in the tank with the
unlaundered section became sluggish and all died within 3 hours. The concentration of
[Formulation 2] in the test water reached 30 mg/L. Fish exposed for 96 hours to the laundered
section of garment did not exhibit signs of toxicity. In another study, Proprietary A in water at 1
mg/L was not toxic to goldfish after 168 hours, but 5 mg/L of Proprietary A killed all (6/6)
goldfish within 24 hours (Ref. 22). Ref. 2 and 21 did not evaluate toxicity using a range of
concentrations of Proprietary A in water and, thus, cannot be used to derive an LC50.
Ref. 46 estimated that the 96-hour LC50 values for killifish (Oryzias latipes) and goldfish were
3.6 mg/L and 5.1 mg/L, respectively. It appears that mortality was not evaluated in a control
group of fish. It is unclear if the Proprietary A concentrations in water reported by Ref. 46 are
measured or nominal values. The latter point is important because a parallel study indicated that
the amount of Proprietary A added to test water declines rapidly and less than 40% of the
original amount of Proprietary A remains in the test water after 96 hours (Ref. 46). Thus, the
lethal concentrations of Proprietary A could be lower than the reported LC50 values.
Ref. 46 reported deformation of the spine in 7/10 killifish exposed to 3.5 mg/L Proprietary A for
24 hours. However, Ref. 46 does not provide sufficient information regarding the spine
deformation in killifish to make meaningful use of these observations. It is unclear whether the
deformations were observed in the acute toxicity study or in a separate assay using killifish only.
It appears that deformation was tested at only one concentration and a control group offish was
not evaluated.
4-28
-------
Another study showed that the 96-hour LC50 of Proprietary A in rainbow trout (currently
classified as Oncorhynchus mykiss) was 1.4 mg/L (95% CI: 0.9-1.9 mg/L) (Unpublished study
conducted in 1990, summarized in Ref. 4, 5). A NOEC was not observed since one fish died at
0.63 mg/L, the lowest concentration tested. Compound purity was not provided in the summary
and the reported concentrations of Proprietary A in the test water appear to be nominal values.
The guideline for acute toxicity in fish (OPPTS 850.1075) indicates that test concentrations must
be measured during the test if, as was the case in this study, aeration is used. Thus, the study
reported by Ref. 4, 5 does not meet the criteria established by the guideline. The studies by Ref.
46 and Ref. 4, 5 suggest that the 96-hour LC50 for Proprietary A in fish is in the range of 1 to 5
mg/L, making it moderately toxic to fish. However, the data are inadequate to satisfy the acute
toxicity endpoint for freshwater fish. A 96-hour LC50 of 1.1 mg/L and a NOEC of 0.56 mg/L for
Proprietary A in rainbow trout (Ref. 42) were reported in Ref. 29. Although the results of the
study by Ref. 42 are in agreement with those of Ref. 4, 5, the study by Ref. 42, or a study
summary, was not available to allow for an independent evaluation of these data. Confirmation
of the results of the study by Ref. 42 might allow the acute toxicity endpoint for freshwater fish
to be satisfied.
Marine Fish
No acute toxicity studies in saltwater fish species were located.
4-29
-------
Table 4-1. Summary of available acute fish toxicity studies for Proprietary Aa
Study
Reference
Ref. 2
Species
Tested
Goldfish
(Carassius
auratus)
96-Hour
T C
Aj*-'50
None
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
None
No. of
Fish/
Cone
6
Analytical
Monitoring
Yes. The
concentration
of
[Formulation
2] in water
was
determined
by gas
chromatograp
hy.
Water Chemistry
pH:NR
Temp: 20°C
DO:NR
Hardness: NR
Water volume: 20 L
Electrical
conductivity: 290
micromhos/cm
Solvent
None
Comments on the Data
A laundered or
unlaundered 38 cm x 64
cm section of garment
(0.24 square meter area;
227 g/m3), which had been
treated with [Formulation
2], was placed in tanks
with six goldfish.
Fish in the tank became
progressively more
sluggish and all died within
3 hours. The measured
concentration of
[Formulation 2] in the test
water was 30 mg/L.
Fish exposed for 96 hours
to the same section of
fabric after it had been
laundered did not die.
Data for mortality in
control fish were not
presented in the study.
Goldfish are not a
designated test species, as
per OPPTS 850. 1075 (Fish
Acute Toxicity Test,
Freshwater and Marine).
The study cannot be used
4-30
-------
Table 4-1. Summary of available acute fish toxicity studies for Proprietary Aa
Study
Reference
Ref. 4, 5
Species
Tested
Rainbow
trout
(Salmo
gairdneri)
96-Hour
T C
Aj*-'50
1.4mg/L
(95% CI:
0.9-1.9
mg/L)
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
Controls, 0.63,
1.25,2.5,5,10
mg/L
No. of
Fish/
Cone
10
Analytical
Monitoring
No
Water Chemistry
pH: 7.14-7.78
Temp: 11. 8-14.8 °C.
DO: 92- 100% of air
saturation value
Hardness: 218-228
mg/L as CaCO3
Solvent
None reported
Comments on the Data
All mortalities occurred
within the first 24 hours.
Mortality was dose related.
One fish died in the lowest
dose group (0.63 mg/L).
All fish died in the 5 and
10 mg/L groups.
A NOEC was not observed.
4-31
-------
Table 4-1. Summary of available acute fish toxicity studies for Proprietary Aa
Study
Reference
Ref. 22
Species
Tested
Goldfish
(Carassius
auratus)
96-Hour
T C
Aj*-'50
None
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
1 and 5 mg/L in
water
No. of
Fish/
Cone
6
Analytical
Monitoring
None
reported
Water Chemistry
pH:NR
Temp: 20°C
DO:NR
Hardness: NR
Electrical
conductivity: 290
micromhos/cm
Solvent
Water or
acetone
Comments on the Data
Fish were exposed to 1 or 5
mg/L Proprietary A in
water or acetone. None of
the fish in the 1 mg/L
treatment had died after
168 hours.
All fish in the 5 mg/L
treatment died within 24
hours.
The most conspicuous
signs of toxicity were
sluggishness and
disoriented swimming prior
to death.
Mortality in control fish
was not reported.
Goldfish are not a
designated test species, as
per OPPTS 850.1075 (Fish
Acute Toxicity Test,
Freshwater and Marine).
The study cannot be used
to establish an LC50 value.
4-32
-------
Table 4-1. Summary of available acute fish toxicity studies for Proprietary Aa
Study
Reference
Ref. 46
Species
Tested
Killifish
(Oryzias
latipes)
Goldfish
(Carassius
auratus)
96-Hour
T C
Aj*-'50
Killifish:
3.6mg/L
Goldfish:
5.1 mg/L
Selected Study Design Parameters'"
Study
Type
Static
Concentrations
Tested
NR
No. of
Fish/
Cone
7 to 9
Analytical
Monitoring
Unclear if
conducted
Water Chemistry
pH:NR
Temp: 25°C.
DO:NR
Hardness: NR
Electrical
conductivity: NR
Solvent
NR
Comments on the Data
Fish were acclimated at
least for 10 days at 25 °C
The test concentrations
used were not reported. A
control group was not
tested.
Killifish, but not goldfish,
are a designated test
species, as per OPPTS
850. 1075 (Fish Acute
Toxicity Test, Freshwater
and Marine).
Deformation of the spine
was observed in 7/10
killifish exposed to 3.5
mg/L Proprietary A for 24
hours.
"Studies that were either published in a foreign language or that were not readily and that were not critical to the hazard assessment were not retrieved.
bNR: Not reported
4-33
-------
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD 202)
Conclusion:
The acute toxicity data for freshwater invertebrates were judged inadequate to meet the endpoint.
However, if the results of the study cited by Ref. 29 (see below) are confirmed independently,
the endpoint might be satisfied given the high degree of agreement of the two available studies in
freshwater invertebrates.
Basis for Conclusion:
The available data are summarized in Table 4-2. A flow-through study revealed a 48-hour LC50
of Proprietary A with Daphnia magna of 3.8 mg/L (95% CI: 3.5-4.2 mg/L) and a NOEC of 1.6
mg/L (Unpublished study conducted in 1999, summarized in Ref. 4, 5). Although some of the
conditions of the study design (such as number of organisms, and water temperature and
chemistry) appear to meet OPPTS Harmonized Guideline 850.1010, other aspects of the study,
including compound purity and condition and fertility of the organisms in culture, were not
reported in the summary. The amount of solvent used in the control group and the Proprietary A
treatments might have exceeded the recommended maximum solvent concentration, as per the
OPPTS Guideline (100 mg/L), but this does not appear to have affected the study results. A 48-
hour LC50 of 4.6 mg/L and a NOEC of 1.8 mg/L were reported for daphnia in a study by Ref. 43,
as cited in Ref. 29. Although the results of the study by Ref. 43 are in agreement with those of
Ref. 4, 5, the study by Ref. 43, or a study summary, was not available to allow for an
independent evaluation of these data. Confirmation of the results of the study by Ref. 43 might
allow the acute freshwater invertebrate toxicity endpoint to be satisfied.
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Conclusion:
No available acute marine/estuarine invertebrate toxicity data.
Basis for Conclusion:
No acute toxicity studies in marine/estuarine invertebrate species were located.
4-34
-------
Table 4-2. Summary of available acute invertebrate toxicity studies for Proprietary Aa
Study
Reference
Ref. 4, 5
Species
Tested
Daphnia
magna
48-Hour
LC50
3.8
mg/L
(95%
CI: 3.5-
4.2
mg/L)
Selected Study Design Parameters
Study
Type
Flow-
through
Concentrations
Tested
Negative control,
solvent control
(dimethyl-
formamide),0.98,
1.6,2.8,3.8,5.1
mg/L
No. of
Organisms/
Concentration
10
Analytical
Monitoring
Yes
Water
Chemistry
pH: 8.3
Temp:
20±2°C
DO: >8 5
mg/L (94%
of air
saturation
value)
Hardness:
126 mg/L as
CaCO3.
Solvent
Dimethyl-
formamide
Comments on the Data
Daphnids in the negative and
solvent control groups appeared
normal, as did the organisms in
the 0.98 and 1.6 mg/L groups.
Mortality in the 2.8, 3.8, and 5. 1
mg/L groups was 0, 70, and
80%, respectively. Daphnids
(15%) in the 2.8 mg/L group
were lethargic at study
termination.
The amount of solvent used in
the control group and the
Proprietary A treatments is
estimated to be approximately
300 mg/L. This exceeds the
recommended maximum solvent
concentration of 100 mg/L. The
estimate is based on a reported
dimethylformamide volume of
0.1 ml, a test chamber volume
of 300 ml and a specific gravity
ofO.95.
aStudies that were either published in a foreign language or that were not readily and that were not critical to the hazard assessment were not retrieved.
4-35
-------
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Conclusion:
No available chronic toxicity data for freshwater and marine fish.
Basis for Conclusion:
No chronic toxicity studies in freshwater and marine fish were located.
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1300;
OECD 211) and Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized
Guideline 850.1350)
Conclusion:
No available chronic toxicity data for freshwater and marine/estuarine invertebrates.
Basis for Conclusion:
No chronic toxicity studies in freshwater and marine/estuarine invertebrates were located.
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Conclusion:
The available algal toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are summarized in Table 4-3. The summary of a 96-hour algal toxicity study
(Unpublished study conducted in 1992, summarized in Ref. 4, 5) indicates that the study does
not meet the OPPTS Harmonized Guideline 850.5400. The pH and temperature of the test water
during the study were outside of the acceptable ranges for Selenastrum capricornutum, as per
Guideline 850.5400. Moreover, the two highest concentrations tested exceed the estimated
water solubility of Proprietary A (42 mg/L) and the concentrations tested were apparently not
verified analytically. Additional information, including test substance purity, hardness, DO,
TOC, TSS, exposure vessel size and head space, and measured chemical concentrations, were
not provided in the summary. Also, there is no evidence that positive controls were used in
order to establish that the algae were responding in the expected manner to a known chemical.
The deviations from the OPPTS Guideline indicate that the study is inadequate to satisfy the
algal toxicity endpoint. Another study indicates that Proprietary A at 10 mg/L had no effect on
growth or biomass of the algal species Scenedesmus subspicatus exposed for 72 hours
4-36
-------
(Unpublished study conducted by Ref. 44, cited in Ref. 29). The study, or a study summary, was
not available for the study by Ref. 44 to allow for an independent evaluation of these data.
4-37
-------
Table 4-3. Summary of available algal toxicity studies for Proprietary Aa
Study
Reference
Ref. 4, 5
Species
Tested
Selenastrum
capricornutum
EC50, NOAEC,
and LOAEC
96-hour EbC50
(biomass)
= 12 mg/L (95%
CI: 10-15 mg/L).
96-hour ErC50
(growth rate) = 39
mg/L (95% CI:
3 1-50 mg/L).
96-hour NOAEC:
6 mg/L.
Selected Study Design Parametersb
Study
Type
Static
Concentration
Range Tested
0 (negative
control), 2, 6, 18,
54, or 162 mg/L
Analytical
Monitoring
No
Water
Chemistry
Temp: 21°C
pH: 6.7-7.9
DO:NR
Hardness: NR
Solvent
None
reported
Comments on the
Data
A number of problems
are evident with this
study, namely the pH
changed markedly
during the study, and the
reported pH and water
temperature were outside
of the recommended
values for this algal
species.
"Studies that were either published in a foreign language or that were not readily and that were not critical to the hazard assessment were not retrieved.
b NR: Not reported.
4-38
-------
Terrestrial Organism Toxicity
Acute Oral (OPPTS Harmonized Guideline 850.2100), Dietary (OPPTS Harmonized
Guideline 850.2200; OECD Guideline 205), or Reproductive Toxicity (OPPTS Harmonized
Guideline 850.2300; OECD Guideline 206) in Birds
Conclusion:
No available acute oral, dietary, and reproductive toxicity data for birds.
Basis for Conclusion:
No acute oral, dietary, or reproductive toxicity studies in birds were located.
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
Conclusion:
The available earthworm subchronic toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No earthworm subchronic toxicity studies were located. An acute (14-hour) LC50 of 130 mg/kg
soil and aNOEC of 100 mg/kg soil with the earthworm, Eisenia fetida (Ref 45), were reported
in Ref. 29. However, the study has also been reported to be a 14-day subchronic toxicity study
(Ref. 39). The study, or a study summary, was not available for an independent evaluation of the
study and the results.
4-39
-------
Physical/Chemical Properties
CAS
MF
MW
SMILES
Physical/Chemical Properties
Water Solubility:
Conclusion: The available water solubility data are adequate.
Basis for Conclusion: The key study (highlighted) was performed according to a reliable
method, and is in reasonable agreement with other values reported in the literature.
Solubility (mg/L)
42
7
100
110
18.1
References
Ref. 4, 5; water solubility determination according to OECD Guideline
flask method)
105 (shake-
Ref. 8 (24°C); Ref. 27; Ref. 49 (24°C); Ref. 28 (24°C)
Ref. 13,21, 31,61 (30°C)
Ref. 15
Confidential submitted study using shake flask method
Log Kow:
Conclusion: The available log Kow data are adequate.
Basis for Conclusion: The key study was performed according to a reliable method.
LogK,,w
2.4
3.8
3.65
3.75
3.69
Reference
4, 5; determination of Octanol-Water Partition Coefficient According to OECD
Guideline 117 (HPLC Method)
Ref. 61
Ref. 28, 49
Shake-flask method, Ref. 46
Confidential submitted study using the HPLC method
Oxidation/Reduction: No data
Melting Point:
4-40
-------
Conclusion: The available melting point data for Proprietary A are adequate.
Basis for Conclusion: The key study was performed according to a reliable method. It is noted
that the other literature data do not agree with the key study; however, the methods used to
measure the melting points are not provided in any of the sources. As an OECD-guideline
compliant method, the key study is better described and better supported.
Melting Point (°C)
-58
27
26.66
References
Ref. 4, 5: melting point determination by DSC (compliant with OECD Guideline 102),
freezing point was determined to be -40 °C, melting point -58°C
Ref. 15
Ref. 6
Boiling Point:
Conclusion: The boiling point data are adequate.
Basis for Conclusion: A variety of literature sources report the same value for the boiling point,
although there is some indication that the compound may decompose at or near the boiling point.
Since experimental details are not provided in any of the sources, it is not possible to determine
whether the temperatures reported are decomposition or boiling temperatures. Nevertheless,
given the high boiling point reported for this material, the available data are adequate to
characterize its potential volatility.
Boiling Point (°C/torr)
236-237/5
200/4
Dec. >200/4
Gradual Dec. >200
References
Ref. 13,31,49,
61
Ref. 6
Ref. 61
Ref. 28
Vapor Pressure:
Conclusion: The available vapor pressure data are not adequate
Basis for Conclusion: Although this measured vapor pressure is reported in two sources, it
appears to be very high relative to the boiling points reported for this chemical. For comparison,
an estimated vapor pressure (Ref. 23) is also included in the table below. The vapor pressure
remains a data need.
4-41
-------
Vapor Pressure (torr/°C)
0.01/30
2.98 xlO'7
Reference
Ref. 4,5,61
Ref. 23 estimate
Odor:
Conclusion: The odor of this compound has been adequately characterized.
Basis for Conclusion: Although no standardized tests are available for characterizing chemical
odors, the two descriptions found are similar, and are consistent with the low volatility expected
for this chemical.
Odor
Mild Odor
Bland Odor
Reference
Ref. 28
6
Oxidation/Reduction Chemical Incompatibility: No data
Flammability:
Conclusion: The flammability (as the flash point and autoignition temperature) has been
adequately characterized.
Basis for Conclusion: Studies on the flash point and autoingition temperature of this chemical
were located and appear reasonable given the other physical/chemical properties available for
this compound.
Flash Point
252° C (coc)
>107.22°C (Seta closed cup)
Reference
Ref. 28, 61
Ref. 6
Autoignition Temperature
512.77°C
Reference
Ref. 6
Explosivity: No data
Corrosion Characteristics: No data
4-42
-------
pH:
This chemical does not contain functional groups expected to influence the pH of aqueous
solutions. Data for this endpoint are therefore not applicable.
UV/Visible Adsorption: No data
Viscosity:
Conclusion: The viscosity of this chemical at various temperatures has been adequately
characterized.
Basis for Conclusion: Studies on the viscosity of this chemical were located and appear
reasonable given the other physical/chemical properties available for this compound.
Viscosity (cP)
1,800 at 25°C
2,200 at 0°C
540 at 40°C
Reference
Ref. 6, 61
Ref. 6
Ref. 6
Density/Relative Density/Bulk Density:
Conclusion: The density of this compound has been adequately characterized.
Basis for Conclusion: Consistent data are provided in several reputable sources.
Density
1.52at25°C
1.5022 at 20°C
1.48kg/Lat25°C
Reference
Specific gravity. Ref. 61
Specific gravity. Ref. 13,
31
Bulk density. Ref. 28
Dissociation Constant in Water:
This compound does not have functional groups that are expected to dissociate in water. This
endpoint is therefore not applicable.
Henry's Law Constant: No data
4-43
-------
Environmental Fate
Bioconcentration
Fish:
Conclusion: The bioconcentration factor has been adequately characterized.
Basis for Conclusion: The two studies cited in the table below provide consistent information
for killifish under both static and flow-through conditions, over a variety of observation times,
and with varying initial concentrations of test substance. The BCF was also measured in
goldfish; the reported BCFs are independent of study length.
Reference
Ref. 46
Ref. 46
Ref. 47
Species
Killifish
Goldfish
Killifish
BCF
113
110
77
5
3
46±5
32±4
31±6
59±16
49±12
Key Design Parameters
Exp.
type
Static
Static
Flow-
through
(all)
Range
(ppb)
1,000
initial
1,000
initial
400
300
40
40
80
Study
length
24 hours
55 hours
96 hours
24 hours
96 hours
3 days
4 days
6 days
30 days
32 days
T(°C)
25
25
25
Comments
Half -life for elimination
of the test compound in
water + fish =31 hours.
Half -life for elimination
of the test compound in
water + fish = 42 hours.
BCF is independent of
concentration; continuous
(flow-through) results
correlate to static results
(Ref. 46).
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism:
Conclusion: The metabolism of Proprietary A in fish is not adequately characterized in the
literature.
Basis for Conclusion: The depuration rate is adequately described in killifish, however, the
metabolite distribution is not addressed.
4-44
-------
Species
Killifish
Killifish
Goldfish
Rate
Elimination half-life, 1.65 hours
Apparent metabolism is much
faster in killifish than in goldfish.
(Quantitative data are not
provided.)
Apparent metabolism is much
slower than in killifish.
(Quantitative data are not
provided.)
Comment
Depuration rate -
elimination of Proprietary
A when exposed fish are
moved to clean water.
-10% of applied
Proprietary A remains in
the water in the presence
of killifish after 96 hours.
Control (no fish) has no
change in TPP
concentration.
-25% of applied
Proprietary A remains in
the water after 96 hours
in presence of goldfish.
Reference
Ref. 47
Ref. 46
Ref. 46
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion: The biodegradation of Proprietary A under aerobic conditions has been adequately
characterized.
Basis for Conclusion: The key study (highlighted) was performed according to a GLP-
compliant OECD guideline test. The other data located in the literature are generally in
agreement with the key study.
Study type/
Method
OECD
Guideline
301B
Modified
Sturm Test
Innoculum
Activated
sludge
Acclim
Degradation
0%byCO2
evolution.
DOC red. not
calculated
due to
solubility
issues.
Time
28 days
Comments
Initial concentrations
2, 10 mg/L. GLP-
compliant.
Also reported:
1) Closed bottle test
(OECD Guideline
30 ID) showed no
inhibition of bacterial
cultures in 10 days.
Reference
Ref. 3, 4, 5
4-45
-------
Study type/
Method
Japanese
MITI test
OECD 302C
River Die-
Away
Innoculum
Activated
sludge
Water from
Oh River
(Osaka,
Japan)
Neya River
(Osaka,
Japan)
Seawater
(Osaka Bay)
Acclim
Degradation
avg. l%by
BOD
0%byO2
uptake
12.5%
18.5%
0%
5.4%
0%
22%
Time
28 days
28 days
7 days
14 days
7 days
14 days
7 days
14 days
Comments
Initial concentrations
100 mg/L (test
substance), 30 mg/L
(sludge).
Initial concentrations
20 mg/L in Oh River
water and 1 mg/L in
Neya River water.
Concentration in
seawater not
reported.
Analysis by
Molybdenum Blue
calorimetric assay for
increase in phosphate
ion.
Reference
Ref. 15, 16, 28
Ref. 61
Ref. 61
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis:
Conclusion: The available pyrolysis data are not adequate.
Basis for Conclusion: Although a semi-quantitative description of the pyrolysis products is
given in Ref. 18, the list of degradates provided accounts for only 60% of the total mass
expected and doesn't contain any oxygenated or phosphorus-containing compounds. Therefore,
this study does not provide a complete profile of the pyrolysis of Proprietary A.
Pyrolysis Products
Relative mol.% degradates, 0.1 mole Proprietary A heated at 250-260°C
under reduced pressure (3 mm Hg), overall yield 60 wt%: [Chemical 3]
26.7%, [Chemical 4] 36.0%, [Chemical 5] 34.4%, [Chemical 6] 2.9%.
Thermal oxidative degradation in air at 370°C: Hydrogen halides,
halogenated C2 and C3 species, acrolein
When heated to decomposition, it emits toxic fumes of Cl+ and POX
Reference
Ref. 18
Ref. 28
Ref. 31
4-46
-------
Hydrolysis as a Function of pH:
Conclusion: The hydrolysis rate data are adequate. The hydrolysis products are not described.
Basis for Conclusion: The studies cited below were GLP-compliant tests run according to
accepted guidelines.
Tw
>1 year
>1 year
14.7
days
28 days
128
days
pH
4
7
9
9
9
Temp.
50°C
40°C
20°C
Comment
OECD 111; EPA Ser. 835 OPPTS No. 835.2110.
GLP-compliant.
Initial concentration, 10 mg/L. Study length, 5
days. Preliminary study.
OECD 111; EPA Ser. 835 OPPTS No. 835.2110.
GLP-compliant.
Definitive 30-day study.
OECD 111; EPA Ser. 835 OPPTS No. 835.2110.
GLP-compliant.
Definitive 30-day study.
Reference
Ref. 4, 5
Ref. 4, 5
Ref. 4, 5
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
4-47
-------
Flame Retardant Alternatives
Proprietary B: Aryl phosphate
Hazard Review
5-1
-------
Proprietary B: Aryl phosphate
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
*
*
*
*
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
*
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
/
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
*
*
*
*
*
5-2
-------
Proprietary B: Aryl phosphate
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It
does not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
*
*
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
5-2
-------
Chemical Identity
Proprietary B: Aryl phosphate
Synonym
CAS
MF
MW
SMILES
Many of the available health effects studies were conducted with commercial mixtures that
commonly contained triphenyl phosphate as well as Proprietary B. The available information
regarding the composition of these mixtures is presented below, but the composition of the
actual samples tested in the health effects studies usually was not reported.
[Formulation 1] is reported to contain 60-100% Proprietary B and 15-40% triphenyl phosphate
(Ref. 24) and [Formulation 2] is reported to contain 60-100% Proprietary B and 4-7% triphenyl
phosphate (Ref. 25).
Major Components of
[Formulation 3] and [Formulation 4] as reported in Ref. 34
Component
Total Proprietary B
[Chemical 1]
[Chemical 2]
[Chemical 3]
[Chemical 4]
[Chemical 5]
Triphenyl Phosphate
[Formulation 3]
49
8
6
2
21
12
33
[Formulation 4]
61
11
7
5
27
11
18
5-4
-------
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401)
Conclusion:
The available acute oral toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are for limit tests on undefined flame retardants for which compositional
information was not provided. The authors of the studies referred to them as "non-definitive",
possibly because of the small group sizes (which, however, are consistent with current
guidelines); in other respects the studies follow current guidelines.
Additional Studies and Information:
No deaths were observed in Sprague-Dawley rats (3/sex) given [Formulation 1] (mixture of
Proprietary B and triphenyl phosphate) as a single oral dose of 5,000 mg/kg (Ref 13). Clinical
signs, which included tremors (0/3 males, 1/3 females), oral discharge, ataxia (0/3 males, 1/3
females), decreased locomotion (1/3 males, 1/3 females), chromorhinorrhea, chromodacryorrhea,
and abdominogenital staining, subsided by day 11. No effects on body weight gain and no gross
internal lesions were observed.
A parallel acute oral study on Sprague-Dawley rats (3/sex) given [Formulation 2] at a dose of
5,000 mg/kg, reported clinical signs (abdominogenital staining and chromorhinorrhea) on the
first 2 days post dosing, but no mortality, body weight gain effects, or gross internal lesions were
reported (Ref. 17).
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are for limit tests on undefined flame retardants for which compositional
information was not provided. The authors of the studies referred to them as "non-definitive",
possibly because of the small group sizes (which, however, are consistent with current
guidelines); in other respects, the studies follow current guidelines.
5-5
-------
Additional Studies and Information:
No deaths were observed among Sprague-Dawley rats (3/sex) that were dermally exposed to
[Formulation 1] (mixture of Proprietary B and triphenyl phosphate) at a dose of 2,000 mg/kg for
24 hours under an occlusive covering (Ref. 14). There were no effects on body weight gain, no
signs of irritation on the test site, and no gross internal lesions observed.
In a parallel study in Sprague-Dawley rats (3/sex) dermally treated with 2,000 mg/kg
[Formulation 2], all but one female gained weight, but there were no deaths, signs of irritation, or
gross internal lesions (Ref, 18).
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300; OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline. A non-guideline study
evaluated neurotoxicity of combustion products of an Proprietary B/triphenyl phosphate mixture
in the presence of cyclic phosphonate compounds.
Additional Studies and Information:
Preliminary results of a study were reported (Ref. 38) investigating whether toxic compounds
were formed when cyclic phosphonate compounds were thermally decomposed in the presence
of other phosphate compounds in trimethylol polyol-based urethane foam. When rats were
exposed (head only) for 20 minutes to smoke and decomposition gases from foam containing
equal proportions of the cyclic phosphonate compounds and a mixture of Proprietary B and
triphenyl phosphate, no convulsive seizures, characteristic of exposure to toxic bicyclic
phosphites or phosphates, were observed.
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available eye irritation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are for undefined flame retardants for which compositional information was
not provided. The authors of the studies referred to them as "non-definitive", although they were
consistent with current guidelines.
5-6
-------
Additional Studies and Information:
Slight conjunctival erythema was observed in the eyes of 1/1 male and 1/2 female New Zealand
White rabbits 24 hours after instillation with 0.01 mL of [Formulation 1] (mixture of Proprietary
B and triphenyl phosphate) but was resolved by 48 hours (Ref. 15). No conjunctival discharge
or effects on the cornea or iris were observed. The material was tentatively characterized as
"practically non-irritating", based on a maximum irritation score of 1.3/110 at 24 hours.
In a parallel study in New Zealand White rabbits (1 male and 2 females) instilled with 0.01 mL
[Formulation 2], there were no signs of eye irritation observed at 1, 24, 48, or 72 hours (Ref. 19).
The material was tentatively characterized as non-irritating to the eyes based on a primary
irritation index of 0/110 at all timepoints.
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available dermal irritation data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are for undefined flame retardants for which compositional information was
not provided. The authors of the studies on the Durad materials referred to them as "non-
definitive", although they were consistent with current guidelines.
Additional Studies:
No dermal irritation (erythema or edema) was observed in one male and two female New
Zealand White rabbits that were dermally exposed for 4 hours to [Formulation 1] (mixture of
Proprietary B and triphenyl phosphate) on two occluded test sites (0.5 mL per site) and examined
at 4.5, 24, 48, or 72 hours (Ref. 16). The material was tentatively rated as non-irritating to intact
rabbit skin, based on scores of 0/8.0 at all timepoints.
In a parallel dermal irritation study in one male and two female New Zealand White rabbits
exposed for 4 hours to [Formulation 2] on two occluded test sites (0.5 mL per site), no irritation
was observed at times between 4.5 and 72 hours (Ref. 20). The material was tentatively rated as
non-irritating to intact rabbit skin, based on scores of 0/8.0 at all timepoints.
In skin irritation assays in male New Zealand White rabbits (6/group), 24-hour topical
administration (0.5 mL/site) of [Formulation 4] or [Formulation 10] did not elicit erythema or
edema to intact or abraded skin (examined at 24 and 72 hours) (Ref. 6). The mean primary
dermal irritation indices were 0/2.0 for both materials, which were characterized as non-irritating
to skin.
5-7
-------
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The skin sensitization endpoint is not satisfied.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
SUBCHRONIC TOXICITY
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Conclusion.
The available subchronic oral toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported preliminary results of a 39-41-day combined
subchronic plus reproductive/developmental toxicity screening study in rats exposed by oral gavage.
Preliminary results suggested adrenal and liver effects, with adrenal weight effects in females at a
LOAEL of 25 mg/kg/day. These data are not adequate because the final results were not available.
No other verifiable data were available for defined substances tested under guideline methods. A
study on undefined [Formulation 4] appeared to follow the guideline for a 28-day oral study, but was
only available as an incomplete robust summary. The unexplained mortality in this study indicates
that it may not be an adequate study.
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
As described in an incomplete robust summary (results were not presented quantitatively) for an
HPV submission, Sprague-Dawley rats (10/sex) received [Formulation 4] in the diet at
concentrations of 0, 0.1, 0.5, or 1.0% for 28 days (Ref 5). Treatment had no effect on survival (but
12 rats died: 1 control, 4 low-dose, 4 mid-dose, and 3 high-dose rats). Treatment also had no effect
on urinalysis results, incidence of gross lesions at necropsy, or histology of the liver and kidney
(histology examined only in high dose animals and controls). It was not specified whether animals
that died during the study were necropsied or examined histologically. Reduced feed consumption
was observed in the mid-dose group in both sexes and reduced body weight gain was noted in high-
dose females. Abnormalities (not specified) were observed in clinical chemistry measurements in
mid- and high-dose groups and in hematology parameters at the high dose. Relative liver weights
-------
were elevated in all treated groups. The unexplained mortality during this short term study raises
concern for study adequacy.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Subchronic Dermal Toxicity (21/28-day or 90-day)
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90-day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD
Guideline 413)
REPRODUCTIVE TOXICITY
Conclusion:
The available reproductive toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported preliminary results of a 39-41-day combined
subchronic plus reproductive/developmental toxicity screening study in rats exposed by oral gavage.
Preliminary results suggest an ovarian weight effect at >25 mg/kg/day, and an epididymal weight
effect and reduced fertility at 100 and 400 mg/kg/day. These data are not adequate because the final
results were not available. No other pertinent studies were located that addressed the reproductive
toxicity endpoints in the guidelines listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
5-9
-------
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported preliminary results of a 39-41-day combined
subchronic plus reproductive/developmental toxicity screening assay in rats exposed by oral gavage.
Preliminary results suggest reduced pre- and post-natal survival at 400 mg/kg/day. These data are
not adequate because the final results were not available. No other pertinent studies were located
that addressed the developmental toxicity endpoints in the guidelines listed below.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
5-10
-------
Basis for Conclusion:
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
Additional information
As described in an unvalidated robust summary, 3 days of exposure to [Formulation 7], tested
without metabolic activation at concentrations between 0.04 and 5.0 |ig/mL, did not induce cell
transformation in cultured Balb/c-3T3 cells (Ref. 36).
NEUROTOXICITY
Conclusion:
The available neurotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
Available acute and 28-day studies indicate that there is a risk of delayed neurotoxicity from
exposure to Proprietary B. Most studies either were conducted on undefined substances or were not
described in sufficient detail. A summary of a study on purified components of [Formulated] flame
retardants suggests that [Chemical 4] or [Chemical 2] are the neurotoxic components of these
mixtures; however, details of the in vivo study in hens were not located. The neurotoxicity of
Proprietary B preparations would be dependent on the relative content of [Formulation 11 ] isomers.
No data are available for the full battery of tests for functional neurotoxicity or for developmental
neurotoxicity.
Delayed Neurotoxicity
Conclusion:
The available delayed neurotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The acute study (experiment A) on a defined Proprietary B mixture departed from guideline in that
enzyme inhibition was assayed 24 hours after dosing rather than 48 hours, but reported significant
suppression of both brain neurotoxic esterase and plasma cholinesterase levels. The longer study
did not conduct a complete battery of neurobehavioral tests as stipulated under the guideline, but
5-11
-------
reported adverse effects on motor coordination at all doses on the day of treatment. The highest dose
(11,700 mg/kg) exceeded that recommended under the guideline, but that deviation does not affect
the conclusion of the study. Studies on purified components of [Formulated] flame retardants
identified the neurotoxic components, but were not adequately described. The majority of studies
suggest that delayed neurotoxicity may result from exposure to oral doses in excess of 1,000 mg//kg.
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Critical Studies
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, 12-14 months old, White Leghorn, 4/dose for experiment A;
10-12/dose for experiment B.
Purity: Proprietary B with the composition as in the following table.
Composition of Proprietary B assayed by Ref. 37
Component
Total Proprietary B
[Chemical 4]
[Chemical 6]
[Chemical 2]
[Chemical 7]
[Chemical 5]
[Chemical 8]
[Chemical 9]
Triphenyl Phosphate
Percent
<75
24
18
10
10
6
7
<1
24
Doses: Experiment A. Six doses between 12 and 11,700 mg/kg;
Experiment B. 0, 12, or 370 mg/kg in corn oil or 11,700 mg/kg undiluted
Vehicle: Corn oil
Positive control: Tri-ort/zo-cresyl phosphate (TOCP)
Route: Oral (not specified)
Exposure duration, frequency: Experiment A, single treatment followed 24 hours later by
biochemical assay; Experiment B, 6 weeks, single treatments 3 weeks apart; study terminated 3
weeks after second dose.
Method: Experiment A. Brain neurotoxic esterase (NTE) and plasma cholinesterase (PChE)
measurements recorded 24 hours after single treatment with Proprietary B, corn oil or TOCP.
5-12
-------
Experiment B. Doses were chosen based on results of experiment A to represent minimal, 50%, and
maximal inhibition of brain NTE. Body weight and food consumption measured every 3-4 days,
walking behavior evaluated weekly. Neurohistopathology evaluated at termination.
Results: Experiment A. The NOAELs for inhibition of NTE or PChE were 12 and 180 mg/kg,
respectively. Doses about 1,000 mg/kg and higher caused -70% inhibition of NTE and -80%
inhibition of PChE. The positive control (500 mg/kg of TOCP) inhibited brain NTE by 85.2% and
PChE by 70%.
Experiment B. Proprietary B had no effect on mortality. Few adverse signs visible at or below 370
mg/kg. All treated at 11,700 mg/kg showed motor incoordination beginning day 1, with feather loss
7-11 days later. Body weights not affected at lowest dose. Body weight effects at mid- and high-
dose are uncertain because text and graph do not match; one dose caused transient weight loss on
days 22-38 and the other persistent weight loss from day 22 to the end of the study. TOCP caused
persistent weight loss beginning day 5. Food consumption was transiently reduced in all groups
(including positive and negative controls) on day 2 and 23, also on day 18 for TOCP. Significant
transient, dose-dependent impairment of gait was observed on day 1 and 22 for hens treated with
Proprietary B at all doses. Hens treated with TOCP showed significant impairment on day 1 and
15, with gradual worsening to the end of the study. Neurohistopathological examinations revealed
no significant difference between Proprietary B treatment and corn oil controls, whereas TOCP
caused a significant increase in axonal degeneration in brain, spinal cord (cervical, thoracic and
sacro-lumbar), and bilateral degeneration of the sciatic nerve.
Reference: Ref 37
Additional Studies:
As described in Ref. 44, a series of acute delayed neurotoxicity assays were conducted on
[Formulated] flame retardants. No ataxia was observed in groups of 4 hens treated with
[Formulation 5] at doses of 2,000, 4,000, or 8,000 mg/kg; 3/30 hens treated with 16,000 mg/kg
showed ataxia (Ref. 7). Only 1/10 hens treated with [Formulation 6] at 20,000 mg/kg exhibited
ataxia (Ref. 8). In one study on [Formulation 4], no ataxia was observed at doses of 500, 1,000, or
2,000 mg/kg, whereas 2/10 treated at 4,000 mg/kg showed ataxia (Ref. 9); inhibition of brain NTE
was 79.5% at the highest dose. In a second study on [Formulation 4], incidences of ataxia (0/10,
3/10, 1/10 and 1/10) and neurohistopathological lesions (1/10, 0/10, 1/10, and 2/10) were not
precisely related to the respective doses of 3,000, 5,000, 7,000, and 9,000 mg/kg (Ref. 10). For
[Formulation 3], incidences of ataxia (1/9,4/10,6/10 and 3/10) and neurohistopathology (0/10,4/10,
7/10 and 1/10) were observed in the 2,000,4,000, 6,000, and 8,000 mg/kg groups, respectively (Ref.
11).
A subchronic (91-day) oral neurotoxicity assay is summarized briefly in a TSCA 8e submission
(Ref. 12), and in more detail by Ref. 44 and in a robust summary in an HPV submission (Ref. 23;
U.S. EPA comments not available). In this study, hens (20/group) were administered [Formulation
3] (mixture of Proprietary B and triphenyl phosphate) daily at doses of 0, 10, 20, 90, and 270
mg/kg/day. Deaths occurred in all dose groups as follows: 2/20 vehicle controls, 4/20 positive
controls, 3/20 at 10 mg/kg/day, 5/20 at 90 mg/kg/day, and 6/20 at 270 mg/kg/day. Ataxia was
observed in 4/20 at 90 mg/kg/day and 9/20 at 270 mg/kg/day. Histopathological examination of
5-13
-------
nervous tissue of 10 hens/group revealed the following: significant degeneration at 3 levels of the
spinal cord in 3 vehicle controls, significant degeneration of the spinal cord in TOCP hens,
degeneration of the spinal cord and peripheral nerves in hens of the 90 and 270 mg/kg/day groups,
with a dose-response relationship for severity and incidence (further details not reported). No ataxia
or brain histopathology was observed at 10 or 20 mg/kg/day.
[Formulation 4] and [Formulation 6] were given in two 2,000 mg/kg doses 21 days apart to hens
(4/group) (Ref. 22). Neither compound caused body weight effects, clinical signs of neurotoxicity
or an increase in gross internal lesions at necropsy (21 days after the second dose). There was no
evidence of neurohistopathology in hens treated with [Formulation 4], but one out of four hens
treated with [Formulation 6] had unilateral brain lesions at two histological levels.
Proprietary B at tested positive for neurotoxicity in hens treated at three 21 -day intervals with 10,000
mg/kg (Ref. 33). Effects included gross paralysis with demyelination confirmed histopathologically.
Several components of the [Formulated] series of flame retardants were isolated to >99% purity and
tested at doses as high as 1,000 mg/kg in hens for neurotoxicity and suppression of neurotoxic
esterase (Ref. 29). Details of these studies were not located. Three isomers of [Chemical 1] and
[Chemical 5] elicited no signs of neurotoxicity and no suppression of NTE levels. [Chemical 5] was
also judged to be non-neurotoxic, eliciting no ataxia or other signs of neurotoxicity and insignificant
suppression of NTE (-4% or -15%) in two tests. Both [Chemical 2] and [Chemical 4] were positive,
eliciting ataxia and neurotoxicity at 1,000 mg/kg, but not at lower doses; [Chemical 2] suppressed
NTE by 85% and [Chemical 4] suppressed NTE by 79 and 90% in two assays. The author suggested
that neurotoxicity was associated with triaryl phosphates containing a 2-alkyl substituent with an
oxidizable alpha-hydrogen.
In a two-hen screening test, a single 1,000 mg/kg dose of [Formulation 3] administered in gelatin
capsules to two hens resulted in a 53.1% inhibition of neurotoxic esterase activity in the brain (Ref.
42). The report was not clear as to the day on which the hens were sacrificed.
No neurotoxicity studies were located that followed or were similar to the guidelines listed below.
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity Study (OPPTS Harmonized Guideline 870.6300)
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat) OPPTS Harmonized Guideline
870.6500
Peripheral Nerve Function (rodent) OPPTS Harmonized Guideline 870.6850
Sensory Evoked Potentials (rat, pigmented strain preferred) OPPTS Harmonized Guideline
870.6855
5-14
-------
These studies may be indicated, for example, to follow up neurotoxic signs seen in other studies, or
because of structural similarity of the substance to neurotoxi cants that affect these endpoints. These
studies may be combined with other toxicity studies.
Other Neurotoxicity Data
Cholinesterase inhibition
[Formulation 3] at doses of 15, 20, or 25 mL/kg did not inhibit blood cholinesterase activity, but
neither species of animal (3/group) nor the specific biological material assayed were reported (Ref.
4).
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion:
No immunotoxicity study was located that followed or was similar to the guideline listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
The available genotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No verifiable genotoxicity data were located. The available studies were only accessible as robust
summaries in a IUCLID Dataset that had not undergone review by the European Commission (Ref.
3). Furthermore, the data were unpublished industry-sponsored studies on commercial products for
which no contemporaneous component analyses were provided. Current compositional information
taken from MSDS documents are presented in the following table. The results of these studies are
summarized below despite their uncertain validity. In general, not enough details were provided to
ascertain whether protocols met the standards of OPPT or OECD guidelines.
5-15
-------
Percentage of Proprietary B and triphenyl phosphate in Currently Available Commercial Products
Product
[Formulation 7]
[Formulation 8]
[Formulation 9]
[Formulation 2]
Proprietary B (%)
60-100
60-100
60-100
60-100
triphenyl phosphate (%)
15-40
10-30
7-13
4-7
Reference
Ref. 26
Ref. 27
Ref. 28
Ref. 25
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
As described in unvalidated robust summaries, negative results were reported for mutagenicity
assays in Salmonella typhimurium with or without metabolic activation. [Formulation 7] and
[Formulation 9] were tested in strains TA98, TA100, andTA1537 at concentrations as high as 1.62
mg/mL (Ref. 1, 2). [Formulation 9] and [Formulation 2] were tested in strains TA98, TA100,
TA1535, TA1537, and TA1538 at concentrations as high as 0.1 mL per plate (Ref. 31, 32).
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
As described in an unvalidated robust summary, [Formulation 7] at concentrations of 0.0013-0.1
|j,L/mL was not mutagenic to cultured mouse lymphoma L5178Y TK+/" cells without metabolic
activation (Ref. 30). Results in the presence of metabolic activation were equivocal in that a dose-
response was observed, but none of the cultures exhibiting >10% total growth had mutant
frequencies 2-fold greater than background.
Gene Mutation in Vivo
Sex-linked Recessive Lethal test in Drosophila melanogaster (OPPTS Harmonized
Guideline 870.5275)
As described in an unvalidated robust summary, [Formulation 7] (32.5, 75, or 150 mg/mL) fed to
adult male fruit flies for 3 days did not induce heritable mutations (Ref. 43).
Chromosomal Aberration in Vitro
No pertinent studies were located.
Chromosomal Aberration in Vivo
5-16
-------
Mammalian Bone Marrow Chromosomal Aberration Test (OPPTS Harmonized
Guideline 870.5385)
As described in an unvalidated robust summary no increase in chromosomal aberrations was
observed in the bone marrow of Chinese hamsters (8/sex/group), 16, 24, or 48 hours after receiving
a single oral dose of 5,000 mg/kg [Formulation 7] by gavage (Ref. 41). The summary
indicated that the study was conducted under OECD Guideline 475 and GLP. Another unvalidated
robust summary reported that a significant increase (compared to controls) in the incidence of bone
marrow cells with chromosomal anomalies was observed in Chinese hamsters (6/sex/group) 24
hours after receiving the second of two consecutive daily doses of 2,500 or 5,000 mg/kg/day
[Formulation 7] by oral gavage (Ref. 40); no increase was observed in animals receiving 1,250
mg/kg/day.
DNA Damage and Repair
Unscheduled DNA synthesis in mammalian cells in culture (OPPTS Harmonized
Guideline 870.5550)
As described in an unvalidated robust summary, [Formulation 7] tested without metabolic activation
at concentrations between 0.6 and 75 nL/mL did not cause unscheduled DNA synthesis in cultured
rat hepatocytes (Ref. 35).
Other
In vivo Sister Chromatid Exchange Assay (OPPTS Harmonized Guideline 870.5915)
As described in an unvalidated robust summary, there was no increase in the frequency of sister
chromatid exchanges in bone marrow cells of Chinese hamsters (4/sex/group) 24 hours after
receiving a single oral dose of 1250, 2,500, or 5,000 mg/kg [Formulation 7] by gavage in
carboxymethylcellulose (Ref. 39).
5-17
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available acute toxicity data for fish, aquatic invertebrates, and algae were judged inadequate
to meet the endpoints.
Basis for Conclusion:
Summaries were located for several acute toxicity studies of Proprietary B in an HPV test plan
submission and accompanying robust summaries (Ref. 23); however, EPA comments on this
submission were not available. The summaries included two 96-hour studies in fathead minnows
(Pimephalespromelas), three 96-hour studies in rainbow trout (Oncorhynchus mykiss), and three
48-hour studies in Daphnia magna. According to Ref. 21, all of the studies were conducted with
100% Proprietary B; however, other reports have identified the tested material in some of these
studies as [Formulation 1] (Ref. 24) or [Formulation 4] (Ref. 21). [Formulation 1] is a mixture
containing 60-100% Proprietary B and 15-40% triphenyl phosphate (Ref. 24). [Formulation 4] has
been reported to contain 61% Proprietary B and 18% triphenyl phosphate (Ref. 34; see table at
beginning of Human Health Effects for details). The available study summaries and Material Safety
Data Sheets are insufficient to precisely establish the composition of the materials tested in the acute
toxicity studies. Without precise knowledge of the composition of the tested materials, it is not
possible to use these studies to make a definitive statement regarding the acute toxicity of
Proprietary B. The publicly available information regarding the acute toxicity of Proprietary B to
freshwater fish or aquatic invertebrates is insufficient to satisfy the endpoints in the guideline
protocols listed below.
A confidential study was submitted that reported a freshwater daphnid 48-hour EC50 >0.77 mg/L,
the maximum test concentration. This concentration is above the water solubility limit of Proprietary
B.
A confidential study was also submitted that reported a freshwater green algal 72-hour EC50 of
approximately 0.480 mg/L. This concentration is above the water solubility limit of Proprietary B.
The available data were judged inadequate to meet this endpoint
No pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located that
addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
5-18
-------
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish or aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
5-19
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Physical/Chemical Properties
Proprietary B
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log Kow: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
5-20
-------
Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion:
The available aerobic biodegradation data are not adequate.
Basis for Conclusion:
A single confidential ready biodegradation study, indicating that Proprietary B is not ready
biodegradable, was submitted. This study is not sufficient to fully characterize the aerobic
biodegradation of Proprietary B under environmental conditions.
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
5-21
-------
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
5-22
-------
Flame Retardant Alternatives
Proprietary C: Chloroalkyl phosphate (2)
Hazard Review
6-1
-------
Proprietary C: Chloroalkyl phosphate (2)
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
/
*
/
/
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
/
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
*
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
*
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
/
/
/
/
6-2
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Proprietary C: Chloroalkyl phosphate (2)
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
/
/
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
/
/
/
/
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
-------
Chemical Identity
Proprietary C: Chloroalkyl phosphate (2)
Synonym
CAS
MF
MW
SMILES
Test materials used in health effects studies included two formulations, [Formulation 1] and
[Formulation 2]. Analysis of [Formulation 1] indicated an approximate -85% content of Proprietary
C, 6.7% [Chemical 1], and 5-10% related compounds. The following table shows a comparison of
properties and of impurities in [Formulation 1 ] and a sample of [Formulation 2] (Ref. 11). [Chemical
2] was an additive to prevent scorching during foam preparation; it is a neuroleptic agent. Results
for [Formulation 2]and [Formulation 3] are provided as supplemental information only, as current
products do not contain [Chemical 2].
A Comparison of [Formulation 1] with [Formulation 2] (Ref. 11)
Acidity (mgKOH/g)
Color (APHA)
Viscosity (corrected to 25°C)
[Chemical Group 1]
[Chemical 1] (%)
[Chemical 2]
[Formulation 1]
0.1-1.0
100-200
2,000-3,500 cp
100-500 ppm
4-9%
absent
[Formulation 2]
1.6
500+
3,950
less than detectable
9.0%
1.5-2.0%
ACUTE TOXICITY
Human Health Endpoints
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401)
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
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Basis for Conclusion.
Acute oral toxicity studies on undiluted [Formulation 1 ] (-85% Proprietary C) conformed to OPPTS
or OECD guidelines except that survivors were not necropsied. The LD50 exceeded the current
limit dose of 5,000 mg/kg for acute oral toxicity.
Critical Study:
Type: Acute oral toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 5/sex/group
Doses: Two tests performed, the first at 5,000 mg/kg (sample 83341) and the second at 2,000 mg/kg
(sample 83365)
Purity: -85% Proprietary C in [Formulation 1]; also contains -6.7% [Chemical 1] and 5-10%
"related compounds"
Vehicle: None
Observation period: 14 days
Method: Rats observed for clinical signs frequently on the first day and daily for 14 days. Animals
dying prematurely were given a gross necropsy examination.
Results: Rats were fasted prior to dosing. Clinical signs included decreased activity, respiratory
distress, lacrimation, oral discharge, soft stool, decreased feces, and perianal discharge. There were
no specific signs of cholinesterase inhibition (myosis or fasciculations). After day 2, all low-dose
survivors showed no clinical signs of toxicity. Necropsy findings included effects in the
gastrointestinal system (stomach containing air and reddish-yellow material, small intestine
containing mucoid material, injected blood vessels of stomach and small intestines), kidney (dark
coloration and congestion), thymus (dark coloration and mottling), lungs (redness), lymph nodes
(darkened), and liver (pale). Mortality, all within 48 hours of dosing, was 1/10 at the low dose and
8/10 at the high dose. Acute oral LD50 (not calculated) was between 2,000 and 5,000 mg/kg.
Comment: The doses used in this study were equivalent to limit doses under OPPT guidelines
Reference: Ref 6
Additional information:
An acute oral toxicity study conducted by Ref. 21 that reported an LD50 of 160 mg/kg in Sprague-
Dawley rats exposed to [Formulation 3] in 10% aqueous solution was not considered, since
compositional data were not available. Analysis of a similar material ([Formulation 2]) indicated
that the [Chemical 1] content was twice that of [Formulation 1], and also indicated the presence of
1.5-2% [Chemical 2], a neuroleptic agent that may have contributed to the higher relative toxicity
compared to [Formulation 1] (Ref. 11).
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged adequate to meet the endpoint.
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Basis for Conclusion:
Despite not fully conforming to OPPTS or OECD guidelines, the available study on [Formulation
1] appears to be adequate since neither clinical signs nor mortality were observed at the limit dose
of 2,000 mg/kg. A similar LD50 was reported for [Formulation 3].
Critical Study:
Type: Acute dermal toxicity
Species, strain, sex, number: Rabbit, New Zealand albino, 3/sex
Dose: 2,000 mg/kg
Purity: -85% Proprietary C in [Formulation 1]
Vehicle: None
Exposure period: 24 hours
Method: Hair was clipped from entire trunk of each rabbit. Skin of 1 male and 2 females was left
intact; skin of 2 males and 1 female was abraded. Test material applied under occlusive bandage.
Animals examined for clinical signs "frequently" during first day and daily for 14 days. Test sites
were washed with saline after 24 hours; irritation assessed at 26 hours, 72 hours, and 7 days. No
gross necropsy was performed.
Results: No deaths occurred; therefore, the acute dermal LD50 exceeded 2,000 mg/kg in rabbits.
There were no clinical signs of toxicity and no body weight effects.
Reference: Ref 7
Additional information:
An acute dermal LD50 exceeding 5,010 mg/kg in rabbits was reported for [Formulation 3] (Ref. 21).
No compositional information was available for this material, but analysis of [Formulation 2]
indicated that the [Chemical 1] content was twice that of [Formulation 1], and also indicated the
presence of 1.5-2% [Chemical 2], a neuroleptic agent (Ref. 11).
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300; OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No verifiable acute inhalation toxicity data were located, but an incomplete robust summary for a
study apparently conducted under the guideline was available in an unevaluated IUCLID Dataset
(Ref. 3).
According to a robust summary for a GLP-compliant study (Ref. 3), the acute (4-hour) inhalation
LC50 for Proprietary C (as [Formulation 4] or [Formulation 5]) exceeded 1.65 mg/L.
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Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available eye irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
An acute eye irritation study on [Formulation 1] was essentially consistent with OPPTS and OECD
guidelines. The only effect was conjunctival irritation that was resolved by 24 hours.
Critical Study:
Type: Acute eye irritation
Species, strain, sex, number: Rabbit, New Zealand White, sex not reported, 6
Doses: 0.1 mL
Purity: -85% Proprietary C in [Formulation 1]
Vehicle: None
Method: 0.1 mL of the neat test material was instilled into one eye and not washed. The eyes were
scored for irritation at 1, 24, 48, and 72 hours.
Results: The average scores (maximal possible 110) were 5.0,0, 0, and 0 at 1,24,48, and 72 hours,
respectively, based on conjunctival effects. No irritation of the cornea or iris was observed.
Reference: Ref 8
Additional information:
An acute eye irritation study on [Formulation 3] reported conjunctival effects persisting to 24 hours,
but resolved by 42 hours (Ref. 21). Compositional information was not available for this material,
but analysis of a related substance ([Formulation 2]) indicated that its greater irritation properties,
relative to [Formulation 1], might be attributed to its greater acidity: titration with 1.6 mg KOH/g,
compared to 0.1-1.0 mg KOH/g, respectively (Ref. 11). A submitted confidential study reported
slight eye (conjunctival) irritation.
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available dermal irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
An acute (24-hour) dermal irritation study for [Formulation 1] was consistent with OPPTS and
OECD guidelines. The test material was characterized as non-irritating.
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Critical Study:
Type: Acute (24-hour) dermal irritation
Species, strain, sex, number: Rabbit, New Zealand White, 3/sex
Doses: 0.5 mL to each test site (abraded, non-abraded) on each animal
Purity: -85% Proprietary C in [Formulation 1]
Vehicle: None
Method: Hair was clipped from sides and backs of 6 rabbits; on one side, skin was abraded with
point of 22 gauge needle. The test material was applied occluded; after 1 hour, Elizabethan collars
were used to prevent disturbance of test sites. Sites were cleaned after 24 hours. Sites were
examined for irritation at 26 hours and 72 hours after application.
Results: Males showed no signs of irritation (erythema or edema). No edema was observed in
females. Barely perceptible irritation (erythema) was detected in 2/3 females at 26 hours (mean
scores of 0.3 on intact and 0.2 on abraded skin), but in none at 72 hours; the primary irritation index
was 0.1/8.0. The study authors characterized the material as a "non irritant" to skin following
occlusive exposure for 24 hours.
Reference: Ref 9
Additional information:
A 4-hour dermal irritation study in rabbits exposed to [Formulation 3] also reported erythema but
no edema, with effects resolving by 48 hours (Ref. 21). No compositional information was available
for this material, but analysis of [Formulation 1] indicated that the [Chemical 1] content was twice
that of [Formulation 1] and its acidity was greater: titration with 1.6 mgKOH/g, compared to 0.1-1.0
mg KOFt/g, respectively (Ref. 11). Of two submitted confidential skin irritation studies, one
reported slight irritation (erythema) and another reported mild irritation (erythema and edema).
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The available skin sensitization data were judged adequate to meet the endpoint.
Basis for Conclusion:
The available studies, two of which indicate no evidence of dermal sensitization and one of which
indicates evidence of mild dermal sensitization, appear to have been consistent with OPPTS and
OECD guidelines. Few details were available for the Buehler test on [Formulation 1] (-85%
Proprietary C), but this method is one considered preferable under OPPTS guideline 870.2600. No
sensitization was reported for [Formulation 2], although analyses suggest that it is less pure than
[Formulation 1], having double the content of [Chemical 1] and slightly greater acidity than the
latter, and containing 1.5-20% [Chemical 2] as a scorch inhibitor (Ref. 11).
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Critical Studies:
Type: Dermal sensitization (Buehler) study
Species, strain, sex, number: Guinea pig, Hartley albino, 5/sex/group
Doses: Not reported, but probably 0.5 mL, since Buehler method is cited.
Purity: -85% Proprietary C in [Formulation 1]
Vehicle: None
Method: Cited as Ritz and Buehler. The test material was applied dermally once per week for 3
weeks. Fourteen and 21 days after the third application, challenge and rechallenge doses were
applied to treated animals and to a set of previously untreated controls (5/sex). Skin responses were
evaluated at 24 and 48 hours after the initial challenge and rechallenge.
Result: No sensitization reactions were observed.
Reference: Ref 19
Type: Dermal sensitization study
Species, strain, sex, number: Guinea pig, albino, 10 males/group
Doses: 0.05 mL of 10% or 25% (v/v)
Purity: Not reported; [Formulation 2]
Vehicle: 13% guinea pig fat dissolved in 50/50 acetone/dioxane (FAD)
Method: The test material was applied to shaved intact shoulder skin and gently rubbed in with a
Teflon rod. Sensitization by 4 sacral intradermal injections of 0.1 mL of 1% solution in DMSO.
Challenge after 2 weeks by 0.05 mL of 10 or 25% (v/v) in FAD applied to shaved intact shoulder
skin. Groups of previously exposed animals (10/dose) were also given the challenge doses.
Result: Reactions after 1 day were negative for all groups. The authors conclude that the material
is not a dermal sensitizer.
Reference: Ref. 4
Additional information:
One-inch squares of acetate fiber with 5.0% [Formulation 2] did not elicit skin reactions when
applied for 6 days to the skin of 211 human subjects (Ref. 4). Two weeks later, no sensitization
reactions were observed following a 48-hour challenge application. A confidential sensitization
study reported mild skin sensitization in a guinea pig maximization test, with 17% of the animals
showing positive results.
SUBCHRONIC TOXICITY
Conclusion:
The available subchronic toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
A submitted confidential 28-day or gavage study was consistent with guidelines.
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Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
A confidential, 4-week, repeated-dose oral gavage study in rats was submitted. The NOAEL and
LOAEL were 15 and 150 mg/kg/day, respectively, based on liver effects
No pertinent studies were located that addressed the subchronic toxicity endpoints in the
guidelines listed below.
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Subchronic Dermal Toxicity (21/28-day or 90-day)
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline 411)
Subchronic Inhalation Toxicity (90-day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the reproductive toxicity endpoints in the guidelines
listed below.
Additional Information
A confidential, 4-week repeated-dose oral gavage study in rats was submitted. No histopathology
was found in the reproductive organs in either sex at a NOAEL of 600 mg/kg/day; however, the
study duration was relatively short and reproductive function was not tested.
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Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
Although [Formulation 2] apparently has a similar if lower Proprietary C content compared to
[Formulation 1] (-85% Proprietary C), it also contains 1.5-2.0% [Chemical 2] as an anti-scorching
additive (Ref. 11). The presence of [Chemical 2], a neuroleptic, could confound the identification
of the maternal NOAEL/LOAEL values. The small group size prevents the identification of fetal
NOAEL/LOAEL values.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700; OECD
Guideline 414)
Type: Prenatal developmental toxicity
Species, strain, sex, number: Rat, CD, 5 pregnant females/group
Purity: Not reported; [Formulation 2]
Doses: 0 (distilled water at volume of high-dose), 100, 200, 400, 800, and 1,600 mg/kg/day
Vehicle: none
Exposure duration, frequency: gestational days (GD) 6-19
Method: Pregnant rats were treated once daily on GD 6-17 by oral gavage and were observed once
daily on GD 6-20 for mortality and clinical signs. Maternal body weights were measured on GD
0, 6, 9, 12, 16, and 20. Dams dying prematurely were necropsied to determine cause of death.
Examinations of thoracic and abdominal cavities for gross lesions, ovaries, and uterine contents were
conducted on all surviving dams on GD 20. Endpoints included fetal viability, early and late
resorptions, post- implantation loss, total implantations, and corpora lutea.
Results: Maternal mortality was observed in 5/5 at 1,600 mg/kg/day (GD 7 and 8) and 1/5 at 800
mg/kg/day (GD 9); causes of death were not determined. Treatment-related clinical signs were not
observed at <200 mg/kg/day. Clinical signs included dry red matter around the nose and forepaws
(in 1 rat at 400 mg/kg/day and 2 rats at 800 mg/kg/day), and staining of the anogenital area (in 4/5
rats at 800 mg/kg/day). Maternal body weight gain was reduced by 32% at 800 mg/kg/day (largely
because of weight loss during GD6-9), but not affected at lower doses. A slight increase in mean
postimplantation losses (1.0 per dam) at 800 mg/kg/day (compared to 0.6 per dam in concurrent
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controls) was similar to the mean historical control value of 0.9 per dam. No other significant
treatment-related effects were observed. The maternal NOAEL was 400 mg/kg/day and the LOAEL
was 800 mg/kg/day for clinical signs (anogenital staining) and increased mortality (1/5).
[Formulation 2] was not a specific developmental toxicant as the only effect in offspring (marginally
increased postimplantation loss) occurred at a maternally toxic dose (800 mg/kg/day). The small
group size (four surviving dams) does not permit accurate identification of fetal NOAEL/LOAEL
values.
Reference: Ref 5
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
No studies were located that followed or were similar to the two tests listed above.
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
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Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
The available neurotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No neurotoxicity studies were available that followed guideline methods. However, inhibition of
cholinesterase activity, an optional parameter for delayed neurotoxicity in hens under OPPTS
Guideline 870.6100, was noted in rats orally exposed to [Formulation 1] (-85% Proprietary C) (Ref.
10, 14).
No studies were located that followed or were similar to the guidelines listed below.
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat) (OPPTS Harmonized
Guideline 870.6500)
Peripheral Nerve Function (rodent) (OPPTS Harmonized Guideline 870.6850)
Sensory Evoked Potentials (rat, pigmented strain preferred) (OPPTS Harmonized
Guideline 870.6855)
These studies may be indicated, for example, to follow up neurotoxic signs seen in other studies, or
because of structural similarity of the substance to neurotoxicants that affect these endpoints. These
studies may be combined with other toxicity studies.
Additional Neurotoxicity Studies:
A submitted confidential, 4-week repeated-dose oral gavage study in rats included a neurotoxicity
screening battery. No behavioral effects or neurohistopathology were found at a NOAEL of 600
mg/kg/day.
Cholineserase Inhibition
Depression of serum cholinesterase activity was observed in male and female Sprague-Dawley rats
given 500 or 1,500 mg/kg [Formulation 1] (-85% Proprietary C) by gavage (Ref. 10); females were
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more sensitive than males. Suppression was by -33% in males and -78% in females after 1 hour
and was maximal at 8 hours by -62% in males and -93% in females.
In a study comparing three different [Formulation 1] samples (from two different manufacturing
protocols), female Sprague-Dawley rats (4/group) were treated with 0 or 250 mg/kg by oral gavage
in 50% aqueous polyethylene glycol 200 (Ref 14). Four hours later, serum cholinesterase activity
was suppressed by 60-70% for [Sample 1] and [Sample 2] and by -30% for [Sample 3].
Groups of four female Sprague-Dawley rats were administered [Formulation 1] at 0, 15, 50, 150,
500, or 1,500 mg/kg by oral gavage in 50% aqueous polyethylene glycol 200 (Ref. 12). After 4
hours, depression of serum cholinesterase activity was statistically significant and dose-related,
compared to controls in groups treated at > 50 mg/kg. In this study, brain cholinesterase levels were
not significantly affected four hours after treatment at doses as high as 1,500 mg/kg.
Groups of three female New Zealand white rabbits were untreated (controls) or dermally
administered 2,000 mg/kg [Formulation 1] (Ref. 13). Dermal treatment caused no significant
suppression of cholinesterase activity measured in serum and whole blood at 7 or 24 hours or in
brain at 24 hours.
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the endpoints in the guidelines listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
The available genotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Mutagenicity testing of [Formulation 1] (-85% Proprietary C) in mammalian cells in vitro was
conducted under methods equivalent to OPPTS and OECD guidelines. The chromosomal aberration
endpoint for Proprietary C is satisfied by adequate submitted confidential studies: a chromosomal
aberrations assay in human lymphocytes in vitro and an in vivo micronucleus assay in mice.
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Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
No verifiable studies were located for bacterial mutagenicity assays following or similar to the
guideline listed above, but a robust summary for a GLP-compliant study was included in an
unevaluated IUCLID Dataset (Ref. 3).
As described in an incomplete robust summary Ref. 2 conducted a mutagenicity (Ames) assay in
Salmonella typhimurium strains TA98 and TA100 for Proprietary C (Formulation 4 or Formulation
5) (Ref. 3). Results were negative with or without metabolic activation at concentrations as high as
5 mg/plate. This study would not completely satisfy the guideline, since only two strains were
tested.
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
Critical Study:
Type: Mammalian Cell Gene Mutation Test: Forward Mutation
Species, strain: Mouse lymphoma L5178Y
Metabolic activation: Tested with and without Aroclor-1242-induced liver S9 from Sprague-
Dawley rat
Concentrations: 0.01-0.8 |j,L/mL without S9 and 0.06-0.15 |j,L/mL with S9
Purity: -85% Proprietary C as [Formulation 1]; also contains 6.7% [Chemical 1], and 5-10% related
compounds
Method: Selection of forward mutation from TK+/" to TK"7" genotype. Activity compared to positive
controls (ethylmethylsulfonate and dimethylbenzanthracene) and vehicle (DMSO).
Results: No increase in forward mutations was observed.
Reference: Ref. 15
Additional information:
Similar mouse lymphoma mutagenicity assays conducted on [Formulation 1] containing 0.05-0.25%
[Chemical 3] also yielded negative results (Ref. 16, 17, 18).
Chromosomal Aberration in Vitro:
In Vitro Mammalian Chromosome Aberration Test (OPPTS Harmonized Guideline
870.5375)
A submitted confidential study reported negative results for chromosomal aberrations in cultured
human lymphocytes.
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Chromosomal Aberrations in Vivo:
Mammalian erythrocyte micronucleus test (OPPTS Harmonized Guideline 870.5395)
A submitted confidential study reported negative results for micronucleus formation in bone marrow
of mice exposed by oral gavage.
No genotoxicity studies relevant to the following categories or to other types of genotoxic effects
were submitted.
Gene Mutation in Vivo
DNA Damage and Repair
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Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The currently available data were judged adequate to meet the endpoints for acute freshwater
toxicity to fish, aquatic invertebrates, and algae.
The existing data for acute marine/estuary toxicity for fish, aquatic invertebrates, and algae
were judged inadequate to meet these endpoints.
Basis for Conclusion:
A study exists of the acute toxicity to mysid shrimp of wastewater generated during the manufacture
of the flame-retardant compound [Formulation 1] (Ref. 20). A handwritten correction on the title
page of the study indicates that the wastewater samples were from the production of [Formulation
1], not [Formulation 4]. [Formulation 1] contains Proprietary C; however, the wastewater samples
used in the study contained a mixture of compounds, none of which appeared to be Proprietary C.
No pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located that
addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
A confidential study with a 96-hour LC50 of 52.2 mg/L in freshwater fish was submitted. These data
were judged adequate to meet the endpoint.
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
A confidential study with a 48-hour EC50 of 41.9 mg/L in freshwater invertebrates was submitted.
These data were judged adequate to meet the endpoint.
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
A study exists of the acute toxicity to mysid shrimp of wastewater generated during the manufacture
of the flame-retardant compound [Formulation 1] (Ref. 20). A handwritten correction on the title
page of the study indicates that the wastewater samples were from the production of [Formulation
1], not [Formulation 4]. [Formulation 1] contains Proprietary C; however, the wastewater samples
used in the study contained a mixture of compounds, none of which appeared to be Proprietary C.
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Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
A confidential study with 96-hour EC50 values for freshwater algal growth inhibition and growth
rate inhibition of 20.1 and 38.5 mg/L, respectively, was submitted. These data were judged adequate
to meet the endpoint.
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
A confidential chronic toxicity to freshwater invertebrates study was submitted. The 23-day EC50
for parental mortality was 7.31 mg/L. The NOEC and LOEC for impaired reproduction were >3.68
mg/L and >3.68 mg/L, respectively. These data were judged adequate to meet the endpoint.
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
No relevant data were located for chronic toxicity to marine/estuarine invertebrates.
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
6-18
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Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
6-19
-------
Physical/Chemical Properties
Proprietary C
CAS
MF
MW
SMILES
Water Solubility (mg/L):
Conclusion:
The available water solubility data are adequate.
Basis for Conclusion:
A confidential experimental study for the water solubility of Proprietary C was submitted. Using
OECD Guideline 105, a water solubility of 232 mg/L at 20°C was measured.
LogKow:
Conclusion:
The available log Kow data are adequate.
Basis for Conclusion:
A confidential experimental study for the log Kow of Proprietary C was submitted. Using OECD
Guideline 107, a log Kow of 2.83 was measured using the shake flask method.
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
6-20
-------
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
6-21
-------
Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation: Confidential experimental studies on the biodegradation of Proprietary
C indicate 37% oxygen uptake after 28 days in OECD 302C, 5% degradation in modified Sturm test
over 28 days, and 8-15% inhibition to activated sludge.
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH:
Conclusion:
The available hydrolysis data are adequate.
Basis for Conclusion:
A confidential experimental study on the hydrolysis of Proprietary C was submitted. Conducted
according to EEC guideline C.7, the hydrolytic stability of Proprietary C at pH 4, 7, and 9 was
6-22
-------
determined at 50°C and it was found to undergo <10% degradation after 5 days. The hydrolysis
half-life at 25°C was determined to be greater than 1 year.
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
6-23
-------
Flame Retardant Alternatives
Proprietary D: Reactive brominated flame retardant
Hazard Review
7-1
-------
Proprietary D: Reactive brominated flame retardant
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
*
*
*
*
*
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
X
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
*
7-2
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Proprietary D: Reactive brominated flame retardant
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
*
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
-------
Chemical Identity
Proprietary D: Reactive brominated flame retardant
Synonyms
CAS
MF
MW
SMILES
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401)
Conclusion:
The available acute oral toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion.
An acute oral study to determine the LD50 of Proprietary D was conducted on rats, but was available
only as an incomplete robust summary.
As described in an incomplete robust summary, Sprague-Dawley rats (5/sex) were administered a
single dose of 10,000 mg/kg of Proprietary D orally in corn oil, and observed for 4 hours and then
daily for 14 days. No deaths occurred, and no gross lesions were seen at necropsy. Therefore, the
LD50 was > 10,000 mg/kg (Ref 2).
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
An acute dermal study was conducted in rabbits, but was available only as an incomplete robust
summary.
As described in an incomplete robust summary, New Zealand white rabbits (2/sex) were exposed
to a single application of 20,000 mg/kg of Proprietary D applied dermally to intact and abraded skin
of the back and flank under an occlusive dressing for 24 hours. The dressings were then removed
7-4
-------
and the application sites were washed. There were no animal deaths. Therefore, the dermal LD50
was>20,000mg/kg. Very slight to slight erythema, edema, and atonia were noted during the 14-day
observation period (Ref. 2).
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
An acute inhalation study in rats was available only as an incomplete robust summary.
As described in an incomplete robust summary, Charles River CD rats (5/sex) were exposed to 0.008
mg/L of Proprietary D as a saturated vapor for 1 hour. There were no animal deaths and no signs
of toxicity during the exposure or the 14-day observation period, and no gross lesions were observed
at necropsy. Thus, the LC50 was >0.008 mg/L (Ref. 5).
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available acute eye irritation data were judged inadequate to meet the endpoint.
Basis for Conclusion:
Two acute eye irritation studies in rabbits were available only as an incomplete data summaries in
an HPV submission.
As described in the data summary, Proprietary D (dose not reported) was instilled into the right eye
of 6 rabbits. Observations recorded at 1, 24, 48, and 72 hours after treatment reported no positive
ocular scores, and found the test material was not irritating to the eyes. The study was conducted
according to Good Laboratory Practices (Ref. 6).
An additional study described in the data summary, instilled 0.1 mL of Proprietary D in the right
sacs of the right eyes of 6 New Zealand albino rabbits (3/sex). In the 72-hour observation period,
redness and chemosis of the conjuctiva were reported. Discharge was also noted in 1 rabbit at 24
hours.
7-5
-------
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available acute dermal irritation data were judged inadequate to meet the endpoint.
Basis for Conclusion:
An acute dermal irritation study in rabbits was available only as an incomplete data summary in an
HPV submission.
As described in the data summary, a single application of 0.5 mL Proprietary D was made to the
clipped backs of 6 New Zealand albino rabbits (3/sex) under a gauze patch and wrapped with an air-
tight occlusive wrap (duration not reported). The skin of 3 rabbits was abraded. Observations
recorded at 24, 48, and 72 hours after treatment reported no irritation on the intact skin, and
erythema and edema on the abraded skin. The primary irritation index, according to the method of
Draize, was 0.7, and the chemical was not considered to be a primary skin irritant (Ref. 3).
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The skin sensitization endpoint is not satisfied.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
SUBCHRONIC TOXICITY
Conclusion:
No available subchronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
7-6
-------
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408),
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422), respectively.
Subchronic Dermal Toxicity (21/28-day or 90-day)
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90 day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the reproductive toxicity endpoints in the guidelines
listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
No available developmental toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the developmental toxicity endpoints in the
guidelines listed below.
7-7
-------
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
7-S
-------
Basis for Conclusion:
No pertinent neurotoxicity studies were located that addressed the endpoints in the guidelines listed
below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Note this guideline is not relevant for Proprietary D, which is not an
Organophosphorus substance.
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion.
No pertinent studies of immunotoxicity were located that addressed the endpoints in the guideline
listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
The available gene mutation data were judged inadequate to meet the endpoint.
Basis for Conclusion.
Two in vitro gene mutation studies were conducted, but were only available as incomplete robust
summaries. Studies of chromosomal aberrations were not available, however, and are needed for
adequate characterization of the genotoxicity endpoint.
7-9
-------
Gene Mutation in vitro
Bacterial Reverse Mutation Test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
An in vitro gene mutation study reported negative results in Salmonella typhimurium bacteria
(strains not specified) and in Saccharomyces cerevisiae (D4) at concentrations up to 1.0 jig/plate of
Proprietary D, with and without metabolic activation (Ref 3).
An additional in vitro gene mutation study, reported negative results in Salmonella typhimurium
bacteria (TA 1535, TA 1537, TA98, andTA 100) at concentrations up to 5,000 jig/plate (which was
cytotoxic) of [Formulation 1] (a trade name for Proprietary D), with and without metabolic
activation. Negative and positive controls were used (Ref. 4).
No genotoxicity studies relevant to the below categories or to other types of genotoxic effects were
located.
Gene Mutation in Vivo
Chromosomal Aberrations in Vitro
Chromosomal Aberrations in Vivo
DNA Damage and Repair
7-10
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available acute toxicity data for fish, aquatic invertebrates, and algae were judged inadequate
to meet the endpoints.
Basis for Conclusion:
A data summary was located for a 96-hour acute toxicity study in bluegill sunfish (Lepomis
macrochirus) exposed to Proprietary D (Ref. 1). Fish were exposed to aqueous dilutions of the test
material at 0, 10, 18, 32, 56, and 100 mg/L. Acetone was used as a carrier solvent. The test waters
were completely opaque at the two highest concentrations. The calculated 96-hour LC50 was 12
mg/L (95% CI: 1-18 mg/L). Study details were unavailable to conduct a thorough, independent
review of the study. The concentrations in the test waters were not analytically verified; however,
the opacity of the water at the two highest concentrations suggest that the test material was not well
dissolved. The available data are not adequate to satisfy the acute toxicity endpoint for freshwater
fish.
No pertinent acute toxicity studies with marine fish, aquatic invertebrates, or algae were located that
followed or were similar to the guideline protocols listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that followed
or were similar to the guideline protocols listed below.
7-11
-------
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that followed or were similar to the guideline
protocols listed below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD Guideline
205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
7-12
-------
Physical/Chemical Properties
Proprietary D: Reactive brominated flame retardant
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log K,,w: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
7-13
-------
Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation: No data
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
7-14
-------
Flame Retardant Alternatives
Proprietary E: Tetrabromophthalate diol diester
Hazard Review
3-1
-------
Proprietary E: Tetrabromophthalate diol diester
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
8-2
-------
Proprietary E: Tetrabromophthalate diol diester
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
-------
Chemical Identity
Proprietary E: Tetrabromophthalate diol diester
CAS
MF
MW
SMILES
Human Health Endpoints
ACUTE TOXICITY
Conclusion:
No available acute toxicity data.
Basis for Conclusion.
No acute toxicity studies were located that addressed the endpoints in the guidelines listed below.
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425,
420, 423, 401)
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline
402)
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline
403)
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline
404)
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The skin sensitization endpoint is not satisfied.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
8-4
-------
SUBCHRONIC TOXICITY
Conclusion:
No available subchronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408),
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422), respectively
Subchronic Dermal Toxicity (21/28-day or 90-day).
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90 day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the reproductive toxicity endpoints in the guidelines
listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
8-5
-------
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
No available developmental toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the developmental toxicity endpoints in the
guidelines listed below.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
8-6
-------
Basis for Conclusion.
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
Basis for Conclusion:
No neurotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion.
No immunotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
3-7
-------
GENOTOXICITY
Conclusion:
No available genotoxicity data.
Basis for Conclusion.
No genotoxicity studies relevant to the below categories or to other types of genotoxic effects were
located.
Gene Mutation in Vitro
Gene Mutation in Vivo
Chromosomal Aberrations in Vitro
Chromosomal Aberrations in Vivo
DNA Damage and Repair
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
No available acute toxicity data for fish, aquatic invertebrates, and algae.
Basis for Conclusion:
No pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located that
addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
8-9
-------
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
8-10
-------
Physical/Chemical Properties
Proprietary E: Tetrabromophthalate diol diester
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log Kow: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
8-11
-------
Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation: No data
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
8-12
-------
Flame Retardant Alternatives
Proprietary F: Halogenated aryl ester
Hazard Review
9-1
-------
Proprietary F: Halogenated aryl ester
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
9-2
-------
Proprietary F: Halogenated aryl ester
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
/
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
/
/
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
/
/
/
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
-------
Chemical Identity
Proprietary F: Halogenated aryl ester
CAS
MF
MW
SMILES
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401)
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
The available acute oral lethality study was conducted according to EEC acute toxicity methods for
fixed-dose studies. Methodological procedures appear consistent with OECD methods for acute oral
toxicity testing (i.e., OECD Guideline 401). The study appears adequate.
Type: Acute oral LD50
Species, strain, sex, number: Rat, Sprague-Dawley, 5 males and 5 females
Dose: 2000 mg/kg
Purity: 99.7%
Vehicle: Not indicated
Observation period: 14 days post dosing
Method: Directive 92/69/EEC (OJ No. L383A, 29.12.92), Part B, Method B.I bis. Acute toxicity
(oral), fixed-dose method.
Results: No deaths; therefore, LD50 >2000 mg/kg. Piloerection and hunched posture in 10/10 rats;
recovery by post-exposure day 4.
Reference: Ref 1
No studies were submitted that conformed to the following guidelines.
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline
402)
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline
403)
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
9-4
-------
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline
404)
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The skin sensitization endpoint is not satisfied.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
SUBCHRONIC TOXICITY
Conclusion:
No available subchronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408),
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422), respectively
Subchronic Dermal Toxicity (21/28-day or 90-day).
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90 day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
9-5
-------
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the reproductive toxicity endpoints in the guidelines
listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
No available developmental toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the developmental toxicity endpoints in the
guidelines listed below.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
9-6
-------
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
Basis for Conclusion:
No neurotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Neurotoxicity (Adult)
9-7
-------
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion.
No immunotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
No available genotoxicity data.
Basis for Conclusion.
No genotoxicity studies relevant to the below categories or to other types of genotoxic effects were
located.
Gene Mutation in Vitro
Gene Mutation in Vivo
Chromosomal Aberrations in Vitro
Chromosomal Aberrations in Vivo
DNA Damage and Repair
9-8
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available acute freshwater toxicity data for fish, aquatic invertebrates, and algae were
judged adequate to meet the endpoints.
The available acute marine/estuary toxicity data for fish, aquatic invertebrates, and algae
were judged inadequate to meet the endpoints.
Basis for Conclusion:
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline 850.1075;
OECD Guideline 203)
A confidential 96-hour study in fish was located that reported no effects at saturation. These data
allow this endpoint to be adequately characterized.
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010; OECD
Guideline 202)
A confidential study in daphnid was located that reported a 24-hour EC50 of 1.2 mg/L and a 48-hour
EC50 of 0.42 mg/L. These data allow this endpoint to be adequately characterized.
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
A confidential 96-hour study in green algae was located that reported no effects at saturation. These
data allow this endpoint to be adequately characterized.
No additional acute toxicity studies with freshwater or saltwater fish, aquatic invertebrates, or algae
were located that followed or were similar to the guideline protocols listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
9-9
-------
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
9-10
-------
Physical/Chemical Properties
Proprietary F: Halogenated aryl ester
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log Kow: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability:
Conclusion: The flammability (as the flash point) has been adequately characterized.
Basis for Conclusion: The key study was performed according to EEC Methods, Directive
92/69/EEC (OJ No. L383A, 29.12.92), Part A, Method A9, flash point.
Flash Point: 215°C (Ref. 2)
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
9-11
-------
Henry's Law Constant: No data
9-12
-------
Environmental Fate
Bioconcentration
Fish:
Conclusion:
The available bioconcentration data are adequate.
Basis for Conclusion:
A confidential guideline study submitted on Proprietary F indicates that the bioconcentration factor
is 1.7-6.2.
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion:
The available aerobic biodegradation data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary F indicates that its half life is 3.5 days in water in a
shake flask die-away test. It was also found to undergo 6% biodegradation after 28 days in closed
bottle test in a submitted confidential study.
9-13
-------
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH:
Conclusion:
The available hydrolysis as a function of pH data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary F indicates that its hydrolysis half life is >1 year at
pH 4, 7, and 9.
Sediment/Water Biodegradation:
Conclusion:
The available sediment/water biodegradation data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary F indicates that its half life is 8.5 days in sediment in
a shake flask die-away test.
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption:
Conclusion:
The available soil adsorption data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary F indicated that the soil adsorption coefficient is
>28,840.
9-14
-------
Flame Retardant Alternatives
Proprietary G: Triaryl phosphate, isopropylated
Hazard Review
10-1
-------
Proprietary G: Triaryl phosphate, isopropylated
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
*
*
*
*
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
*
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
/
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
*
*
*
*
*
10-2
-------
Proprietary G: Triaryl phosphate, isopropylated
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
*
*
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
10-2
-------
Chemical Identity
Proprietary G: Triaryl phosphate, isopropylated
Synonym:
CAS
MF
MW
SMILES
Many of the available health effects studies were conducted with commercial mixtures that
commonly contained triphenyl phosphate as well as Proprietary G. The available information
regarding the composition of these mixtures is presented below, but the composition of the actual
samples tested in the health effects studies usually was not reported.
[Formulation 1 ] is reported to contain 60-100% Proprietary G and 15-40% triphenyl phosphate (Ref
24) and [Formulation 2] is reported to contain 60-100% Proprietary G and 4-7% triphenyl phosphate
(Ref. 25).
Major Components of
[Formulation 3] and [Formulation 4] as reported in Ref. 34
Component
Total Proprietary G
[Chemical 1]
[Chemical 2]
[Chemical 3]
[Chemical 4]
[Chemical 5]
Triphenyl Phosphate
[Formulation 3]
49
8
6
2
21
12
33
[Formulation 4]
61
11
7
5
27
11
18
ACUTE TOXICITY
Human Health Endpoints
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401)
Conclusion:
The available acute oral toxicity data were judged inadequate to meet the endpoint.
10-4
-------
Basis for Conclusion.
The available data are for limit tests on undefined flame retardants for which compositional
information was not provided. The authors of the studies referred to them as "non-definitive",
possibly because of the small group sizes (which, however, are consistent with current guidelines);
in other respects the studies follow current guidelines.
Additional Studies and Information:
No deaths were observed in Sprague-Dawley rats (3/sex) given [Formulation 1] (mixture of
Proprietary G and triphenyl phosphate) as a single oral dose of 5,000 mg/kg (Ref. 13). Clinical
signs, which included tremors (0/3 males, 1/3 females), oral discharge, ataxia (0/3 males, 1/3
females), decreased locomotion (1/3 males, 1/3 females), chromorhinorrhea, chromodacryorrhea,
and abdominogenital staining, subsided by day 11. No effects on body weight gain and no gross
internal lesions were observed.
A parallel acute oral study on Sprague-Dawley rats (3/sex) given [Formulation 2] at a dose of 5,000
mg/kg, reported clinical signs (abdominogenital staining and chromorhinorrhea) on the first 2 days
post dosing, but no mortality, body weight gain effects, or gross internal lesions were reported (Ref.
17).
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are for limit tests on undefined flame retardants for which compositional
information was not provided. The authors of the studies referred to them as "non-definitive",
possibly because of the small group sizes (which, however, are consistent with current guidelines);
in other respects, the studies follow current guidelines.
Additional Studies and Information:
No deaths were observed among Sprague-Dawley rats (3/sex) that were dermally exposed to
[Formulation 1] (mixture of Proprietary G and triphenyl phosphate) at a dose of 2,000 mg/kg for 24
hours under an occlusive covering (Ref. 14). There were no effects on body weight gain, no signs
of irritation on the test site, and no gross internal lesions observed.
In a parallel study in Sprague-Dawley rats (3/sex) dermally treated with 2,000 mg/kg
[Formulation 2], all but one female gained weight, but there were no deaths, signs of irritation, or
gross internal lesions (Ref, 18).
10-5
-------
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300; OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline. A non-guideline study
evaluated neurotoxicity of combustion products of an Proprietary G/triphenyl phosphate mixture in
the presence of cyclic phosphonate compounds.
Additional Studies and Information:
Preliminary results of a study were reported (Ref. 38) investigating whether toxic compounds were
formed when cyclic phosphonate compounds were thermally decomposed in the presence of other
phosphate compounds in trimethylol polyol-based urethane foam. When rats were exposed (head
only) for 20 minutes to smoke and decomposition gases from foam containing equal proportions of
the cyclic phosphonate compounds and a mixture of Proprietary G and triphenyl phosphate, no
convulsive seizures, characteristic of exposure to toxic bicyclic phosphites or phosphates, were
observed.
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available eye irritation data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are for undefined flame retardants for which compositional information was not
provided. The authors of the studies referred to them as "non-definitive", although they were
consistent with current guidelines.
Additional Studies and Information:
Slight conjunctival erythema was observed in the eyes of 1/1 male and 1/2 female New Zealand
White rabbits 24 hours after instillation with 0.01 mL of [Formulation 1] (mixture of Proprietary G
and triphenyl phosphate) but was resolved by 48 hours (Ref. 15). No conjunctival discharge or
effects on the cornea or iris were observed. The material was tentatively characterized as
"practically non-irritating", based on a maximum irritation score of 1.3/110 at 24 hours.
In a parallel study in New Zealand White rabbits (1 male and 2 females) instilled with 0.01 mL
[Formulation 2], there were no signs of eye irritation observed at 1, 24, 48, or 72 hours (Ref. 19).
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The material was tentatively characterized as non-irritating to the eyes based on a primary irritation
index of 0/110 at all timepoints.
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available dermal irritation data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available data are for undefined flame retardants for which compositional information was not
provided. The authors of the studies on the Durad materials referred to them as "non-definitive",
although they were consistent with current guidelines.
Additional Studies:
No dermal irritation (erythema or edema) was observed in one male and two female New Zealand
White rabbits that were dermally exposed for 4 hours to [Formulation 1] (mixture of Proprietary G
and triphenyl phosphate) on two occluded test sites (0.5 mL per site) and examined at 4.5, 24, 48,
or 72 hours (Ref. 16). The material was tentatively rated as non-irritating to intact rabbit skin, based
on scores of 0/8.0 at all timepoints.
In a parallel dermal irritation study in one male and two female New Zealand White rabbits exposed
for 4 hours to [Formulation 2] on two occluded test sites (0.5 mL per site), no irritation was observed
at times between 4.5 and 72 hours (Ref. 20). The material was tentatively rated as non-irritating to
intact rabbit skin, based on scores of 0/8.0 at all timepoints.
In skin irritation assays in male New Zealand White rabbits (6/group), 24-hour topical
administration (0.5 mL/site) of [Formulation 4] or [Formulation 10] did not elicit erythema or edema
to intact or abraded skin (examined at 24 and 72 hours) (Ref. 6). The mean primary dermal irritation
indices were 0/2.0 for both materials, which were characterized as non-irritating to skin.
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The available skin sensitization data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
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SUBCHRONIC TOXICITY
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Conclusion.
The available subchronic oral toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported preliminary results of a 39-41-day combined
subchronic plus reproductive/developmental toxicity screening study in rats exposed by oral gavage.
Preliminary results suggested adrenal and liver effects, with adrenal weight effects in females at a
LOAEL of 25 mg/kg/day. These data are not adequate because the final results were not available.
No other verifiable data were available for defined substances tested under guideline methods. A
study on undefined [Formulation 4] appeared to follow the guideline for a 28-day oral study, but was
only available as an incomplete robust summary. The unexplained mortality in this study indicates
that it may not be an adequate study.
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
As described in an incomplete robust summary (results were not presented quantitatively) for an
HPV submission, Sprague-Dawley rats (10/sex) received [Formulation 4] in the diet at
concentrations of 0, 0.1, 0.5, or 1.0% for 28 days (Ref. 5). Treatment had no effect on survival (but
12 rats died: 1 control, 4 low-dose, 4 mid-dose, and 3 high-dose rats). Treatment also had no effect
on urinalysis results, incidence of gross lesions at necropsy, or histology of the liver and kidney
(histology examined only in high dose animals and controls). It was not specified whether animals
that died during the study were necropsied or examined histologically. Reduced feed consumption
was observed in the mid-dose group in both sexes and reduced body weight gain was noted in high-
dose females. Abnormalities (not specified) were observed in clinical chemistry measurements in
mid- and high-dose groups and in hematology parameters at the high dose. Relative liver weights
were elevated in all treated groups. The unexplained mortality during this short term study raises
concern for study adequacy.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Subchronic Dermal Toxicity (21/28-day or 90-day)
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21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90-day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD
Guideline 413)
REPRODUCTIVE TOXICITY
Conclusion:
The available reproductive toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported preliminary results of a 39-41-day combined
subchronic plus reproductive/developmental toxicity screening study in rats exposed by oral gavage.
Preliminary results suggest an ovarian weight effect at >25 mg/kg/day, and an epididymal weight
effect and reduced fertility at 100 and 400 mg/kg/day. These data are not adequate because the final
results were not available. No other pertinent studies were located that addressed the reproductive
toxicity endpoints in the guidelines listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported preliminary results of a 39-41-day combined
subchronic plus reproductive/developmental toxicity screening assay in rats exposed by oral gavage.
Preliminary results suggest reduced pre- and post-natal survival at 400 mg/kg/day. These data are
not adequate because the final results were not available. No other pertinent studies were located
that addressed the developmental toxicity endpoints in the guidelines listed below.
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Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
Additional information
As described in an unvalidated robust summary, 3 days of exposure to [Formulation 7], tested
without metabolic activation at concentrations between 0.04 and 5.0 jig/mL, did not induce cell
transformation in cultured Balb/c-3T3 cells (Ref. 36).
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NEUROTOXICITY
Conclusion:
The available neurotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
Available acute and 28-day studies indicate that there is a risk of delayed neurotoxicity from
exposure to Proprietary G. Most studies either were conducted on undefined substances or were not
described in sufficient detail. A summary of a study on purified components of [Formulated] flame
retardants suggests that [Chemical 4] or [Chemical 2] are the neurotoxic components of these
mixtures; however, details of the in vivo study in hens were not located. The neurotoxicity of
Proprietary G preparations would be dependent on the relative content of [Formulation 11 ] isomers.
No data are available for the full battery of tests for functional neurotoxicity or for developmental
neurotoxicity.
Delayed Neurotoxicity
Conclusion:
The available delayed neurotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
The acute study (experiment A) on a defined Proprietary G mixture departed from guideline in that
enzyme inhibition was assayed 24 hours after dosing rather than 48 hours, but reported significant
suppression of both brain neurotoxic esterase and plasma cholinesterase levels. The longer study
did not conduct a complete battery of neurobehavioral tests as stipulated under the guideline, but
reported adverse effects on motor coordination at all doses on the day of treatment. The highest dose
(11,700 mg/kg) exceeded that recommended under the guideline, but that deviation does not affect
the conclusion of the study. Studies on purified components of [Formulated] flame retardants
identified the neurotoxic components, but were not adequately described. The majority of studies
suggest that delayed neurotoxicity may result from exposure to oral doses in excess of 1,000 mg//kg.
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Critical Studies
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, 12-14 months old, White Leghorn, 4/dose for experiment A;
10-12/dose for experiment B.
Purity: Proprietary G with the composition as in the following table.
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Composition of Proprietary G assayed by Ref. 37
Component
Total Proprietary G
[Chemical 4]
[Chemical 6]
[Chemical 2]
[Chemical 7]
[Chemical 5]
[Chemical 8]
[Chemical 9]
Triphenyl Phosphate
Percent
<75
24
18
10
10
6
7
<1
24
Doses: Experiment A. Six doses between 12 and 11,700 mg/kg;
Experiment B. 0, 12, or 370 mg/kg in corn oil or 11,700 mg/kg undiluted
Vehicle: Corn oil
Positive control: Tri-ort/zo-cresyl phosphate (TOCP)
Route: Oral (not specified)
Exposure duration, frequency: Experiment A, single treatment followed 24 hours later by
biochemical assay; Experiment B, 6 weeks, single treatments 3 weeks apart; study terminated 3
weeks after second dose.
Method: Experiment A. Brain neurotoxic esterase (NTE) and plasma cholinesterase (PChE)
measurements recorded 24 hours after single treatment with Proprietary G, corn oil or TOCP.
Experiment B. Doses were chosen based on results of experiment A to represent minimal, 50%, and
maximal inhibition of brain NTE. Body weight and food consumption measured every 3-4 days,
walking behavior evaluated weekly. Neurohistopathology evaluated at termination.
Results: Experiment A. The NOAELs for inhibition of NTE or PChE were 12 and 180 mg/kg,
respectively. Doses about 1,000 mg/kg and higher caused -70% inhibition of NTE and -80%
inhibition of PChE. The positive control (500 mg/kg of TOCP) inhibited brain NTE by 85.2% and
PChE by 70%.
Experiment B. Proprietary G had no effect on mortality. Few adverse signs visible at or below 370
mg/kg. All treated at 11,700 mg/kg showed motor incoordination beginning day 1, with feather loss
7-11 days later. Body weights not affected at lowest dose. Body weight effects at mid- and high-
dose are uncertain because text and graph do not match; one dose caused transient weight loss on
days 22-38 and the other persistent weight loss from day 22 to the end of the study. TOCP caused
persistent weight loss beginning day 5. Food consumption was transiently reduced in all groups
(including positive and negative controls) on day 2 and 23, also on day 18 for TOCP. Significant
transient, dose-dependent impairment of gait was observed on day 1 and 22 for hens treated with
Proprietary G at all doses. Hens treated with TOCP showed significant impairment on day 1 and
15, with gradual worsening to the end of the study. Neurohistopathological examinations revealed
10-12
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no significant difference between Proprietary G treatment and corn oil controls, whereas TOCP
caused a significant increase in axonal degeneration in brain, spinal cord (cervical, thoracic and
sacro-lumbar), and bilateral degeneration of the sciatic nerve.
Reference: Ref 37
Additional Studies:
As described in Ref. 44, a series of acute delayed neurotoxicity assays were conducted on
[Formulated] flame retardants. No ataxia was observed in groups of 4 hens treated with
[Formulation 5] at doses of 2,000, 4,000, or 8,000 mg/kg; 3/30 hens treated with 16,000 mg/kg
showed ataxia (Ref. 7). Only 1/10 hens treated with [Formulation 6] at 20,000 mg/kg exhibited
ataxia (Ref. 8). In one study on [Formulation 4], no ataxia was observed at doses of 500, 1,000, or
2,000 mg/kg, whereas 2/10 treated at 4,000 mg/kg showed ataxia (Ref. 9); inhibition of brain NTE
was 79.5% at the highest dose. In a second study on [Formulation 4], incidences of ataxia (0/10,
3/10, 1/10 and 1/10) and neurohistopathological lesions (1/10, 0/10, 1/10, and 2/10) were not
precisely related to the respective doses of 3,000, 5,000, 7,000, and 9,000 mg/kg (Ref. 10). For
[Formulation 3], incidences of ataxia (1/9,4/10,6/10 and 3/10) andneurohistopathology (0/10,4/10,
7/10 and 1/10) were observed in the 2,000,4,000, 6,000, and 8,000 mg/kg groups, respectively (Ref.
11).
A subchronic (91-day) oral neurotoxicity assay is summarized briefly in a TSCA 8e submission
(Ref. 12), and in more detail by Ref. 44 and in a robust summary in an HPV submission (Ref. 23;
U.S. EPA comments not available). In this study, hens (20/group) were administered [Formulation
3] (mixture of Proprietary G and triphenyl phosphate) daily at doses of 0, 10, 20, 90, and 270
mg/kg/day. Deaths occurred in all dose groups as follows: 2/20 vehicle controls, 4/20 positive
controls, 3/20 at 10 mg/kg/day, 5/20 at 90 mg/kg/day, and 6/20 at 270 mg/kg/day. Ataxia was
observed in 4/20 at 90 mg/kg/day and 9/20 at 270 mg/kg/day. Histopathological examination of
nervous tissue of 10 hens/group revealed the following: significant degeneration at 3 levels of the
spinal cord in 3 vehicle controls, significant degeneration of the spinal cord in TOCP hens,
degeneration of the spinal cord and peripheral nerves in hens of the 90 and 270 mg/kg/day groups,
with a dose-response relationship for severity and incidence (further details not reported). No ataxia
or brain histopathology was observed at 10 or 20 mg/kg/day.
[Formulation 4] and [Formulation 6] were given in two 2,000 mg/kg doses 21 days apart to hens
(4/group) (Ref. 22). Neither compound caused body weight effects, clinical signs of neurotoxicity
or an increase in gross internal lesions at necropsy (21 days after the second dose). There was no
evidence of neurohistopathology in hens treated with [Formulation 4], but one out of four hens
treated with [Formulation 6] had unilateral brain lesions at two histological levels.
Proprietary G at tested positive for neurotoxicity in hens treated at three 21-day intervals with
10,000 mg/kg (Ref. 33). Effects included gross paralysis with demyelination confirmed
histopathologically.
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Several components of the [Formulated] series of flame retardants were isolated to >99% purity and
tested at doses as high as 1,000 mg/kg in hens for neurotoxicity and suppression of neurotoxic
esterase (Ref 29). Details of these studies were not located. Three isomers of [Chemical 1] and
[Chemical 5] elicited no signs of neurotoxicity and no suppression of NTE levels. [Chemical 5] was
also judged to be non-neurotoxic, eliciting no ataxia or other signs of neurotoxicity and insignificant
suppression of NTE (-4% or -15%) in two tests. Both [Chemical 2] and [Chemical 4] were positive,
eliciting ataxia and neurotoxicity at 1,000 mg/kg, but not at lower doses; [Chemical 2] suppressed
NTE by 85% and [Chemical 4] suppressed NTE by 79 and 90% in two assays. The author suggested
that neurotoxicity was associated with triaryl phosphates containing a 2-alkyl substituent with an
oxidizable alpha-hydrogen.
In a two-hen screening test, a single 1,000 mg/kg dose of [Formulation 3] administered in gelatin
capsules to two hens resulted in a 53.1% inhibition of neurotoxic esterase activity in the brain (Ref.
42). The report was not clear as to the day on which the hens were sacrificed.
No neurotoxicity studies were located that followed or were similar to the guidelines listed below.
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity Study (OPPTS Harmonized Guideline 870.6300)
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat) OPPTS Harmonized Guideline
870.6500
Peripheral Nerve Function (rodent) OPPTS Harmonized Guideline 870.6850
Sensory Evoked Potentials (rat, pigmented strain preferred) OPPTS Harmonized Guideline
870.6855
These studies may be indicated, for example, to follow up neurotoxic signs seen in other studies, or
because of structural similarity of the substance to neurotoxicants that affect these endpoints. These
studies may be combined with other toxicity studies.
Other Neurotoxicity Data
Cholinesterase inhibition
[Formulation 3] at doses of 15, 20, or 25 mL/kg did not inhibit blood cholinesterase activity, but
neither species of animal (3/group) nor the specific biological material assayed were reported (Ref.
4).
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IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion:
No immunotoxicity study was located that followed or was similar to the guideline listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
The available genotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No verifiable genotoxicity data were located. The available studies were only accessible as robust
summaries in a IUCLID Dataset that had not undergone review by the European Commission (Ref.
3). Furthermore, the data were unpublished industry-sponsored studies on commercial products for
which no contemporaneous component analyses were provided. Current compositional information
taken from MSDS documents are presented in the following table. The results of these studies are
summarized below despite their uncertain validity. In general, not enough details were provided to
ascertain whether protocols met the standards of OPPT or OECD guidelines.
Percentage of Proprietary G and triphenyl phosphate in Currently Available Commercial Products
Product
[Formulation 7]
[Formulation 8]
[Formulation 9]
[Formulation 2]
Proprietary G (%)
60-100
60-100
60-100
60-100
triphenyl phosphate (%)
15-40
10-30
7-13
4-7
Reference
Ref. 26
Ref. 27
Ref. 28
Ref. 25
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
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As described in unvalidated robust summaries, negative results were reported for mutagenicity
assays in Salmonella typhimurium with or without metabolic activation. [Formulation 7] and
[Formulation 9] were tested in strains TA98, TA100, and TA1537 at concentrations as high as 1.62
mg/mL (Ref. 1, 2). [Formulation 9] and [Formulation 2] were tested in strains TA98, TA100,
TA1535, TA1537, and TA1538 at concentrations as high as 0.1 mL per plate (Ref. 31, 32).
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
As described in an unvalidated robust summary, [Formulation 7] at concentrations of 0.0013-0.1
|j,L/mL was not mutagenic to cultured mouse lymphoma L5178Y TK+/" cells without metabolic
activation (Ref. 30). Results in the presence of metabolic activation were equivocal in that a dose-
response was observed, but none of the cultures exhibiting >10% total growth had mutant
frequencies 2-fold greater than background.
Gene Mutation in Vivo
Sex-linked Recessive Lethal test in Drosophila melanogaster (OPPTS Harmonized
Guideline 870.5275)
As described in an unvalidated robust summary, [Formulation 7] (32.5, 75, or 150 mg/mL) fed to
adult male fruit flies for 3 days did not induce heritable mutations (Ref. 43).
Chromosomal Aberration in Vitro
No pertinent studies were located.
Chromosomal Aberration in Vivo
Mammalian Bone Marrow Chromosomal Aberration Test (OPPTS Harmonized
Guideline 870.5385)
As described in an unvalidated robust summary no increase in chromosomal aberrations was
observed in the bone marrow of Chinese hamsters (8/sex/group), 16, 24, or 48 hours after
receiving a single oral dose of 5,000 mg/kg [Formulation 7] by gavage (Ref. 41). The summary
indicated that the study was conducted under OECD Guideline 475 and GLP. Another unvalidated
robust summary reported that a significant increase (compared to controls) in the incidence of bone
marrow cells with chromosomal anomalies was observed in Chinese hamsters (6/sex/group) 24
hours after receiving the second of two consecutive daily doses of 2,500 or 5,000 mg/kg/day
[Formulation 7] by oral gavage (Ref. 40); no increase was observed in animals receiving 1,250
mg/kg/day.
DNA Damage and Repair
Unscheduled DNA synthesis in mammalian cells in culture (OPPTS Harmonized
Guideline 870.5550)
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As described in an unvalidated robust summary, [Formulation 7] tested without metabolic activation
at concentrations between 0.6 and 75 nL/mL did not cause unscheduled DNA synthesis in cultured
rat hepatocytes (Ref. 35).
Other
In vivo Sister Chromatid Exchange Assay (OPPTS Harmonized Guideline 870.5915)
As described in an unvalidated robust summary, there was no increase in the frequency of sister
chromatid exchanges in bone marrow cells of Chinese hamsters (4/sex/group) 24 hours after
receiving a single oral dose of 1250, 2,500, or 5,000 mg/kg [Formulation 7] by gavage in
carboxymethylcellulose (Ref. 39).
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Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available acute toxicity data for fish, aquatic invertebrates, and algae were judged inadequate
to meet the endpoints.
Basis for Conclusion:
Summaries were located for several acute toxicity studies of Proprietary G in an HPV test plan
submission and accompanying robust summaries (Ref. 23); however, EPA comments on this
submission were not available. The summaries included two 96-hour studies in fathead minnows
(Pimephalespromelas), three 96-hour studies in rainbow trout (Oncorhynchus mykiss), and three
48-hour studies in Daphnia magna. According to Ref. 21, all of the studies were conducted with
100% Proprietary G; however, other reports have identified the tested material in some of these
studies as [Formulation 1] (Ref. 24) or [Formulation 4] (Ref. 21). [Formulation 1] is a mixture
containing 60-100% Proprietary G and 15-40% triphenyl phosphate (Ref. 24). [Formulation 4] has
been reported to contain 61% Proprietary G and 18% triphenyl phosphate (Ref. 34; see table at
beginning of Human Health Effects for details). The available study summaries and Material Safety
Data Sheets are insufficient to precisely establish the composition of the materials tested in the acute
toxicity studies. Without precise knowledge of the composition of the tested materials, it is not
possible to use these studies to make a definitive statement regarding the acute toxicity of
Proprietary G. The publicly available information regarding the acute toxicity of Proprietary G to
freshwater fish or aquatic invertebrates is insufficient to satisfy the endpoints in the guideline
protocols listed below.
A confidential study was submitted that reported a freshwater daphnid 48-hour EC50 >0.77 mg/L,
the maximum test concentration. This concentration is above the water solubility limit of Proprietary
G. A confidential study was also submitted that reported a freshwater green algal 72-hour EC50 of
approximately 0.480 mg/L. This concentration is also above the water solubility limit of Proprietary
G. The available data were judged inadequate to meet this endpoint.
No pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located that
addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
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Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
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Physical/Chemical Properties
Proprietary G: Triaryl phosphate, isopropylated
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log Kow: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
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Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion:
The available aerobic biodegradation data are not adequate.
Basis for Conclusion:
A single confidential ready biodegradation study, indicating that Proprietary G is not ready
biodegradable, was submitted. This study is not sufficient to fully characterize the aerobic
biodegradation of Proprietary G under environmental conditions.
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
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-------
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
10-22
-------
Flame Retardant Alternatives
Proprietary H: Halogenated aryl ester
Hazard Review
11-1
-------
Proprietary H: Halogenated aryl ester
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
11-2
-------
Proprietary H: Halogenated aryl ester
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
/
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
/
/
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
/
/
/
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
11-:
-------
Chemical Identity
Proprietary H: Halogenated aryl ester
CAS
MF
MW
SMILES
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401)
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
The available acute oral lethality study was conducted according to EEC acute toxicity methods for
fixed-dose studies. Methodological procedures appear consistent with OECD methods for acute oral
toxicity testing (i.e., OECD Guideline 401). The study appears adequate.
Type: Acute oral LD50
Species, strain, sex, number: Rat, Sprague-Dawley, 5 males and 5 females
Dose: 2000 mg/kg
Purity: 99.7%
Vehicle: Not indicated
Observation period: 14 days post dosing
Method: Directive 92/69/EEC (OJ No. L383 A, 29.12.92), Part B, Method B. 1 bis. Acute toxicity
(oral), fixed-dose method.
Results: No deaths; therefore, LD50 >2000 mg/kg. Piloerection and hunched posture in 10/10 rats;
recovery by post-exposure day 4.
Reference: Ref 1
No studies were submitted that conformed to the following guidelines.
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline
402)
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline
403)
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
11-4
-------
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline
404)
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The skin sensitization endpoint is not satisfied.
Basis for Conclusion
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
SUBCHRONIC TOXICITY
Conclusion:
No available subchronic toxicity data.
Basis for Conclusion:
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408),
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422), respectively.
Subchronic Dermal Toxicity (21/28-day or 90-day)
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90 day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
11-5
-------
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the reproductive toxicity endpoints in the guidelines
listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
No available developmental toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the developmental toxicity endpoints in the
guidelines listed below.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
11-6
-------
Basis for Conclusion.
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
Basis for Conclusion:
No neurotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
11-7
-------
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion.
No immunotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
No available genotoxicity data.
Basis for Conclusion.
No genotoxicity studies relevant to the below categories or to other types of genotoxic effects were
located.
Gene Mutation in Vitro
Gene Mutation in Vivo
Chromosomal Aberrations in Vitro
Chromosomal Aberrations in Vivo
DNA Damage and Repair
11-8
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available acute freshwater toxicity data for fish, aquatic invertebrates, and algae were
judged adequate to meet the endpoints.
The available acute marine/estuary toxicity data for fish, aquatic invertebrates, and algae
were judged inadequate to meet the endpoints.
Basis for Conclusion:
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline 850.1075;
OECD Guideline 203)
A confidential 96-hour study in fish was located that reported no effects at saturation. These data
allow this endpoint to be adequately characterized.
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010; OECD
Guideline 202)
A confidential study in daphnid was located that reported a 24-hour EC50 of 1.2 mg/L and a 48-hour
EC50 of 0.42 mg/L. These data allow this endpoint to be adequately characterized.
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
A confidential 96-hour study in green algae was located that reported no effects at saturation. These
data allow this endpoint to be adequately characterized.
No additional acute toxicity studies with freshwater or saltwater fish, aquatic invertebrates, or algae
were located that followed or were similar to the guideline protocols listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
11-9
-------
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
11-10
-------
Physical/Chemical Properties
Proprietary H: Halogenated aryl ester
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log Kow: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability:
Conclusion: The flammability (as the flash point) has been adequately characterized.
Basis for Conclusion: The key study was performed according to EEC Methods, Directive
92/69/EEC (OJ No. L383A, 29.12.92), Part A, Method A9, flash point.
Flash Point: 215°C(Ref.2)
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
11-11
-------
Henry's Law Constant: No data
11-12
-------
Environmental Fate
Bioconcentration
Fish:
Conclusion:
The available bioconcentration data are adequate.
Basis for Conclusion:
A confidential guideline study submitted on Proprietary H indicates that the bioconcentration factor
is 1.7-6.2.
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion:
The available aerobic biodegradation data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary H indicates that its half life is 3.5 days in water in a
shake flask die-away test. It was also found to undergo 6% biodegradation after 28 days in closed
bottle test in a submitted confidential study.
11-13
-------
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH:
Conclusion:
The available hydrolysis as a function of pH data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary H indicates that its hydrolysis half life is >1 year at
pH 4, 7, and 9.
Sediment/Water Biodegradation:
Conclusion:
The available sediment/water biodegradation data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary H indicates that its half life is 8.5 days in sediment
in a shake flask die-away test.
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption:
Conclusion:
The available soil adsorption data are adequate.
Basis for Conclusion:
A confidential study submitted on Proprietary H indicates that the soil adsorption coefficient is
>28,840.
11-14
-------
Flame Retardant Alternatives
Proprietary I: Organic phosphate ester
Hazard Review
12-1
-------
Proprietary I: Organic phosphate ester
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
/
/
/
/
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
/
/
/
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
/
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
/
/
/
12-2
-------
Proprietary I: Organic phosphate ester
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
/
/
X
X
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
/
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
/
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
/
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
12-2
-------
Chemical Identity
Proprietary I: Organic phosphate ester
CAS
MF
MW
SMILES
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401)
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential acute oral toxicity study was submitted that reported an LD50 greater than 5 g/kg for
rats. These data allow this endpoint to be adequately characterized.
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential acute dermal toxicity study was submitted that reported an LD50 greater than 5 g/kg
for rats. These data allow this endpoint to be adequately characterized.
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD
Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged adequate to meet the endpoint.
12-4
-------
Basis for conclusion:
A confidential acute inhalation toxicity study was submitted that reported an LC50 greater than 1.55
mg/L for rats. These data allow this endpoint to be adequately characterized.
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline
405)
Conclusion:
The available acute eye irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported mild and transient eye irritation in rabbits. These
data allow this endpoint to be adequately characterized.
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available acute dermal irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported negative results for skin irritation in rabbits. These
data allow this endpoint to be adequately characterized.
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The available skin sensitization data were judged adequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported negative results for skin sensitization in guinea
pigs. These data allow this endpoint to be adequately characterized.
SUBCHRONIC TOXICITY
Conclusion:
No available subchronic toxicity data.
12-5
-------
Basis for Conclusion.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408),
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422), respectively
Subchronic Dermal Toxicity (21/28-day or 90-day).
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90 day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
REPRODUCTIVE TOXICITY
Conclusion:
The available reproductive toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
A confidential reproductive/developmental screening assay satisfies the requirements for this
endpoint.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
A confidential reproductive/developmental screening study was submitted that found no
reproductive effects at doses up to 1000 mg/kg/day.
No other pertinent studies were located that addressed reproductive toxicity endpoints in the
guidelines listed below.
12-6
-------
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
A confidential reproductive/developmental screening assay satisfies the requirements for this
endpoint.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
A confidential reproductive/developmental screening study was submitted that found no
developmental effects at doses up to 1000 mg/kg/day.
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
12-7
-------
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
Basis for Conclusion:
No neurotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion.
No immunotoxicity studies were located that addressed the endpoints in the guidelines listed below.
12-8
-------
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
The available genotoxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
Adequate studies are available for gene mutations in bacterial and mammalian cells in vitro, and
chromosomal aberrations in vitro and for micronucleus formation in vivo. All tests yielded negative
results for genotoxicity.
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100;
OECDGuideline 471)
Confidential studies were submitted that found negative results for gene mutation in Salmonella and
Escherichia coli.
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
A confidential study was submitted that found negative results for gene mutation in cultured mouse
lymphoma cells.
Chromosomal Aberrations in Vitro:
In Vitro Mammalian Chromosome Aberration Test (OPPTS Harmonized Guideline
870.5375)
A confidential study was submitted that reported negative results for an in vitro chromosomal
aberrations assay.
Chromosomal Aberrations in Vivo:
Mammalian erythrocyte micronucleus test (OPPTS Harmonized Guideline 870.5395)
A confidential study was submitted that reported negative results for micronucleus formation in mice
exposed by intraperitoneal injection.
12-9
-------
No studies were located that were relevant to the categories below.
Gene Mutation in Vivo
DNA Damage and Repair
12-10
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available data for the acute toxicity endpoint for fish were judged adequate to meet this
endpoint. The currently available data for the acute toxicity endpoints for aquatic invertebrates or
algae were judged inadequate to meet the endpoint.
Basis for Conclusion:
A confidential study was submitted that reported a freshwater fish 96-hour LC50 = 0.205 mg/L.
These data were judged adequately to meet this endpoint. A confidential study was submitted that
reported a freshwater daphnid 48-hour LC50 > 0.846 mg/L. These data were judged inadequate to
meet this endpoint.
No other pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located that
addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
The available chronic toxicity data for fish and aquatic invertebrates were judged inadequate to meet
the endpoints.
Basis for Conclusion:
A confidential chronic toxicity study was submitted that reported a fish LOEC of 0.088 mg/L, based
on reduced larval survival and growth. These data were judged in adequate to meet this endpoint.
A confidential chronic toxicity study was submitted that reported a daphnid LOEC of 0.147 mg/L.
These data were judged inadequate to meet this endpoint.
No other pertinent chronic toxicity studies with fish or aquatic invertebrates were located that
addressed the endpoints in the guidelines listed below.
12-11
-------
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
12-12
-------
Physical/Chemical Properties
Proprietary I: Organic phosphate ester
CAS
MF
MW
SMILES
Water Solubility (mg/L):
Conclusion:
The available water solubility data are adequate.
Basis for Conclusion:
A confidential guideline study indicating that the water solubility of Proprietary I is 0.8 mg/L was
submitted..
Log K,,w: No data
Oxidation/Reduction: No data
Melting Point: No data
Boiling Point:
Conclusion:
The available boiling point data are adequate.
Basis for Conclusion:
A confidential guideline study indicating that the boiling point of Proprietary I is >300 degrees C
at 760 mm Hg was submitted.
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
12-13
-------
Explosivity: No data
Corrosion Characteristics: No data
pH: It is anticipated that the pH for this compound will be not applicable because the functional
groups present are not expected to affect the pH of an aqueous solution.
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: It is anticipated that the dissociation constant for this compound
will be not applicable because the functional groups present are not expected to dissociate.
Henry's Law Constant: No data
12-14
-------
Environmental Fate
Bioconcentration
Fish:
Conclusion:
The available bioconcentration data are adequate.
Basis for Conclusion:
A confidential guideline study indicating that the bioconcentration factor of Proprietary I is 245 was
submitted.
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion:
The available aerobic biodegradation data are adequate.
Basis for Conclusion:
Submitted confidential guideline studies indicated that Proprietary I underwent 2.3% degradation
after 28 days in the MITI-II test and 30% removal in 28 days (52% removal in 140 days) in a closed
bottle test.
12-15
-------
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH:
Conclusion:
The available hydrolysis data are adequate.
Basis for Conclusion:
A confidential guideline study was submitted and indicated that Proprietary I had a half-life at pH
9 and 25 degrees C of 20 days.
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
12-16
-------
Flame Retardant Alternatives
Proprietary J: Aryl phosphate
Hazard Review
13-1
-------
Proprietary J: Aryl phosphate
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
/
/
*
/
/
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
*
*
*
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
*
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
/
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
*
*
*
13-2
-------
Proprietary J: Aryl phosphate
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
/
/
/
/
/
/
/
/
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
*
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
/
*
/
*
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
*
*
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm EC50,
LC50, NOAEC,
LOAEC
10 "
1J-J
-------
Chemical Identity
Proprietary J: Aryl phosphate
Synonyms
CAS
MF
MW
SMILES
Omitted from this report are a number of studies conducted on [Formulation 2] (-43% Proprietary
J). The omitted studies included 21 -day dermal toxicity, 90-day aerosol inhalation toxicity, and 90-
day oral (feeding) toxicity in rats and neurotoxicity studies in hens. Replacement studies
subsequently commissioned by the contracting company are reviewed here.
Many health effects studies have been conducted on commercial products that are mixtures of
Proprietary J and closely related compounds: [Chemical 1], [Chemical 2], and [Chemical 3].
Typical composition data for these products are given in Table 13-1 below.
Table 13-1. Composition data (%) for selected t-butylated aryl phosphate products
Component
Proprietary J
[Chemical Class 1]
[Chemical 1]
[Chemical 2]
[Chemical 3]
stabilizers
[Formulation
l]a
43
23
34
[Formulation
2]"
43
14
2
40
[Formulation
3]c
>99
<1
[Formulation
4]-
30-35
30-35
10-15
15-25
[Formulation
5]e
73
27
aRef. 15
bRef. 42
cRef. 7
dRef. 22
eRef. 63. Ref. 58 reported that [Formulation 5] was [Chemical Class 1], but did not report the precise concentration of
Proprietary J. After saponification, the isomer distribution of the [Chemical Class 2] portion was 39.2% [Chemical 4]
and [Chemical 5] and 59.7% [Chemical 6].
13-4
-------
Human Health Endpoints
ACUTE TOXICITY
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425, 420,
423, 401).
Conclusion:
The available acute oral toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion.
Despite reporting deficiencies in some studies (lack of precise information on substance purity,
group size), the available data indicate acute oral LD50 values exceeding 5,000 mg/kg for [Chemical
Class 1] tested by methods equivalent to guidelines.
Critical Studies:
Type: Acute oral toxicity
Species, strain, sex, number: Rat, CD Sprague-Dawley, 5/sex
Doses: 5,000 mg/kg
Purity: isomeric mixture of [Chemical Class 1] as [Formulation 7] (Ref 7)
Vehicle: None
Method: Based on OECD Guideline 401. Rats examined for mortality and clinical signs frequently
on day 1, twice daily thereafter to day 14. Body weights recorded on days 1, 8, and 15. Gross
necropsy on all rats.
Results: No deaths. Clinical signs in all rats after dosing included pilo-erection, hunched posture,
and abnormal gait (waddling). Half of the animals had diarrhea. Clinical signs resolved by day 8.
There were no effects on body weight gain or terminal necropsy findings. Acute oral LD50 was
greater than 5,000 mg/kg in rats.
Reference: Ref 25
Type: Acute oral toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 3/sex
Dose: 5,000 mg/kg
Purity: Not reported; isomeric mixture of Proprietary J as [Formulation 10]. Ref. 20 reports
composition of 60-100% [Chemical Class 1] and 7-13% [Chemical 3].
Vehicle: None
Observation period: 14 days
Method: Rats observed 14 days after single dose, gross necropsy on all rats. Body weights recorded
days 0, 7, and 14.
13-5
-------
Results: No deaths. Clinical signs included abdominogenital staining, chromorhinorrhea, and
decreased locomotion, all subsiding by day 10. All rats gained weight. No gross lesions. TheLDSO
exceeded 5,000 mg/kg.
Comment: This study was equivalent to a limit test under OPPTS 870.1100 except that the group
size was 3/sex rather than 5/sex.
Reference: Ref. 16
Type: Acute oral toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, males and females, numbers not reported
Dose: 15,800 mg/kg
Purity: Near pure Proprietary J
Vehicle: None
Observation period: 14 days
Method: Rats observed 14 days after single dose.
Results: The LD50 exceeded 15,800 mg/kg in rats (specific mortality results were not reported).
Reference: Ref. 34
Additional Studies and Information:
Ref. 10 evaluated the oral toxicity of [Chemical Class 1] administered to rabbits by oral gavage in
8% gum acacia; rabbits were observed "several days" for clinical signs of toxicity. There were no
effects in single rabbits receiving 1,000 or 3,000 mg/kg of Proprietary J or [Chemical 1], or 1,000
mg/kg of [Chemical 2].
In another study, male rabbits were administered [Chemical Class 1] by oral gavage in 5% gum
acacia and observed for varying amounts of time (Ref. 11). One rabbit received 2,000 mg/kg of
Proprietary J and was observed for 5 days and two rabbits received 5,000 mg/kg and were observed
for 4 or 16 days. All showed hepatic degeneration and two had kidney effects (tubular degeneration
and congestion or swelling); necrosis of the stomach (high dose) and moderate lung congestion (low
dose) were seen in single animals. A parallel experiment with rabbits treated with [Chemical 1 ] had
similar results: liver effects in 1/1 at 2,000 mg/kg (killed day 5) and 2/2 at 5,000 mg/kg (killed day
4 or 17), and lung congestion and cloudy swelling of the kidneys in one high- and one low-dose
animal. No deaths and no overt clinical signs were seen in rabbits treated with either compound.
A related compound, [Chemical 2] (containing 1-2% [Chemical 5]), was administered at doses of
3,000 or 10,000 mg/kg by oral gavage in olive oil to rats (Ref. 12). Mortality was 1/5 at the low
dose and 1/3 at the high dose, but the length of the observation period was not reported.
As described in a robust summary, there were no deaths and no gross lesions in Sprague-Dawley rats
(5/sex) orally exposed to 5,000 mg/kg [Formulation 5] (see Note e in Table 1) and observed for 14
days (Ref. 53 cited in Ref. 1). Clinical signs (depression, diarrhea, and stains on fur and around the
nose) resolved by day 6. A letter from Ref. 52 to EPA suggests that this study was conducted under
the 1978 EPA proposed test guidelines.
13-6
-------
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline 402)
Conclusion:
The available acute dermal toxicity data were judged adequate to meet the endpoint.
Basis for Conclusion:
Despite reporting deficiencies in some studies (lack of precise information on substance purity,
group size), the available data indicate acute dermal LD50 values exceeding 2,000 mg/kg for
Proprietary J tested by methods equivalent to guidelines.
Critical Studies
Type: Acute (24-hour) dermal toxicity
Species, strain, sex, number: Rat, Sprague-Dawley, 3/sex
Dose: 2,000 mg/kg
Purity: Not reported; isomeric mixture of Proprietary J as [Formulation 10]
Vehicle: None
Exposure period: 24 hours
Method: Undiluted test material applied to intact clipped dorsal skin. Treated areas occluded,
washed after 24 hours with methanol and then water. Animals observed for 3 hours after dosing and
daily thereafter for 14 days. Body weights recorded on days 0, 7, and 14. All subjected to gross
necropsy.
Results: No deaths, clinical signs, local irritation of the application site, or gross necropsy lesions.
All rats gained weight. The acute dermal LD50 exceeded 2,000 mg/kg in rats.
Comment: This study was equivalent to a limit test under OPPTS 870.1200 except that the group
size was 3/sex rather than 5/sex.
Reference: Ref 17
Type: Acute (24-hour) dermal toxicity
Species, strain, sex, number: Rabbit, New Zealand albino, male and female, numbers not reported
Dose: 7,900 mg/kg
Purity: near pure Proprietary J
Vehicle: None
Exposure period: 24 hours
Method: Undiluted test material applied to intact clipped dorsal skin. Treated areas occluded,
washed (liquid unspecified) after 24 hours. Animals held for 14 days after which all subjected to
gross necropsy.
Results: The acute dermal LD50 exceeded 7,900 mg/kg. The study did not report necropsy findings
or specific mortality results.
Reference: Ref. 34
13-7
-------
As described in a robust summary, mortality was 1/10 among New Zealand White rabbits (5/sex)
that received a dose of 2,000 mg/kg [Formulation 5] (see Note e in Table 1) on intact and abraded
skin and were observed for 14 days (Ref. 54 cited in Ref. 1). Clinical signs included depression and
mild diarrhea. No gross lesions were observed at necropsy. A letter from Ref. 52 to EPA suggests
that this study was conducted under 1978 EPA proposed test guidelines.
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300; OECD Guideline 403)
Conclusion:
The available acute inhalation toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The only relevant data were for a study available only as a robust summary and for which the
Proprietary J content was uncertain.
As described in a robust summary, no mortality and no body weight effects were observed among
Sprague-Dawley rats (5/sex) that were exposed for 4 hours to an aerosol of [Formulation 5] (see
Note e in Table 1) at the highest attainable concentration, 3.1 mg/L (Ref. 54 cited in Ref. 1); the
particle size distribution of 2.5-2.8 |im suggests that the particles were respirable. Ruffled fur was
the only clinical sign observed over a period of 14 days. The only gross lesions observed were lung
effects (reddened or whitish coloration) in two females.
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Conclusion:
The available eye irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Despite some uncertainty as to the purity of test substances, the available studies used methods
equivalent to the guidelines and agreed that Proprietary J was not an eye irritant.
Type: Acute eye irritation
Species, strain, sex, number: Rabbit, New Zealand White, 3 (sex not reported)
Doses: 0.1 mL
Purity: Not reported; isomeric mixture of Proprietary J as [Formulation 7]
Vehicle: None
Method: Cites OECD Guideline 405. Eyes examined after 1 hour, then 1, 2, 3, 4, and 7 days.
Results: No positive responses; no damage to cornea or iris. Mild conjunctival inflammation was
observed in 3/3 animals 1 hour after instillation only. All normal by 24 hours.
Reference: Ref. 27
13-8
-------
Type: Acute (4-hour) eye irritation
Species, strain, sex, number: Rabbit, New Zealand White, 3 females
Doses: 0.1 mL
Purity: Not reported; isomeric mixture of Proprietary J as [Formulation 10]. Ref. 20 reports
composition of 60-100% [Chemical Class 1] and 7-13% [Chemical 3].
Vehicle: None
Method: Instilled into eye. Eyes assessed via Draize method at 1, 24, 48, and 72 hours.
Results: No eye irritation was observed at any timepoint.
Comment: Although the study was designated "non-definitive", it was consistent with the OPPTS
guideline.
Reference: Ref. 18
Additional information
As described in a robust summary, 0.1 mL [Formulation 5] (see Note e in Table 1) was a mild ocular
irritant to rabbits (Ref. 56 cited in Ref. 1). Mild redness of the conjunctiva persisted to 24 hours in
2/9 and to 48 hours in 1/9, but was resolved by 72 hours. The eye irritation observed in this study
may reflect compositional differences between [Formulation 5] and the other Proprietary J materials
tested.
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline 404)
Conclusion:
The available dermal irritation data were judged adequate to meet the endpoint.
Basis for Conclusion:
Despite some uncertainty as to the purity of test substances, the available studies used methods
equivalent to the guidelines. Results indicated no or mild dermal irritation.
Critical Studies:
Type: Acute (4-hour) dermal irritation
Species, strain, sex, number: Rabbit, New Zealand White, 3
Doses: 0.5 mL
Purity: Not reported; isomeric mixture of Proprietary J as [Formulation 7] (relationship to the
composition of [Formulation 3] reported in Table 1 is not known)
Vehicle: None
Method: Followed OECD Guideline 404. Hair clipped. Material applied for 4 hours to
approximately 10-cm square area on back, semi-occlusive dressing. Site rinsed with water,
examined after 30 minutes and days 2, 3, and 4; additional observations on days 5 through 11.
Results: Very slight or well-defined erythema with or without very slight edema was seen in two
animals immediately, persisting though day 8 and day 10. Very slight erythema without edema in
13-9
-------
third animal on days 2 and 3 only. A 4-hour exposure to the test material elicited mild reversible
irritation.
Reference: Ref. 26
Type: Acute (4-hour) dermal irritation
Species, strain, sex, number: Rabbit, New Zealand White, 2 males and 1 female
Doses: 0.5 mL
Purity: Not reported; isomeric mixture of Proprietary J as [Formulation 10]. Ref. 20 reports
composition of 60-100% [Chemical Class 1] and 7-13% [Chemical 3].
Vehicle: None
Method: Test material applied to clipped, intact skin and occluded. After 4 hours, sites were wiped
clean with methanol and rinsed with tap water. Scoring for irritation was done 30 minutes after
wiping and then daily for 3 days. Clinical signs were observed.
Results: No signs of irritation (erythema or edema) were noted at any timepoint. The primary
irritation index was 0/8.0; the material was non-irritating to intact rabbit skin
Reference: Ref. 19
As described in a robust summary, [Formulation 5] (see Note e in Table 1) was a mild dermal irritant
to rabbits, yielding a primary irritation score of 0.50 (Ref. 57 cited in Ref. 1).
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
No available skin sensitization data.
Basis for Conclusions:
No pertinent studies were located that followed or were similar to the guideline listed above, or were
otherwise relevant to skin sensitization.
SUBCHRONIC TOXICITY
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Conclusion.
The available subchronic oral toxicity data were judged marginally adequate to meet the endpoint.
Basis for Conclusion:
A 90-day oral toxicity assay on 73% [Formulation 11] was similar to guidelines except for the lack
of testing for ophthalmological effects and neurological function and that the high dose was
significantly lower than the limit dose. The study did identify target organs that might show
13-10
-------
histopathology at higher exposure levels. The Proprietary J content of tested materials was less than
50% in a 1-month assay.
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
Ref. 42 exposed groups of Sprague-Dawley rats (10/sex/group) to diets providing [Formulation 2]
(43% Proprietary J, see Table 1) at target doses of 0, 250, 500, 750, 1,000, or 2,000 mg/kg/day
(nominal doses of 213, 442, 660, 898, and 1,710 for males and 234, 454, 690, 898, and 1,867 for
females) for 1 month. Reduced food consumption was observed in males at 2,000 mg/kg/day;
reduced body weight gain in males at >750 mg/kg/day and females at 2,000 mg/kg/day. There were
no deaths, but hepatic enlargement was noted in all groups in a dose-related fashion; discoloration
of kidneys was observed in male rats at >500 mg/kg/day. The lowest dose was a LOAEL;
methodological limitations of the study include the lack of examinations for histopathology,
hematology, or clinical chemistry.
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408)
Type: 90-day oral (diet) toxicity in rodents
Species, strain, sex, number: Rat, Sprague-Dawley (20/sex/group)
Doses: 0, 100, 400, or 1,600 ppm [Formulation 5]; average intakes of 0, 6.6, 26.7 or 107.5
mg/kg/day in males and 0, 7.7, 30.0 or 124.8 mg/kg/day in females.
Purity: About 73% isomeric mixture of [Formulation 11] and 27% triphenyl phosphate as
[Formulation 5].
Vehicle: Feed
Method: Rats were examined twice daily for clinical signs and mortality, weekly physical
examinations (with palpation) and measurements of body weights and food consumption.
Hematology, clinical chemistry and urinalyses were performed prior to testing, at mid-test and just
prior to termination. At termination, all animals were subjected to gross necropsy; organ weights
of adrenal, brain, heart, liver, kidney and gonads were recorded. More than 30 organs/tissues were
examined for histopathology in all groups. Brain cholinesterase was measured at termination in all
groups.
Results: Treatment had no significant effect on survival, food consumption, body weight gain,
hematology or clinical chemistry parameters, cholinesterase values, or the incidence of gross or
microscopic lesions (including reproductive organs, brain and spinal cord). At the highest dose, there
were statistically significant increases in absolute and relative liver weights in males (increased 18-
24%) and females (increased -15%), relative kidney weights in males (increased 6%), and absolute
and relative adrenal weights in females (increased 12-14.7%). These changes were not accompanied
by histopathological lesions or changes in clinical chemistry parameters. In this study, 400 ppm
(26.7 mg/kg/day for males and 30 mg/kg/day for females) was a NOAEL and 1600 ppm (107.5
mg/kg/day for males and 124.8 mg/kg/day for females) was a LOAEL for increased liver weights
in both sexes and adrenal weights in females. The study is marginally acceptable because the
highest dose was considerably lower than the limit dose of 1000 mg/kg/day. The study does,
13-11
-------
however, identify target organs that might show lesions if testing were conducted at higher exposure
levels.
Reference: (Ref. 59, 60, 63)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
No relevant studies were located that followed or were similar to the guideline listed above.
Subchronic Dermal Toxicity (21/28-day or 90-day)
Conclusion:
The available subchronic dermal toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available study was conducted on a substance with a Proprietary J content of less than 50%.
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
[Formulation 2] (43% Proprietary J; see Table 1) was applied to intact and abraded skin of New
Zealand White rabbits (10/sex/group) at doses levels of 10, 100, or 1,000 mg/kg/day, 5 days/week
for 3 weeks (Ref. 6); controls were treated with distilled water. Treatment-related effects included
skin changes at the application site (edema at 1,000 mg/kg/day in males and >10 mg/kg/day in
females; atonia at > 100 mg/kg/day in both sexes; desquamation at > 10 mg/kg/day in both sexes; and
fissuring at 1,000 mg/kg/day in both sexes), higher blood urea nitrogen values at 1,000 mg/kg/day
in both sexes, and dose-related depression of plasma cholinesterase at >100 mg/kg/day, and of
erythrocyte and brain cholinesterase at > 10 mg/kg/day in both sexes. Changes in other parameters
(mortality, clinical signs, body weight, hematology, clinical chemistry, organ weights, gross or
microscopic lesions) were not related to treatment.
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
No relevant studies were located that followed or were similar to the guideline listed above.
13-12
-------
Subchronic Inhalation Toxicity (90-day)
Conclusion:
No available subchronic inhalation toxicity data.
Basis for Conclusion:
No pertinent studies were located that followed or were similar to the guideline listed below, or were
otherwise relevant to subchronic inhalation toxicity.
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD
Guideline 413)
REPRODUCTIVE TOXICITY
Conclusion:
The available reproductive toxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
No studies were located that followed or were similar to the three guidelines listed below. No
histopathology of the male (testes, epididymides, prostate) or female (ovary, uterus, cervix, vagina)
reproductive organs was observed in rats fed diets containing up to 1600 ppm [Formulation 5] (73%
[Formulation 11]; see Note e to Table 1) for 3 months (Ref. 59, 60, 63).
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
The available developmental toxicity data were judged inadequate to meet the endpoint.
13-13
-------
Basis for Conclusion:
The only available developmental toxicity data are for formulations containing only about 43%
Proprietary J.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700; OECD
Guideline 414)
Ref 32, 33 evaluated the developmental toxicity of [Formulation 2] (43% Proprietary J, see Table
1) in rats. In a pilot study (Ref. 32), pregnant CD rats (5/group) received undiluted [Formulation
2] at doses of 250, 500, 1,000, 2,500, or 5,000 mg/kg/day by oral gavage on gestational days (GD)
6-19; controls received 4.2 mL of water per day. Treatment had no effect on survival, behavior, or
maternal necropsy findings. Anogenital staining was observed in all test groups (incidences of 1/5,
2/5,2/5, 5/5, and 4/5 in the lowest-to-highest dose groups, respectively) and red and/or brown matter
around the nose, mouth, and forelimbs in all receiving 5,000 mg/kg/day. Dose-related reductions
in body weight gain for GD 0-20 were observed at > 1,000 mg/kg/day, but were only biologically
significant at the highest dose (-33% compared to control). At the highest dose, decreases in viable
fetuses and increases in mean postimplantation losses compared to historical controls were observed
at 5,000 mg/kg/day (values for concurrent controls were higher than historical control value).
In the main study (Ref. 33), groups of 25 pregnant CD rats received 2.542 mL of water or undiluted
[Formulation 2] at doses of 300, 100, or 3,000 mg/kg/day by oral gavage on GD 6-19. Treatment
had no significant effect on maternal survival, behavior, body weight gain, the incidence of gross
necropsy findings, or most reproductive/developmental parameters (mean number of viable fetuses,
postimplantation loss, early or late resorptions, total implantations, corpora lutea, fetal sex
distribution, mean fetal body weight, and incidences of external malformations and visceral
variations). High-dose dams had a higher incidence of clinical signs (all with yellow staining of
anogenital area and half with dried red matter on nose and forepaws) compared to other groups. At
3,000 mg/kg/day, there was a slight increase compared to controls in the percentage of litters with
skeletal malformations (3/24 or!2% vs 1/20 or 5%); the percentage in historical controls was 6.23%
No relevant studies were located that followed or were similar to the two tests listed below.
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
13-14
-------
Basis for Conclusion:
No pertinent studies following or similar to the guidelines listed below or otherwise relevant to
chronic toxicity were located.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
Basis for Conclusion:
No pertinent studies following or similar to the guidelines listed below or otherwise relevant to
carcinogenicity were located.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
Basis for Conclusion:
No studies examined developmental neurotoxicity or neurological function. Acceptable negative
are available for delayed neurotoxicity in adults. In the 90-day oral toxicity assay by (Ref 59, 60,
63) described above, rats exposed to [Formulation 5] (73% Formulation 11]; see Note e to Table 1)
in the diet at concentrations up to 1600 ppm exhibited no neurohistopathology and no inhibition of
brain cholinesterase activity.
Delayed Neurotoxicity
Conclusion:
The available delayed neurotoxicity data were judged adequate to meet the endpoint.
13-15
-------
Basis for Conclusion:
The available studies were consistent with guidelines and overall suggest that exposure to large
doses of Proprietary J does not evoke delayed neurotoxicity in hens
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Critical Studies
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, "hybrid", females, older than 14 months, 4 water controls and
8 treated with Proprietary J
Purity: Not reported; >99% Proprietary J as [Formulation 3] (see Table 1)
Doses: The plan was 1,000 mg/kg, 5 times daily for 5 consecutive days (total 25,000 mg/kg);
because of shortage of material, only 3 doses were given on day 4, so 7 doses were given on day 5
to make up the difference.
Vehicle: None
Positive control: None
Route: Oral gavage
Exposure duration, frequency: 5 days, 5 times daily
Method: Observations for up to 32 days. Birds examined daily for signs of neurotoxicity; body
weights, food consumption, egg numbers, and egg weights recorded twice weekly.
Results: There were no signs of ataxia. Mortality rates, body weight gain, and feed consumption
did not differ between test and control groups; egg production in test group was about 50% of
controls although egg weights were slightly higher in test animals.
Reference: Ref 28
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Chicken, White Leghorn, females, 9/group
Purity: near pure Proprietary J
Doses: 10,000 mg/kg, twice daily (20 mg/kg/day)
Vehicle: None
Positive control: Corn oil
Route: Oral gavage
Exposure duration, frequency: Twice daily for three consecutive days; dosing regimen repeated
21 day slater.
Method: Daily observations for mortality and neurotoxicity for up to 42 days. Body weights
recorded at 0, 21, and 42 days. At gross necropsy, brain, spinal cord, and sciatic nerve were
examined for histopathology. The neurotoxicity study was preceded by an acute oral toxicity assay
in hens given 10,000 mg/kg.
Results: There were no signs of ataxia or neurohistopathological lesions in 9 hens treated with
Proprietary J at cumulative doses of 120,000 mg/kg. Other [Chemical Class 3] chemicals tested at
the same time were neurotoxic. The positive control, tri-ort/zo-cresyl phosphate (TOCP), caused
13-16
-------
neurotoxicity in 4/4 hens treated with 300 mg/kg/day for 5 days (cumulative dose of 1,500 mg/kg).
The acute oral LD50 in hens exceeded 10,000 mg/kg (no mortality data reported).
Reference: Ref 34
Type: Acute oral delayed neurotoxicity
Species, strain, sex, number: Hen, female, older than 14 months, 4 control and 8 test birds
Purity: Not reported; [Formulation 3] is >99% Proprietary J and <1% stabilizers (Ref. 7)
Doses: 1,000 mg/kg five times daily for five consecutive days (= 25,000 mg/kg total)
Vehicle: None
Positive control: None
Negative control: Water
Route: Oral gavage
Exposure duration, frequency: five days, five times daily
Method: Observations for up to 32 days. Birds examined daily for signs of neurotoxicity; body
weights, food consumption, egg numbers, and egg weights recorded twice weekly.
Results: No ataxia observed; no treatment-related effects on mortality or body weight gain. Mean
daily food consumption in test animals was about 15% lower than in controls, largely because intake
was reduced by 47% during days 0-4. In test group, egg production was about 70% of controls and
egg weights about 11% lower than in controls.
Reference: Ref. 30
Additional Studies:
Several components of the [Formulation 6] series of flame retardants were isolated to >99% purity
and tested at doses as high as 1,000 mg/kg in mature hens for neurotoxicity and suppression of
neurotoxic esterase (Ref. 24). Details of these studies were not located. [Chemical 2], [Chemical
1], and Proprietary J elicited no signs of neurotoxicity and no suppression of NTE levels. [Chemical
7] was also judged to be non-neurotoxic, eliciting no ataxia or other signs of neurotoxicity and
insignificant suppression of NTE (-4% or -15%) in two tests. However, [Chemical 8] was
neurotoxic, eliciting ataxia and neurotoxicity, as well as suppression of NTE levels (by -71% and
-57 to -62% in two tests) at 1 mL/kg. The author suggested that neurotoxicity was associated with
[Chemical Class 1] with an oxidizable alpha-hydrogen.
Hens given [Formulation 4] (100% [Chemical Class 1]; 30-35% Proprietary J, see Table 1) at a dose
of 5,000 mg/kg/day on five consecutive days by oral gavage lost weight and developed paralysis
(4/4) and 3/4 died before the end of the test (Ref. 14). The study authors suggested that residual
[Chemical Class 4] chemicals may have been responsible for the observed neurotoxicity.
Hens treated with 2,000 mg/kg of [Formulation 10] did not elicit clinical signs of neurotoxicity,
lesions of the nervous system, or depression in NTE, whereas hens treated with TOCP at 500 mg/kg
showed all of these effects (Ref. 35 abstract as described in Ref. 61).
There was no effect on survival or walking behavior among a group of 15 hens (12-14 months old)
given oral doses of 11, 679 mg/kg [Formulation 5] (see Note e in Table 1) on days 1 and 21 under
13-17
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EPA proposed guidelines (Ref. 58). All showed slight motor incoordination on day 1; body weights
were reduced on day 38, but terminal weights were as in corn oil controls. Neurohistopathology and
feed consumption were equivalent to corn oil controls. Hens treated with TOCP had increased
mortality, progressive leg weakness, persistently reduced feed intake and body weight loss, and
significant axonal degeneration.
No neurotoxicity studies were located that were relevant to the categories listed below.
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
Additional neurotoxicity studies:
Schedule-Controlled Operant Behavior (mouse or rat); OPPTS Harmonized Guideline
870.6500
Peripheral Nerve Function (rodent); OPPTS Harmonized Guideline 870.6850
Sensory Evoked Potentials (rat, pigmented strain preferred); OPPTS Harmonized Guideline
870.6855
These additional neurotoxicity studies may be indicated, for example, to follow up
neurotoxic signs seen in other studies, or because of structural similarity of the
substance to neurotoxicants that affect these endpoints. These studies may be
combined with other toxicity studies.
Other Neurotoxicity Data
Cholinesterase inhibition
In five hens that received 25,000 mg/kg of [Formulation 7] in divided doses (8, 8, and 9 g/kg at 4-
hour intervals) by oral gavage, plasma cholinesterase (pChE) levels 30-60 minutes later were about
60-70% of pre-dose levels (Ref. 29); 9 days later, pChE levels had risen to 83.1% of the pre-dose
level. One bird that showed clinical signs (quiet with subdued behavior) after dosing did not show
appreciable recovery of pChE on day 9. The authors concluded that because of the very high dose
administered, the test material was not a significant inhibitor of plasma cholinesterase.
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
13-18
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Basis for Conclusion:
No pertinent studies were located that followed or were similar to the guideline listed below, or were
otherwise relevant to immunotoxicity.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
GENOTOXICITY
Conclusion:
The available genotoxicity data were judged inadequate to meet the endpoint.
Basis for Conclusion:
The available studies followed methods equivalent to guidelines, but tested materials for which the
Proprietary J content was low (less than 50%) or uncertain; the latter studies were only available as
robust summaries. None of the studies indicate the Proprietary J-containing mixtures are mutagenic
in bacteria or mammalian cells.
Gene Mutation in Vitro:
Bacterial Reverse Mutation test (OPPTS Harmonized Guideline 870.5100; OECD
Guideline 471)
[Formulation 1] (typical analysis 43% Proprietary J; see Table 1) was not mutagenic in S.
typhimurium strains TA98, TA100, TA1535, TA1537, or TA1538 with or without metabolic
activation (Ref. 15).
[Formulation 2] (typical analysis 43.2% Proprietary J, see Table 1) at concentrations between 0.01
and 10 |iL/plate produced negative results in S. typhimurium strains TA98, TA100, TA1535,
TA1537, or TA1538 and Saccharomyces cerevesiae D4 with or without metabolic activation (Ref.
36).
As described in a robust summary, [Formulation 5] (see Note e in Table 1) at concentrations
between 0.005 and 10 |j,g/plate produced negative results in S. typhimurium strains TA98, TA100,
TA1535, TA1537, or TA1538 with or without metabolic activation (Ref. 38); cytotoxicity was
observed at 0.1 jig/plate and higher.
In vitro Mammalian Cell Gene Mutation Test (OPPTS Harmonized Guideline
870.5300; OECD Guideline 476)
13-19
-------
[Formulation 2] (typically 43% Proprietary J, see Table 1) at concentrations between 0.011 and 0.1
|j,L/mL (0.2 |iL/mL was cytotoxic) did not induce forward mutations in cultured mouse lymphoma
L5178Y/TK+/' cells with or without metabolic activation (Ref. 37).
As described in a robust summary, [Formulation 5] (see Note e in Table 1) at concentrations
between 0.975 and 125 nL/mL (> 15.6 nL/mL was cytotoxic) did not induce forward mutations in
cultured mouse lymphoma L5178Y/TK+/" cells with or without metabolic activation (Ref. 39).
Chromosomal Aberration in Vitro
In Vitro Mammalian Chromosome Aberration Test (OPPTS Harmonized Guideline
870.5375)
As described in a robust summary, [Formulation 5] (see Note e in Table 1) at concentrations
between 0.625 and 20 nL/mL (>2.5 nL/mL was cytotoxic) did not increase the frequency of
chromosomal aberrations in cultured mouse lymphoma L5178Y/TK+/" cells with or without
metabolic activation (Ref. 40).
No studies were located that were relevant to the categories listed below.
Gene Mutation in Vivo
Chromosomal Aberration in Vivo
DNA Damage and Repair
Other
In vitro Sister Chromatid Exchange Assay (OPPTS Harmonized Guideline 870.5900)
As described in a robust summary, [Formulation 5] (see Note e in Table 1) at concentrations
between 0.625 and 20 nL/mL (>2.5 nL/mL was cytotoxic) did not increase the frequency of sister
chromatid exchanges in cultured mouse lymphoma L5178Y/TK+/" cells with or without metabolic
activation (Ref. 40).
13-20
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Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
The available acute toxicity data for fish, aquatic invertebrates, and algae were judged inadequate
to meet the endpoints.
Basis for Conclusion:
Summary data were located for a screening-level assessment of the acute toxicity of Proprietary J
to rainbow trout and bluegill (Ref 31). Proprietary J was dissolved in acetone and added to water.
Fish were exposed to aqueous solutions of 0.1, 1.0, 10.0, or 100 mg Proprietary J/L for 96 hours.
The estimated 96-hour LC50 values for rainbow trout and bluegill were 1.1 and 1.0 mg/L,
respectively. The two highest test concentrations exceeded the reported water solubility of
Proprietary J (Ref. 49). The summary did not provide sufficient information regarding study
conditions, including test substance purity, to allow for an independent evaluation of the studies.
Summary data were located for studies of the toxicity of Proprietary J toDaphnia magna and the
midge Chironomus tentans (Ref. 62). The reported 48-hour LC50values for/), magna and C. tentans
were 0.30 and 0.15 mg/L, respectively. Study details, including test substance purity, were not
presented in the summary, so the results could not be independently evaluated.
Summaries were located for studies of the acute toxicity of the commercial aryl phosphate ester
mixtures [Formulation 8], [Formulation 9], and [Formulation 2] to fish, aquatic invertebrates, and
algae (revised HPV Robust Summaries submitted by Ref. 2, as part of the HPV Challenge Program).
Although some of the tested products may have contained Proprietary J, their actual composition
was not presented in the study summaries. Without precise knowledge of the composition of the
tested materials, it is not possible to use these studies to make a definitive statement regarding the
toxicity of Proprietary J. [Formulation 2] has been reported (by a different chemical company) to
contain <50% Proprietary J (Table 1).
Studies of the acute toxicity of [Formulation 8] to rainbow trout, bluegill, fathead minnow, channel
catfish (Ref. 8), D. magna., the midge C. plumosus, the amphipod Gammamspseudolimnaeus, and
algae (Ref. 50) were located. [Formulation 8] contains 15-20% [Chemical 3] and unspecified
amounts of at least five other compounds (Ref. 8). Chemical analysis of the aqueous test solutions
in a chronic toxicity study (discussed below) (Ref. 8) suggested that the concentration of Proprietary
J in the test waters may have been 40% or less of nominal concentrations of [Formulation 8]. Given
that the organisms in these tests were exposed to a mixture of compounds, which was predominantly
not Proprietary J, it is concluded that it is not possible to use these studies to make a definitive
statement regarding the toxicity of Proprietary J.
13-21
-------
No additional, pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located
that addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
The available chronic toxicity data for fish and aquatic invertebrates were judged inadequate to meet
the endpoints.
Basis for Conclusion:
Studies of the chronic toxicity of the commercial phosphate ester compound [Formulation 8] to
fathead minnow (Ref 8), Daphnia magna, the midge Chironomus plumosus, and the amphipod
Gammaruspseudolimnaeus (Ref. 50) were located. Formulation 8] contains 15-20% [Chemical 3]
(Ref. 8). Measured concentrations of Proprietary J in the test waters were 25% to 40% of nominal
concentrations of [Formulation 8] (Ref. 8). Thus, the organisms in these tests were exposed to
aqueous solutions that contained a mixture of compounds that were predominantly not Proprietary
J. Therefore, it is concluded that it is not possible to use these studies to make a definitive statement
regarding the toxicity of Proprietary J.
No additional, pertinent chronic toxicity studies with fish or aquatic invertebrates were located that
addressed the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
13-22
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Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
13-23
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Physical/Chemical Properties
Proprietary J: Aryl phosphate
CAS
MF
MW
SMILES
Water Solubility (mg/L):
Conclusion: The available water solubility data are adequate.
Basis for Conclusion: Ref. 49 gives a measured value for the water solubility of Proprietary J.
Solubility (mg/L)
3.20
References
Ref. 49, 51
LogKow:
Conclusion: The data for this endpoint are adequate.
Basis of Conclusion: The Log Kow values of 5.12 are identical as found in two sources Ref. 49 and
Ref. 3). Ref. 4 estimates the Log Kow value based on HPLC that are in reasonable agreement with
the key study indicated above. Ref. 45, however, gives a Log Kow value of 13.2, which is much
higher than that found in the other sources and this value does not appear reasonable for compounds
of this class.
LogK,,w
5.12
3.234.766.44
13.2
13.3
Reference
Ref. 3,49, 51
Ref. 4 (estimated from reverse phase HPLC data by Ref.
48)
Ref. 45
Ref. 13
Oxidation/Reduction: No data
Melting Point:
Conclusion: The data are adequate for this endpoint.
Basis for Conclusion: A value of -20 °C is given for the melting point of Proprietary J. Another
study provides a pour point for Proprietary J that is in reasonable agreement with the melting point
value.
13-24
-------
Melting Point (°C)
-20
-21 (pour point)
Reference
Ref. 13
Ref. 45
Boiling Point:
Conclusion: The available boiling point data are adequate to characterize this endpoint.
Basis for Conclusion: Two sources contained measured boiling point information. A third source
required calculating the boiling point from the Clausius-Clapeyron equation using data measured
by Ref. 9. The boiling points given here (including the calculated boiling point) are within a
reasonable range of each other.
BP (°C/torr)
261/6
425/760
dec. 405
420/760
155/2
References
Ref. 49, 51
Ref. 9 (extrapolated according to the Clausius-Clapeyron Equation using experimentally-
derived parameters: Log P(torr) = -A/T + C, where T is in Kelvin, A= 4444, C=9.24)
The decomposition temperature was reported in this same paper.
Ref. 4 (estimated using Meissner's method)
Ref. 13
Vapor Pressure (torr):
Conclusion: The majority of available vapor pressure data give an adequate endpoint.
Basis for Conclusion: Two sources contained measured vapor pressure data. These two values were
in agreement with each other. The third source required calculating the boiling point from the
Clausius-Clapeyron equation using data measured by Ref. 9. The calculated value was in reasonable
agreement with the measured values.
VP (torr/"C)
1.40xlO-6/25
4.6xlO'7
2.16xlO-6/25
1.35/200
10.2/250
Reference
Ref. 51; Ref. 4 (measured)
Ref. 4 (estimated from b.p. using
Ref. 9 (extrapolated according to
derived parameters Log P(torr) =
Method 2 in Ref. 21)
the Clausius-Clapeyron Equation using experimentally -
-A/T + C, where T is in Kelvin, A= 4444, C=9.24)
Ref. 45
Ref. 13
13-25
-------
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
Corrosion characteristics: No data
pH: No data
UV/VIS absorption: No data
Viscosity:
Conclusion: The viscosity of this compound has been adequately characterized.
Basis for Conclusion: A single study on the viscosity of Proprietary J was located and appears
reasonable given the other physical/chemical properties available for this compound.
Viscosity at 25
"C
58
Reference
Ref. 13
Density/Relative Density/Bulk Density:
Conclusion: The density of this compound has been adequately characterized.
Basis for Conclusion: A single study on the density of Proprietary J was located and appears
reasonable given the other physical/chemical properties available for this compound.
Density
1.175-1.185
Reference
Ref. 13
Dissociation Constant in Water: No data
Henry's Law Constant:
Conclusion: The data are adequate to characterize the Henry's Law constant.
Basis for Conclusion: The key study provides an estimated Henry's Law constant based on
measured vapor pressure and water solubility data and is taken from Ref. 45. This is a reasonable
method for estimating a Henry's Law constant. The other studies identified provide estimates
although they are based on estimated vapor pressures and not experimental values and are not
sufficiently reliable to categorize this end point.
13-26
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Henry's Law Constant
8.48xlO'7 atm-mVmole
7.2xlO'8 atm-nrVmole
2.2xlO'7 atm-mVmole
2. 15xlO"5 atm-nrVmole
Reference
Ref. 45, 51
Ref. 4 (calculated from vapor pressure
3.2)
Ref. 4 (calculated from vapor pressure
3.2)
of 4.6xlO"7 mm Hg and water solubility
of 1.4xlO"6 mm Hg and water solubility
Ref. 46
13-27
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Environmental Fate
Bioconcentration
Fish:
Conclusion: The bioconcentration of Proprietary J has not been adequately characterized.
Basis for Conclusion: Studies conducted by Ref. 44 give three different methods for determining
the BCF value for both rainbow trout and fathead minnows. The first two methods used were Biofac
and initial rate. Biofac is a computer program that requires constant water concentration for its
calculations. The "initial rate" method assumes that the rate of uptake of Proprietary J from water
is much greater than the rate of clearance during the initial exposure period. The static test method
yields equilibrium BCFs if the fish exposure continues until a maximum concentration is observed.
The maximum concentration was not reached in rainbow trout, so the BCFs may be underestimated.
Although the maximum concentrations appeared to have been reached in fathead minnows, further
studies conducted by Ref. 46 show the BCF value for fathead minnows measured using the static
test method may be very different to those measured previously (Ref. 44) using this same method.
Given that none of these tests were conducted according to EPA or OECD guidelines, and that the
results vary widely, this endpoint is not adequately characterized by the available experimental data.
Reference
Ref. 44
Ref. 44
Ref. 44
Species
Rainbow
trout
Rainbow
trout
Rainbow
trout
BCF
1096
1335
2298
Key Design Parameters
Exp.
type
Static
Biofac
Initial
rate
Range
(ppb)
1.8-55
1.8-55
1.8-55
Study
length
1-24
hours
1-24
hours
1-24
hours
T(°C)
10
10
10
Comments
The calculation of BCF
from this method comes
from the following
equation:
k1=[CFish(max)k2]/[A
exp(-Btmax)] and is
based on the total 14C.
kj and k2 values were
estimated by use of this
nonlinear regression
program. In these
calculations, the initial
exposure concentration (0
hr) was used.
The calculation of BCF
from this method comes
from the following
equation:
k^CACFish/AftCw
13-28
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Reference
Ref. 44
Ref. 44
Ref. 44
Ref. 45
Ref. 45
Ref. 46
Ref. 4
Species
Fathead
minnow
Fathead
minnow
Fathead
minnow
Rainbow
trout
Fathead
minnow
Fathead
minnow
Estimated
BCF
498
785
3316
1096
785
528
4400
Key Design Parameters
Exp.
type
Biofac
Static
Initial
rate
Static
Static
Range
(ppb)
0.8-36.5
0.8-36.5
0.8-36.5
5-50
5-50
50
Study
length
1-24
hours
1-24
hours
1-24
hours
24 hours
24 hours
8 hours
T(°C)
10
10
10
Comments
kj and k2 values were
estimated by use of this
nonlinear regression
program. In these
calculations, the initial
exposure concentration (0
hours) was used.
The calculation of BCF
from this method comes
from the following
equation:
k1=[CFish(max)k2]/[A
exp(-Btmax)]
The calculation of BCF
from this method comes
from the following
equation:
k!=(ACFish/At)Cw
Ref. 45 takes this value
from Ref. 44.
Ref. 45 takes this value
from Ref. 44.
The value is estimated
from measured values of
Log Kow from Ref. 49 and
Ref. 41 using the
equation in Ref. 5).
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
13-29
-------
Degradation and Transport
Photolysis in the Atmosphere: No data
Photolysis in Water:
Conclusion: This endpoint has been adequately characterized.
Basis for Conclusion: The products from the photolysis of Proprietary J in water as determined by
GC/MS have been summarized (Ref 13). The products are [Chemical 9] and [Chemical 10].
Photolysis in Soil: No data
Aerobic Biodegradation:
Conclusion: The biodegradation of Proprietary J under aerobic conditions has not been adequately
characterized.
Basis for Conclusion: Several different types of studies have been carried out and the weight of
evidence indicates that Proprietary J is likely to biodegrade under aerobic conditions. Only the
studies by Ref. 23 differ greatly from those in other literature sources, which is likely a result of the
water/sediment innoculum used.
Study type/
Method
Thompson-
Duthie-Sturm
Procedure
Monsanto
Shake Flask
Procedure
River Die-
away
Simulated
Biological
Treatment/
SCAS
Innoculum
Activated
sludge
Activated
sludge
Activated
sludge
Activated
sludge
Acclim
4 days
24-hour
cycle
Degradation
90% as CO2
Evolution
43% as CO2
Evolution
50%
93+
S4+/-3
>93
S4+/-3
Time
28 days
28 days
11 days
9 weeks
8 weeks
1 day
Comments
The initial
concentration
was 1 ppm; after
4 days, 50%
primary
degradation
occurred.
3 mg/L/24 hours
13 mg/L/24
hours
3 ppm/cycle
13ppm/cycle
Reference
Ref. 43
Ref. 43
Ref. 43, 49
Ref. 13, 49
Ref. 43
13-30
-------
Study type/
Method
SCAS and
RDA
Analytical
Method
(Method AC-
72-M-S)
Innoculum
Activated
sludge with
domestic
sewage feed
Acclim
Degradation
75.9%
recovery
Time
24 hours
Comments
Mixed liquor
extraction
Reference
Ref. 43
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
Sediment/Water Biodegradation:
Conclusion: The biodegradation of Proprietary J in the presence of pond and/or river sediment has
been adequately characterized.
Basis for Conclusion: Biodegradation of Proprietary J has been studied under a variety of
conditions and temperatures in the presence of both river and pond sediment. The weight of
evidence indicates the potential for Proprietary J to degrade under these environmental conditions.
Sediment
Pond water
Pond sediment
Pond sediment
Pond sediment
Sediment-
water
microcosms
Temp.
25
25
25
10
Tw
0.44
days
39
4.2
5.5
Comments
Time interval was 0-3 days.
Static conditions. Sediment was collected from
a pond made specifically for this experiment at
Glenlea Research Station, University of
Manitoba.
Initial Proprietary J concentration 0. 10 ng/mL.
Sediment:water ratio 1:10.
Time interval was 2-105 days.
Time interval was 0-6 days.
Time interval was 0-6 days.
39% (0.1 mg concentration),
18% (1 mg concentration), and
5% (10 mg concentration) mineralization after
8 weeks with innoculum from Lake Chicot, AR
after 1 week of lag time.
Reference
Ref. 46
Ref. 46
Ref. 47
Ref. 47
Ref. 23
13-31
-------
Sediment
Sediment-
water
microcosms
Sediment-
water
microcosms
Sediment-
water
microcosms
Sediment-
water
microcosms
Pond sediment
Temp.
5
Tw
16.1
Comments
14% (0.1 mg concentration),
8% (1 mg concentration), and
2% (10 mg concentration) mineralization after
8 weeks with innoculum from Little Dixie
Reservoir, MO after 1 week of lag time.
12.5% (0.1 mg concentration and 10 mg
concentration) mineralization after 8 weeks
with innoculum from Redfish Bay, TX.
1.9% (0.1 mg concentration) and
1.8% (10 mg concentration) mineralization
after 8 weeks with innoculum DeGray
Reservior, AR.
9.9% (0.1 mg concentration) and
6% (10 mg concentration) mineralization after
8 weeks with innoculum Arkansas River, AR.
Time interval was 0-6 days.
Reference
Ref. 23
Ref. 23
Ref. 23
Ref. 23
Ref. 47
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption:
Conclusion: The Koc has not been adequately characterized.
Basis for Conclusion: In both literature reports (Ref. 45 and Ref. 4), the values obtained for the K0
are calculated. No experimental values for this endpoint were located.
KOC
14600
2300
Source
Calculated from Kow using the
Kenaga and Goring equation
Calculated from water solubility
using the Kenaga and Goring
equation
Reference
Ref. 45
Ref. 4
13-32
-------
Flame Retardant Alternatives
Proprietary K: Aryl phosphate
Hazard Review
14-1
-------
Proprietary K: Aryl phosphate
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
14-2
-------
Proprietary K: Aryl phosphate
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
14-2
-------
Chemical Identity
Proprietary K: Aryl phosphate
CAS
MF
MW
SMILES
Human Health Endpoints
ACUTE TOXICITY
Conclusion:
No available acute toxicity data.
Basis for Conclusion.
No acute toxicity studies were located that addressed the endpoints in the guidelines listed below.
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425,
420, 423, 401)
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline
402)
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline
403)
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline
404)
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The skin sensitization endpoint is not satisfied.
Basis for Conclusion:
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
14-4
-------
SUBCHRONIC TOXICITY
Conclusion:
No available subchronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408),
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422), respectively
Subchronic Dermal Toxicity (21/28-day or 90-day).
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90 day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the reproductive toxicity endpoints in the guidelines
listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
14-5
-------
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
No available developmental toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the developmental toxicity endpoints in the
guidelines listed below.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
14-6
-------
Basis for Conclusion.
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
Basis for Conclusion:
No neurotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion.
No immunotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
14-7
-------
GENOTOXICITY
Conclusion:
No available genotoxicity data.
Basis for Conclusion.
No genotoxicity studies relevant to the below categories or to other types of genotoxic effects were
located.
Gene Mutation in Vitro
Gene Mutation in Vivo
Chromosomal Aberrations in Vitro
Chromosomal Aberrations in Vivo
DNA Damage and Repair
14-8
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
No available acute toxicity data for fish, aquatic invertebrates, and algae.
Basis for Conclusion:
No pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located that
addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
14-9
-------
Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
14-10
-------
Physical/Chemical Properties
Proprietary K: Aryl phosphate
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log Kow: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
14-11
-------
Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation: No data
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
14-12
-------
Flame Retardant Alternatives
Proprietary L: Aryl phosphate
Hazard Review
15-1
-------
Proprietary L: Aryl phosphate
Existing Data Summary Table - Human Health Endpoints
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
Acute Toxicity
Oral
Dermal
Inhalation
Eye irritation
Dermal irritation
Skin sensitization
Subchronic Toxicity
28-Day oral
90-Day oral
Combined repeated
dose with reproduction/
developmental toxicity
screen
2 1/28-Day dermal
90-Day dermal
90-Day inhalation
Reproductive
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Reproduction and
fertility effects
Developmental
Toxicity
Reproduction/
developmental toxicity
screen
Combined repeated
dose with reproduction/
developmental toxicity
screen
Prenatal developmental
Chronic Toxicity
Chronic toxicity (two
species)
Combined chronic
toxicity/
carcinogenicity
Carcinogenicity
Carcinogenicity (rat
and mouse)
Combined chronic
toxicity/
carcinogenicity
Neurotoxicity
Acute and 28-day
delayed neurotoxicity
of organophosphorus
substances (hen)
Neurotoxicity
screening battery
(adult)
Developmental
neurotoxicity
Additional
neurotoxicity studies
Immunotoxicity
Immunotoxicity
Genotoxicity
Gene mutation in vitro
Gene mutation in vivo
Chromosomal
aberrations in vitro
Chromosomal
aberrations in vivo
DNA damage and
repair
Other
15-2
-------
Proprietary L: Aryl phosphate
Existing Data Summary Table - Properties, Fate, and Ecotoxicity
/= Endpoint characterized by existing data * = Data available but not adequate X = Endpoint not applicable
As noted in this key, a check mark indicates that an endpoint was adequately characterized by existing studies. It does
not indicate a positive or negative result for that particular endpoint.
P/Chem Properties
Water solubility
Octanol/water partition
coefficient
Oxidation/reduction
Melting point
Boiling point
Vapor pressure
Odor
Oxidation/reduction
chemical
incompatibility
Flammability
Explosivity
Corrosion
characteristics
pH
UV/visible absorption
Viscosity
Density/relative
density /bulk density
Dissociation constant in
water
Henry's Law constant
Environmental Fate
Biocon centration
Fish
Daphnids
Green algae
Oysters
Earthworms
Metabolism in fish
Degradation and
Transport
Photolysis, atmosphere
Photolysis, water
Photolysis in soil
Aerobic biodegradation
Anaerobic
biodegradation
Porous pot test
Pyrolysis
Hydrolysis as a
function of pH
Sediment/water
biodegradation
Soil biodegradation w/
product identification
Indirect photolysis in
water
Sediment/soil
adsorption/desorption
Ecotoxicity
Aquatic Toxicity
Fish acute LC50
Daphnia acute
EC50
Mysid shrimp acute
LC50
Green algae EC50,
NOAEC, LOAEC
Fish chronic
NOAEC, LOAEC
Daphnia chronic
NOAEC, LOAEC
Mysid shrimp chronic
NOAEC, LOAEC
Terrestrial
Organism Toxicity
Bird LD50 (two
species)
Bird LC50 (two
species)
Bird reproduction
Earthworm subchronic
EC50, LC50, NOAEC,
LOAEC
15-2
-------
Chemical Identity
Proprietary L: Aryl phosphate
Synonyms
CAS
MF
MW
SMILES
Human Health Endpoints
ACUTE TOXICITY
Conclusion:
No available acute toxicity data.
Basis for Conclusion.
No acute toxicity studies were located that addressed the endpoints in the guidelines listed below.
Acute Oral Toxicity (OPPTS Harmonized Guideline 870.1100; OECD Guidelines 425,
420, 423, 401)
Acute Dermal Toxicity (OPPTS Harmonized Guideline 870.1200; OECD Guideline
402)
Acute Inhalation Toxicity (OPPTS Harmonized Guideline 870.1300 (OECD Guideline
403)
Acute Eye Irritation (OPPTS Harmonized Guideline 870.2400; OECD Guideline 405)
Acute Dermal Irritation (OPPTS Harmonized Guideline 870.2500; OECD Guideline
404)
Skin Sensitization (OPPTS Harmonized Guideline 870.2600; OECD Guideline 429)
Conclusion:
The skin sensitization endpoint is not satisfied.
Basis for Conclusion
No studies were located that followed or were similar to the guideline listed above or otherwise
addressed skin sensitization.
15-4
-------
SUBCHRONIC TOXICITY
Conclusion:
No available subchronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the subchronic toxicity endpoints in the guidelines
listed below.
Subchronic Oral Toxicity (28-day, 90-day, or combined with reproductive/developmental)
Repeated Dose 28-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline
870.3050; OECD Guideline 407)
90-Day Oral Toxicity in Rodents (OPPTS Harmonized Guideline 870.3100; OECD
Guideline 408),
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422), respectively
Subchronic Dermal Toxicity (21/28-day or 90-day).
21/28-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3200 (OECD Guideline
410)
90-Day Dermal Toxicity (OPPTS Harmonized Guideline 870.3250; OECD Guideline
411)
Subchronic Inhalation Toxicity (90 day)
90-Day Inhalation Toxicity (OPPTS Harmonized Guideline 870.3465; OECD Guideline
413)
REPRODUCTIVE TOXICITY
Conclusion:
No available reproductive toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the reproductive toxicity endpoints in the guidelines
listed below.
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
15-5
-------
Reproduction and Fertility Effects (OPPTS Harmonized Guideline 870.3800; OECD
Guideline 416)
DEVELOPMENTAL TOXICITY
Conclusion:
No available developmental toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the developmental toxicity endpoints in the
guidelines listed below.
Prenatal Developmental Toxicity Study (OPPTS Harmonized Guideline 870.3700;
OECD Guideline 414)
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental
Toxicity Screening Test (OPPTS Harmonized Guideline 870.3650; OECD Guideline
422)
Reproduction/Developmental Toxicity Screening (OPPTS Harmonized Guideline
870.3550; OECD Guideline 421)
CHRONIC TOXICITY
Conclusion:
No available chronic toxicity data.
Basis for Conclusion.
No pertinent studies were located that addressed the chronic toxicity endpoints in the guidelines
listed below.
Chronic Toxicity (OPPTS Harmonized Guideline 870.4100; OECD Guideline 452)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
CARCINOGENICITY
Conclusion:
No available carcinogenicity data.
15-6
-------
Basis for Conclusion.
No pertinent studies were located that addressed the carcinogenicity endpoints in the guidelines
listed below.
Carcinogenicity (OPPTS Harmonized Guideline 870.4200; OECD Guideline 451)
Combined Chronic Toxicity/Carcinogenicity (OPPTS Harmonized Guideline 870.4300;
OECD Guideline 453)
NEUROTOXICITY
Conclusion:
No available neurotoxicity data.
Basis for Conclusion:
No neurotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Delayed Neurotoxicity
Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances (OPPTS
Harmonized Guideline 870.6100; OECD Guideline 418, 419)
Neurotoxicity (Adult)
Neurotoxicity Screening Battery (OPPTS Harmonized Guideline 870.6200; OECD
Guideline 424)
Developmental Neurotoxicity
Developmental Neurotoxicity: Developmental Neurotoxicity Study (OPPTS
Harmonized Guideline 870.6300)
IMMUNOTOXICITY
Conclusion:
No available immunotoxicity data.
Basis for Conclusion.
No immunotoxicity studies were located that addressed the endpoints in the guidelines listed below.
Immunotoxicity (OPPTS Harmonized Guideline 870.7800)
15-7
-------
GENOTOXICITY
Conclusion:
No available genotoxicity data.
Basis for Conclusion.
No genotoxicity studies relevant to the below categories or to other types of genotoxic effects were
located.
Gene Mutation in Vitro
Gene Mutation in Vivo
Chromosomal Aberrations in Vitro
Chromosomal Aberrations in Vivo
DNA Damage and Repair
15-8
-------
Ecotoxicity
Acute Toxicity to Aquatic Organisms
Conclusion:
No available acute toxicity data for fish, aquatic invertebrates, and algae.
Basis for Conclusion:
No pertinent acute toxicity studies with fish, aquatic invertebrates, or algae were located that
addressed the endpoints in the guidelines listed below.
Acute Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1075; OECD Guideline 203)
Acute Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline 850.1010;
OECD Guideline 202)
Acute Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1035)
Algal Toxicity (OPPTS Harmonized Guideline 850.5400; OECD Guideline 201)
Chronic Toxicity to Aquatic Organisms
Conclusion:
No available chronic toxicity data for fish and aquatic invertebrates.
Basis for Conclusion:
No pertinent chronic toxicity studies with fish or aquatic invertebrates were located that addressed
the endpoints in the guidelines listed below.
Chronic Toxicity to Freshwater and Marine Fish (OPPTS Harmonized Guideline
850.1400; OECD Guideline 210)
Chronic Toxicity to Freshwater Invertebrates (OPPTS Harmonized Guideline
850.1300; OECD Guideline 211)
Chronic Toxicity to Marine/Estuarine Invertebrates (OPPTS Harmonized Guideline
850.1350)
15-9
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Acute and Subchronic Toxicity to Terrestrial Organisms
Conclusion:
No available acute and subchronic toxicity data for terrestrial organisms.
Basis for Conclusion:
No pertinent acute oral, acute dietary, or reproductive toxicity studies with birds and no subchronic
toxicity studies with earthworms were located that addressed the endpoints in the guidelines listed
below.
Acute Oral Toxicity in Birds (OPPTS Harmonized Guideline 850.2100)
Acute Dietary Toxicity in Birds (OPPTS Harmonized Guideline 850.2200; OECD
Guideline 205)
Reproductive Toxicity in Birds (OPPTS Harmonized Guideline 850.2300; OECD
Guideline 206)
Earthworm Subchronic Toxicity (OPPTS Harmonized Guideline 850.6200; OECD
Guideline 207)
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Physical/Chemical Properties
Proprietary L: Aryl phosphate
CAS
MF
MW
SMILES
Water Solubility (mg/L): No data
Log Kow: No data
Oxidation/Reduction: No data
Melting Point: No data
Vapor Pressure (torr): No data
Odor: No data
Oxidation/Reduction Chemical Incompatibility: No data
Flammability: No data
Explosivity: No data
Corrosion Characteristics: No data
pH: No data
UV/VIS Absorption: No data
Viscosity: No data
Density/Relative Density/Bulk Density: No data
Dissociation Constant in Water: No data
Henry's Law Constant: No data
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Environmental Fate
Bioconcentration
Fish: No data
Daphnids: No data
Green Algae: No data
Oysters: No data
Earthworms: No data
Fish Metabolism: No data
Degradation
Photolysis in the Atmosphere: No data
Photolysis in Water: No data
Photolysis in Soil: No data
Aerobic Biodegradation: No data
Anaerobic Biodegradation: No data
Porous Pot Test: No data
Pyrolysis: No data
Hydrolysis as a Function of pH: No data
Sediment/Water Biodegradation: No data
Soil Biodegradation with Product Identification: No data
Indirect Photolysis in Water: No data
Sediment/Soil Adsorption/Desorption: No data
15-12
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Disclaimer
This document has not been through a formal external peer review process and does not
necessarily reflect all of the most recent policies of the U.S. Environmental Protection Agency
(EPA), in particular those now under development. The use of specific trade names or the
identification of specific products or processes in this document are not intended to represent an
endorsement by EPA or the U.S. Government. Discussion of environmental statutes is intended
for information purposes only; this is not an official guidance document and should not be relied
upon to determine applicable regulatory requirements.
For More Information
To learn more about the Design for the Environment (DfE) Furniture Flame Retardancy
Partnership or the DfE Program, please visit the DfE Program web site at: www.epa.gov/dfe
To obtain copies of DfE Program technical reports, pollution prevention case studies, and project
summaries, please contact:
National Service Center for Environmental Publications
U.S. Environmental Protection Agency
P.O. Box 42419
Cincinnati, OH 45242
Phone: (513) 489-8190, (800) 490-9198
Fax:(513)489-8695
E-mail: ncepimal@one.net
Acknowledgments
This alternatives assessment was prepared by Eastern Research Group and Syracuse Research
Corporation under funding from the U.S. Environmental Protection Agency's Design for the
Environment (DfE) Program in the Economics, Exposure, and Technology Division (EETD) of
the Office of Pollution Prevention and Toxics (OPPT) and Region IX.
This document was produced as part of the DfE Furniture Flame Retardancy Partnership, under
the direction of the project's steering committee. Special thanks to the Risk Assessment Division
of OPPT, for their assistance in evaluating the chemicals in the report. Many thanks also to all
the stakeholders who participated in the technical workgroups and who provided valuable input
for the report.
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United States
Environmental Protection Agency
Design for the Environment (7406M)
EPA742-R-05-002B
September 2005
www.epa.gov/dfe
U.S. EPA
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