SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
SPONSORED CHEMICAL
Tris(2,4-di-(terf)-butylphenyl)phosphite (CAS No. 31570-04-4)
[9th CI Name: Phenol, 2,4-bis(l,l-dimethylethyl)-, phosphite (3:1)]
December 2007
INTERIM
Prepared by
High Production Volume Chemicals Branch
Risk Assessment Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001
-------
SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making
publicly available screening-level health and environmental effects information on chemicals manufactured in or
imported into the United States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do
not exist, and making both new and existing data and information available to the public. Each complete data
submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that
are screening-level indicators of potential hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data
submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals. OPPT is using a hazard-
based screening process to prioritize review of the submissions. The hazard-based screening process consists of two
tiers described below briefly and in more detail on the Hazard Characterization website3.
Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established
criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as
submitted by the sponsor. It does not include evaluation of the quality or completeness of the data.
In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is
performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors.
EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have
become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent
data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar
chemical structures, properties and biological activities may be grouped together and their data shared across the
resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all
category members. As part of Tier 2, evaluation of chemical category rationale and composition and data
extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance.
The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing
chemicals review process. These hazard characterizations are technical documents intended to support subsequent
decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general
public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on
HPV chemicals and provide information previously not readily available to the public. The public, including
sponsors, may offer comments on the hazard characterization documents.
The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical
or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of
and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the
Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the
IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the
screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level
risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts
are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk-
based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production
Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action.
1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3 U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html).
4 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
5 OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf.
6 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm.
2
-------
SCREENING-LEVEL HAZARD CHARACTERIZATION
Tris(2,4-di-(terf)-butylphenyl)phosphite (CAS No. 31570-04-4)
Introduction
The sponsor, the Additives Division of Ciba Specialty Chemicals Corporation, submitted a Test Plan and
Robust Summaries to EPA for tris(2,4-di-(fer/)-butylphenyl)phosphite (CAS No. 31570-04-4; 9th CI name:
phenol, 2,4-bis(l, 1-dimethylethyl)-, phosphite (3:1)) on May 30, 2000. EPA posted the submission on the
ChemRTK HPV Challenge website on July 20, 2000
(http://www.epa.gov/chemrtk/pubs/summaries/cibaspec/12667b3t.htm'). EPA comments on the original
submission were posted to the website on November 20, 2000. Public comments were also received and posted
to the website. The sponsor submitted updated/revised documents on February 20, 2001, which were posted to
the ChemRTK website on March 5, 2001.
This screening-level hazard characterization is based primarily on the review of the test plan and robust summaries
of studies submitted by the sponsor(s) under the HPV Challenge Program. In preparing the hazard characterization,
EPA considered its own comments and public comments on the original submission as well as the sponsor's
responses to comments and revisions made to the submission. A summary table of SIDS endpoint data with the
structure(s) of the sponsored chemical(s) is included in the appendix. The screening-level hazard characterization
for environmental and human health toxicity is based largely on SIDS endpoints and is described according to
established EPA or OECD effect level definitions and hazard assessment practices.
Sum m ;m-Conclusion
I lie estimated log kow fur trisi 2.4-di-(/r/v i-hul\ Ipliem I iphosplnie is limli llowc\er. I lie low w aler solubility (2 ')
In mu I. al 25 C. estimated) and estimated l!(T' < v2) siiuuest I lie potential fortius chemical in hioacciiniulalc is
low (2.4-di-(/i /7i-hui\ Ipliem hphosphiie is not readiK biodegradable, indicatnm dial il lias ilie potential In persist mi
llie eii\ iroiinicui
I lie e\ alualiou of a\ ailahle aquatic lo\icil> dala lor fish, aquatic iii\ eriehrales and aquatic plains and ph\ sieal-
cheniical properties mdicales ilie potential acule lia/ard of iiis(2.4-di-(/i //i-hiii\ Iphen> hphosphiie lo aquatic
organisms is low I lie aquatic lo\icit> dala siihiiniied were difliciill lo iiiierprel because lhe\ were ucucraled in ilie
presence of soheuKs). ilie concentration of chemical mi I lie lesi walerwas uoi measured and el Tec Is concentrations
reported were aho\e I lie cheniicars water soluhilits 11 mil The siihiiniied dala uidicale low to\icil> fins
iiiformalioii and I lie ph\ sieal-cheniical properiies of ilie chenucal. indicate quahtali\el> llial no effecls are e\peeled
al saiiiraliou In addiliou. ilie walersoluhihn <2 K> lo nm I. al 25 ('. esiinialedi and log k i Siofihe
chemical uidicale il is uiihkcK llial walercolumu coiiceuiialious ilial would resuli mi to\icil\ of niodei.ile or liiuli
coiiceru could he achic\ed
\cuieoml to\icil> of ii'is(2.4-di-(/r/7)-hui\ Ipliem hphosphiie mi rals. mice and hanisiers and acule dermal lo\icil> in
rals is low follow iiiu repealed oral exposures of rals lor i nioiiihs. laruel oruaus lor to\icil> included ilie ih\ roid
and kidnes Dons exposed lor ' nioiiihs and rals exposed lor I moiiili did uoi exhibit ireainieiii-relaled effects lu a
iwo-ucueraliou reproduce e lo\icil> studs mi rals. reductions iu hods weiulit were ohser\ed anioiiu pareuial
females Se\eml ahsoluie and rclali\e oruau weiuhl differences were seen m adulis ilieari. h\er. hraiu |rclali\e
oul\ |. kidue> and or spleen al one or more doses) and weauhims ispleen. h\ er. Iieari i These el fecls mi pareuis and
olTspriuu occurred al all doses
I'risi 2.4-di-i/( / /i-hui\ Ipliem I iphosplnie did uoi induce ueue miiialions mi hacleria or dominant lethal mutations ui
11i;i11111i;iIs Tris(2.4-di-(/r/7)-hui\ Ipliem hphosphiie induced au increase iu sister-chronialid e\chauue (SCI!)
licquciics mi au in \ i\ " hamster studs al liiuli doses, hut did not induce chromosome aherralions iu spernialocs tes
from mice Ilie positi\e results reported lor SCI! iu hamsters. hut ik
-------
The potential health hazard of tris(2.4-di-(/m)-bulylphcnvl)phosphilc is moderate based on the results of the
repeated-dose and reproductive toxicity.
No data gaps were identified under the HPV Challenge Program.
1. Physical-Chemical Properties and Environmental Fate
A summary of physical-chemical properties and environmental fate data submitted is provided in the Appendix. For
the purpose of the screening-level hazard characterization, the review and summary of these data was limited to the
octanol-water partition coefficient and biodegradation endpoints as indictors of bioaccumulation and persistence,
respectively.
Octanol-Water Partition Coefficient
Log Kow: 18.1 (estimated)
The model used to estimate the Kow submitted (KOWWIN v. 1.66) has been demonstrated to be accurate in
predicting log Kow between -4 and 10. Because the estimate for tris(2,4-di-(fer/)-butylphenyl)phosphite is outside
this range, the absolute value may not be accurate. Nonetheless, it is reasonable to conclude that this prediction is
indicative that the log Kow for this chemical is high (> 4).
Biodegradation
In the Modified Sturm method using activated sludge inoculum, only 3 - 6% of tris(2,4-di-(fer/)-
butylphenyl)phosphite had degraded after 28 days.
Tris(2,4-di-(tert)-butylphenyl)phosphate is not readily biodegradable.
Conclusion: The estimated log Kow for tris(2,4-di-(fer/)-butylphenyl)phosphite is high. However, the low water
solubility (2.9 x 10"14 mg/L at 25°C; estimated) and estimated BCF (3.2) suggest the potential for this chemical to
bioaccumulate is low. (2,4-di-(fer/)-butylphenyl)phosphite is not readily biodegradable, indicating that it has the
potential to persist in the environment.
2. Environmental Effects - Aquatic Toxicity
Acute Toxicity to Fish
(1) Bluegill sunfish (Lepomis macrochirus) were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite at nominal
concentrations of 0, 65, 87 or 100 mg/L for 96 hours. Tris(2,4-di-(fer/)-butylphenyl)phosphite was dissolved in
acetone.
96-h LC50 = 84 mg/L
(2) Rainbow trout (Oncorhynchus mykiss) were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite at nominal
concentrations of 0, 37, 49 or 65 mg/L for 96 hours. Tris(2,4-di-(fer/)-butylphenyl)phosphite was dissolved in
acetone.
96-h LCS0 = 49 mg/L
(3) Carp (Cyprinus carpio) were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite at nominal concentrations of 0,
28, 49, 65 or 87 mg/L for 96 hours. Tris(2,4-di-(fer/)-butylphenyl)phosphite was dissolved in acetone.
96-h LCS0 = 66 mg/L
(4) Catfish (Ictalurus melas) were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite at nominal concentrations of 0,
37, 65 or 87 mg/L for 96 hours. Tris(2,4-di-(fer/)-butylphenyl)phosphite was dissolved in acetone.
96-h LC50 = 70 mg/L
4
-------
(5) Golden orfe (Leuciscus idus forma orfus) were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite at nominal
concentrations of 0, 37, 49 or 65 mg/L for 96 hours. Tris(2,4-di-(fer/)-butylphenyl)phosphite was dissolved in
acetone.
96-h LCS0 = 42 mg/L
Acute Toxicity to Aquatic Invertebrates
Water fleas (Daphnia magna) were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite for 24 hours at nominal
concentrations of 0, 32, 58, 100, 180, 320, 580 or 1000 mg/L under static conditions. The stock solution was
prepared by mixing tris(2,4-di-(fer/)-butylphenyl)phosphite with a small amount of alkylphenol poly glycol ether.
24-h ECS0 = 510 mg/L
Toxicity to Aquatic Plants
Green algae (Scenedesmus subspicatus) were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite at nominal
concentrations of 0, 1.23, 3.7, 11, 33 or 100 mg/L for 72 hours. Tween 80 was used to increase solubility of
tris(2,4-di-(fer/)-butylphenyl)phosphite. Analysis of test concentrations was conducted at 0 and 72 hours; measured
concentrations were reported as 1.1, 3.1, 8.1, 23.8 and 75.2 mg/L at 72 hours.
72-h EC50 (biomass) > 75.2 mg/L
Conclusion: The evaluation of available aquatic toxicity data for fish, aquatic invertebrates and aquatic plants and
physical-chemical properties indicates the potential acute hazard of tris(2,4-di-(fer/)-butylphenyl)phosphite to
aquatic organisms is low. The aquatic toxicity data submitted were difficult to interpret because they were
generated in the presence of solvent(s), the concentration of chemical in the test water was not measured and effects
concentrations reported were above the chemical's water solubility limit. The submitted data indicate low toxicity.
This information and the physical-chemical properties of the chemical, indicate qualitatively that no effects are
expected at saturation. In addition, the water solubility (2.9 x 10"14mg/L at 25°C; estimated) and log Kow (> 8) of
the chemical indicate it is unlikely that water column concentrations that would result in toxicity of moderate or high
concern could be achieved.
3. Human Health Effects
Acute Oral Toxicity
Tif:RAI rats (5/sex/dose) were administered tris(2,4-di-(fer/)-butylphenyl)phosphite suspended in polyethylene
glycol (PEG) 400 via gavage at doses of 1000, 3170, 4640 and 6000 mg/kg-bw and were observed for 7 days. No
mortality or gross abnormalities were observed. Clinical signs of toxicity included sedation, difficult breathing,
protruding eyes, curved position and ruffled fur. Animals recovered within 6-7 days.
LDS0 > 6000 mg/kg-bw
Acute Dermal Toxicity
TIF:RAI f(SPF) rats (5/sex) were administered tris(2,4-di-(fer/)-butylphenyl)phosphite in 0.5% (w/v)
carboxymethylcellulose (in 0.1% aqueous polysorbate 80) via the dermal route at 2000 mg/kg-bw under semi-
occlusive conditions. No deaths occurred. Piloerection and hunched posture were seen in some animals, which
recovered within 2 days. No gross abnormalities were observed.
LDS0 > 2000 mg/kg-bw
5
-------
Repeated-Dose Toxicity
(1) Sprague-Dawley rats (20/sex/dose) were administered tris(2,4-di-(fer/)-butylphenyl)phosphite in 1%
carboxymethyl cellulose via gavage at doses of 0 (vehicle control), 125, 250, 500 and 1000 mg/kg-bw/day for 90
days. Ten controls and 10 high-dose rats were observed for 4 weeks after exposure ended. In females, increased
absolute kidney weights were observed at 500 and 1000 mg/kg-bw/day and increased absolute thyroid weights were
observed at > 250 mg/kg-bw/day. Kidney weights remained increased in females at 1000 mg/kg-bw/day after the 4-
week recovery period. No relevant clinical symptoms, body weight changes, effects on urinalysis, clinical chemistry
findings or ophthalmic, gross necropsy or histopathological changes were observed.
NOAEL (male) = 1000 mg/kg-bw/day (highest dose tested)
LOAEL (female) = 250 mg/kg-bw/day (based on increased thyroid weights)
NOAEL (female) = 125 mg/kg-bw/day
(2) Beagle dogs (4/sex/dose) were administered tris(2,4-di-(fer/)-butylphenyl)phosphite daily in the diet at
concentrations of 0, 719, 2208 or 8092 ppm for 90 days. The highest dose corresponds to 318 mg/kg-bw/day
(conversion provided only for the highest dose). No deaths occurred. No changes in clinical symptoms, food or
water consumption, hearing, eyes, body weights, hematology, clinical chemistry, urinalysis, gross pathology or
histopathology were observed in treated animals compared with controls.
NOAEL = 318 mg/kg-bw/day (highest dose tested)
(3) Sprague-Dawley rats (5/sex/dose) were administered tris(2,4-di-(fer/)-butylphenyl)phosphite in 2%
carboxymethylcellulose via gavage at 0 (vehicle control), 10, 50 or 250 mg/kg-bw/day for 28 days. No abnormal
clinical symptoms were seen and no animals died. There were no changes in body weight, laboratory parameters
(hematology or clinical chemistry), necropsy or histopathology.
NOAEL = 250 mg/kg-bw/day (highest dose tested)
Reproductive Toxicity
(1) In a two-generation study, Tif:RAI f(SPF) rats (12/sex/dose) were administered tris(2,4-di-(fer/)-
butylphenyl)phosphite continuously via the diet at doses of 0, 1600, 4000 or 10,000 ppm (approximately 107, 267 or
667 mg/kg-bw/day) during a 70-day pre-mating period and 12-day mating period (both parental generations), in
utero and during lactation (both F1 and F2 generations). Dams were allowed to raise their young to day 23 post-
partum. No effects were observed on mating rate, fertility index, implantation rate, litter size, male to female sex
ratio or post-partum mortality. Reductions in body weight were observed among F0 parental females exposed to
10,000 ppm and in F1 parental females exposed to 1600 ppm. The absolute and/or relative weights (relative to body
or brain weight) of several organs among F0 and F1 adults and F1 and F2 weanlings differed from controls. No
changes were seen during macroscopic or histopathological evaluation of the high-dose or control parents or
offspring.
LOAEL (systemic toxicity) ~ 107 mg/kg-bw/day (based on decreased brain weights and increased liver weights
relative to brain weight in males; additional sporadic body and organ weight changes also seen)
NOAEL (systemic toxicity) = Not established
NOAEL (reproductive toxicity) = 667 mg/kg-bw/day (based on no effects at the highest dose tested)
(2) In a dominant lethal assay, NMRI-derived (Tif:MAG f[SPR]) mice (20 males/dose) were administered a single
oral dose of tris(2,4-di-(fer/)-butylphenyl)phosphite in aqueous carboxymethylcellulose at either 1000 or 3000
mg/kg-bw. Each male was mated with two untreated females immediately after treatment. Necropsy of females
was performed on day 18 of pregnancy. Mating ratios and number of implantations/embryonic deaths (resorptions)
did not differ between treated groups and controls
There was no evidence of dominant lethal effects or reduced male fertility in this study.
6
-------
Developmental Toxicity
(1) Developmental effects observed in offspring in the prenatal developmental toxicity study are difficult to interpret
because they occurred in the presence of excessive maternal toxicity (mortality > 10%). Therefore, data from that
study are of limited value.
(2) In the two-generation study in rats described previously, reductions in body weight were observed among F0
parental females exposed to 10,000 ppm and in F1 parental females exposed to 1600 ppm. The absolute and/or
relative weights (relative to body or brain weight) of several organs among F0 and F1 adults and F1 and F2 weanlings
differed from controls.
LOAEL (parental toxicity) ~ 107 mg/kg-bw/day (based on decreased brain weights and increased liver weights
relative to brain weight in males; additional sporadic body and organ weight changes also seen)
NOAEL (parental toxicity) = Not established
LOAEL (developmental toxicity) ~ 107 mg/kg-bw/day (based on decreased absolute and/or relative spleen
weights inFl female weanlings)
NOAEL (developmental toxicity) = Not established
Genetic Toxicity - Gene Mutation
In vitro
(1) Salmonella strains TA98, TA100, TA1535 and TA1537 were exposed to tris(2,4-di-(fer/)-butylphenyl)phosphite
at concentrations of 0, 1, 3, 9,27 and81 ng/0.1 mL with and without metabolic activation. Both positive and
negative controls were run. Positive controls induced dose-related increases in the number of revertants. No
information on cytotoxicity was included. Tris(2,4-di-(fer/)-butylphenyl)phosphite did not result in an increase in
revertants.
Tris(2,4-di-(fc/?)-l)uty I phenyl (phosphite was not mutagenic in this assay.
(2) Saccharomyces cerevisiae MP-1 were exposed to tris(2,4-di-(tert)-butylphenyl)phosphite dissolved in dimethyl
sulfoxide at concentrations of 625, 1250, 2500, 5000 and 10,000 |ag/mL with and without metabolic activation.
Both positive and negative controls were run and cytotoxicity occurred at the highest concentration tested. Positive
control responses were provided in the robust summary indicating clear differences from control values. Tris(2,4-di-
(fer/)-butylphenyl)phosphite did not result in an increase in revertants.
Tris(2,4-di-(ferf)-butylphenyl)phosphite was not mutagenic in this assay.
Genetic Toxicity - Chromosomal Aberrations
In vivo
(1) NMRI-derived male mice were administered tris(2,4-di-(fer/)-butylphenyl)phosphite via gavage 5 times over 10
days at doses of 1481 or 4444 mg/kg-bw. Tris(2,4-di-(fer/)-butylphenyl)phosphite was suspended in 20 mL/kg
PEG, which was also used as a solvent control. Fifteen animals at each dose and 12 control animals were used.
Colcemide was injected 3 days after the final dose and animals were sacrificed 3 hours later. No increases in
chromosomal aberrations were seen in primary or secondary spermatocytes compared with controls.
Tris(2,4-di-(fc/?)-l)uty I phenyl) phosphite did not induce chromosomal aberrations in the assay.
7
-------
(2) Chinese hamsters (2/sex/dose) were administered tris(2,4-di-(fer/)-butylphenyl)phosphite in 20 mL/kg PEG 400
via gavage at doses of 1111, 2222 or 4444 mg/kg-bw. Negative (vehicle) and positive controls were used. One of
four animals showed an increased frequency of sister chromatid exchanges (SCEs) at 4444 mg/kg-bw.
Tris(2,4-di-(fc/?)-l)uty I phenyl) phosphite induced sister chromatid exchange in this assay.
(3) Chinese hamsters (4 - 6/sex/dose) were exposed administered tris(2,4-di-(fer/)-butylphenyl)phosphite in 20
mL/kg PEG 400 via gavage at doses of 1777, 2666, 4000 or 6000 mg/kg-bw. Negative (vehicle) and positive
controls were used. A small increase in SCEs was seen at the highest dose.
Tris(2,4-di-(te/?)-l)uty I phenyl) phosphite induced sister chromatid exchange in this assay.
Genetic Toxicity - Other
In vivo
(1) In an nuclear anomaly assay, Chinese hamsters (6/sex/dose) were administered tris(2,4-di-(fer/)-
butylphenyl)phosphite (in 20 mL/kg PEG 400) via gavage at 500, 1000 or 2000 mg/kg-bw/day for 2 consecutive
days. Positive (cyclophsophamide) and negative (vehicle) controls were used. The incidence of bone marrow cells
with nuclear anomalies in the treated groups was not different from the control groups.
Tris(2,4-di-(fc/?)-l)uty I phenyl) phosphite did not induce anomalies in this assay.
(2) In a dominant lethal assay, NMRI-derived (TifMAG f[SPR]) mice (20 males/dose) were administered a single
oral dose of tris(2,4-di-(fer/)-butylphenyl)phosphite in aqueous carboxymethylcellulose at either 1000 or 3000
mg/kg-bw. Each male was mated with two untreated females immediately after treatment. Necropsy of females
was performed on day 18 of pregnancy. Mating ratios and number of implantations/embryonic deaths (resorptions)
did not differ between treated groups and controls
There was no evidence of dominant lethal effects or reduce male fertility in this study.
Conclusion: Acute oral toxicity of tris(2,4-di-(fer/)-butylphenyl)phosphite in rats, mice and hamsters and acute
dermal toxicity in rats is low. Following repeated oral exposures of rats for 3 months, target organs for toxicity
included the thyroid and kidney. Dogs exposed for 3 months and rats exposed for 1 month did not exhibit treatment-
related effects. In a two-generation reproductive toxicity study in rats, reductions in body weight were observed
among parental females. Several absolute and relative organ weight differences were seen in adults (heart, liver,
brain [relative only], kidney and/or spleen at one or more doses) and weanlings (spleen, liver, heart). These effects
in parents and offspring occurred at all doses.
Tris(2,4-di-(fer/)-butylphenyl)phosphite did not induce gene mutations in bacteria or dominant lethal mutations in
mammals. Tris(2,4-di-(fer/)-butylphenyl)phosphite induced an increase in sister-chromatid exchange (SCE)
frequency in an in vivo hamster study at high doses, but did not induce chromosome aberrations in spermatocytes
from mice. The positive results reported for SCE in hamsters, but not in mice, raise a slight concern for genetic
toxicity fortris(2,4-di-(fer/)-butylphenyl)phosphite; however, negative results are shown for gene mutations in
bacteria and the dominant lethal assays and negative findings for chromosome aberrations in germ cells in
mammals.
The potential health hazard of tris(2,4-di-(fer/)-butylphenyl)phosphite is moderate based on the results of the
repeated-dose and reproductive toxicity.
4. Hazard Characterization
The estimated log Kow for tris(2,4-di-(fer/)-butylphenyl)phosphite is high. However, the low water solubility (2.9 x
10"14 mg/L at 25°C; estimated) and estimated BCF (3.2) suggest the potential for this chemical to bioaccumulate is
low. (2,4-di-(fer/)-butylphenyl)phosphite is not readily biodegradable, indicating that it has the potential to persist in
the environment.
The evaluation of available aquatic toxicity data for fish, aquatic invertebrates and aquatic plants and physical-
chemical properties indicates the potential acute hazard of tris(2,4-di-(fer/)-butylphenyl)phosphite to aquatic
8
-------
organisms is low. The aquatic toxicity data submitted were difficult to interpret because they were generated in the
presence of solvent(s), the concentration of chemical in the test water was not measured and effects concentrations
reported were above the chemical's water solubility limit. The submitted data indicate low toxicity. This
information and the physical-chemical properties of the chemical, indicate qualitatively that no effects are expected
at saturation. In addition, the water solubility (2.9 x 10"14 mg/L at 25°C; estimated) and log Kow (> 8) of the
chemical indicate it is unlikely that water column concentrations that would result in toxicity of moderate or high
concern could be achieved.
Acute oral toxicity of tris(2,4-di-(fer/)-butylphenyl)phosphite in rats, mice and hamsters and acute dermal toxicity in
rats is low. Following repeated oral exposures of rats for 3 months, target organs for toxicity included the thyroid
and kidney. Dogs exposed for 3 months and rats exposed for 1 month did not exhibit treatment-related effects. In a
two-generation reproductive toxicity study in rats, reductions in body weight were observed among parental
females. Several absolute and relative organ weight differences were seen in adults (heart, liver, brain [relative
only], kidney and/or spleen at one or more doses) and weanlings (spleen, liver, heart). These effects in parents and
offspring occurred at all doses.
Tris(2,4-di-(fer/)-butylphenyl)phosphite did not induce gene mutations in bacteria or dominant lethal mutations in
mammals. Tris(2,4-di-(fer/)-butylphenyl)phosphite induced an increase in sister-chromatid exchange (SCE)
frequency in an in vivo hamster study at high doses, but did not induce chromosome aberrations in spermatocytes
from mice. The positive results reported for SCE in hamsters, but not in mice, raise a slight concern for genetic
toxicity fortris(2,4-di-(fer/)-butylphenyl)phosphite; however, negative results are shown for gene mutations in
bacteria and the dominant lethal assays and negative findings for chromosome aberrations in germ cells in
mammals.
The potential health hazard of tris(2,4-di-(fer/)-butylphenyl)phosphite is moderate based on the results of the
repeated-dose and reproductive toxicity.
5. Data Gaps
No data gaps were identified under the HPV Challenge Program.
9
-------
APPENDIX
Summary Tabic of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Tris (2,4-di-(fcrt)-butylphcnyl)phosphitc
(31570-04-4)
Structure
c
h3c
;h3
ch3
XX/cH3
/ch3 h3c CH3
h=c^ch3 h3c^ch=
Summary of Physical-Chemical Properties and Environmental Fate Data
Melting Point (°C)
181 - 184
Boiling Point (°C)
620 (estimated)
Vapor Pressure
(hPa at 25°C)
6.5 x 10"13
Log K„w
18.1
Water Solubility
(mg/L at 25°C)
2.95 x 10-14
Direct Photodegradation
Direct photolysis is not expected since this substance does
not absorb in the region 290 - 800 nm.
Indirect (OH) Photodegradation
Half-Life (t1/2)
5.4 h
Stability in Water (Hydrolysis) (t1/2)
Unable to perform test due to extremely low estimated
water solubility.
Fugacity
(Level III Model)
Air (%)
Water (%)
Soil (%)
Sediment (%)
5.1 x 10"5
5.6 x 10"3
99.3
0.65
Biodegradation at 28 days (%)
3 - 6%
Not readily biodegradable
Summary of Environmental Effects-Aquatic Toxicity Data
Fish
96-h LC50 (mg/L)
42-84
Aquatic Invertebrates
48-h EC50 (mg/L)
510 mg/L (24-h)
Aquatic Plants
72-h ECS„ (mg/L)
(growth)
(biomass)
> 75.2 mg/L
10
-------
Summarv Tabic of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Tris (2,4-di-(fc.vtf)-butylphcnyl)phosphitc
(31570-04-4)
Acute Oral Toxicity
LDS0 (mg/kg-bw)
>6000
Acute Dermal Toxicity
LDS0 (mg/kg-bw)
>2000
Repeated-Dose Toxicity
(mg/kg-bw/day)
NOAEL/LOAEL
(male)
NOAEL =1000
(female)
NO A F.I. = 125
LOAEL = 250
Reproductive Toxicity
(mg/kg-bw/day)
NOAEL/LOAEL
Systemic and Reproductive Toxicity
NOAEL = Not established
LOAEL = 107
Developmental Toxicity
(mg/kg-bw/day)
NOAEL/LOAEL
Parental and Developmental Toxicity
NOAEL = Not established
LOAEL = 107
Genetic Toxicity - Gene Mutation
In vitro
Negative
Genetic Toxicity - Chromosomal Aberrations
In vivo
Negative
Genetic Toxicity - Other
In vivo
Nuclear Anomalies
Negative
Additional Information
Eye Irritation
Slightly irritating
— indicates that endpoint was not addressed for this chemical.
11
------- |