FINAL DRAFT
ll> ' United Stales ECAO-CIN-6083
f,. Environmental Protection c«r.4.««,Kflr. IQOQ
V/<- Agency September, 1989
(
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR ARAMITE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environ-mentaTProtection Agency
Cincinnati, OH 45268
DRAFI: 00 NOT CITE OR QUOTE
U.S. Environmental Protection
Library. Room 2-<04 PM-211-A
NOTICE Wl v Street, S.W.
a* Washington. DC 20460
o>
^ This document 1s a preliminary draft. It has not been formally released
o by the U.S. Environmental Projection Agency and should not at this stage be
2: construed to represent Agency policy. It 1s being circulated for comments
Sj on Us technical accuracy and policy Implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSHER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for
emergency and remedial actions under the Comprehensive Environmental
Response, Compensation and Liability Act (CERCLA). Both published
literature and Information obtained for Agency Program Office files are
evaluated as they pertain to potential human health, aquatic life and
environmental effects of hazardous waste constituents. The literature
searched for In this document and the dates searched are Included In
"Appendix: Literature Searched." Literature search material Is current up
to 8 months previous to the final draft date listed on the front cover.
Final draft document dates (front cover) reflect the date the document Is
sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include: Reference doses
(RfD's) for chronic and subchronlc exposures for both the Inhalation and
oral exposures. The subchronlc or partial lifetime RfO, 1s an estimate of
an exposure level which would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval which
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfD's Is the same as traditionally employed for chronic
estimates, except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfD's are not estimated. Instead,
a carcinogenic potency factor, or qf (U.S. EPA, 1980) Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and
carclnogenlclty are derived. The RQ Is used to determine the quantity of a
hazardous substance for which notification 1s required 1n the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxlclty
and carclnogenlclty) represent two of six scores developed (the remaining
four reflect 1gn1tab1lHy, reactivity, aquatic toxldty, and acute mammalian
toxlclty). Chemical-specific RQ's reflect the lowest of these six primary
criteria. The methodology for chronic toxlclty and cancer based RQs are
defined In U.S. EPA, 1984 and 198&a, respectively.
111
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EXECUTIVE SUMMARY
AramHe 1s the common name for the chemical known as sulfurous add, 2-
chloroethyl 2-[4-(d1melhylethyl)phenoxy]-l-methylethyl ester by the 9th
•i
Collective Indices of the CAS. AramHe Is a pesticide (mltldde) and has
been known by the trade names AcaMdde, Aratron, Nlagaramlte and Ortho-
Mite {SANSS, 1989). It Is a colorless liquid when pure, although the
technical material 1s a dark amber liquid. It 1s practically Insoluble In
water but Is mlsdble 1n most organic solvents. Being an ester, AramHe Is
hydrolyzed by alkalies and Is Incompatible with alkaline materials, such as
lime (Spencer. 1968). The United States International Trade Commission
(formerly United States Tariff Commission) has not reported the production
of aramlte In the United States since 1970. AramHe 1s currently listed as
a pesticide with little Interest (Worthing and Walker, 1987). It Is not
listed In the 1977 U.S. EPA TSCA production file. No data are available to
Indicate that aramlte Is currently Imported Into the United States. AramHe
was used as a mltlclde on various fruits, nuts and trees, but Hs use on
trees bearing fruits and nuts has been restricted since 1970 (Spencer, 1968;
IARC, 1974).
Environmental fate data pertaining to aramlte are limited.
Insufficient data are available to predict the relative Importance or
occurrence of chemical or biological degradation of aramlte In soil or
water. Although aramlte 1s hydrolyzed by alkalies (Spencer, 1968). rate
constant data are not available to~determ1ne hydrolysis rates In alkaline
soil or water. Experimental studies Indicate that aramlte 1s not susceptible
to direct photolysis (Gore et al., 1971; Mitchell, 1961). Based upon a
reported water solubility of 0.1 mg/s. (Nalshteln, 1964), the K for
aramlte Is an estimated 15,500 from a regression-derived prediction equation
1v
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(Lyman, 1982), which Indicates that aramUe Is Immobile In soil (Swann et
al., 1983). The estimated KQC value suggests that aramlte may partition
significantly from the water column to sediment and suspended material;
therefore, the bulk of aramlte released to the aquatic environment may
become associated with sediment material. Aramlte Is nonvolatile {Mitchell,
1961} and Is not expected to volatilize significantly from water or soil.
Aramlte aerosol released to the atmosphere during spraying of the mltlclde
Is expected to be removed from air by dry and wet deposition.
Pertinent monitoring data regarding water, food, Inhalation, and dermal
exposure of aramlte were not located 1n the available literature dted 1n
Appendix A; therefore, 1t 1s Impossible to estimate Inhalation. Ingestlon
and dermal exposure to this chemical. Workers Involved In spraying or other
applications of aramlte as a mltlclde are probably subject to Inhalation and
dermal exposure. Consumption of fruits and nuts sprayed with this pesticide
Is also a likely source of exposure for the general population.
Static acute toxlclty data on aramlte have been reported for four
species of freshwater fish and one saltwater fish (Applegate et al., 1957;
Clemens and Sneed, 1959; LeBlanc, 1984). Lethality was noted at
concentrations >0.35 mg/8. In blueglll sunflsh, Lepomls tnacrochlrus
(LeBlanc, 1984). This concentration 1s the only 96-hour LC&0 for fishes
1n the available literature; data for other species were collected from
shorter-duration tests.
Frear and Boyd (1967) reported" a 26-hour LD50 of 0.069 for the water
flea, 0. magna. which Is a lower concentration than the 48-hour EC5_ of
0.16 mg/i reported by LeBlanc (1984) and Sanders and Cope (1966). The
48-hour EC5 of 0.18 mg/l reported by Sanders and Cope (1966) for the
cladoceran, S. serrulatus. Indicates similar sensitivity for these two
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crustaceans. The scud, G. lacustrls. was slightly more sensitive than
either of the other crustaceans, with a 96-hour LC5Q of 0.06 mg/l.
Data regarding the toxic effects of aramlte to saltwater species were
not located 1n the available literature.
Acute toxic effects of aramlte In terrestrial fauna have been assessed
In birds (Hill and Camardese, 1986; H111 et al., 1975; Heath et al., 1972)
and In mites (Streu, 1972; Oeppson et al., 1969; Eldefrawl et al., 1965).
These data Indicate that acute toxic effects can occur at concentrations
>0.90 ppm In mites, but that young birds (bobwhHes, C. vlrqlnlanus;
Japanese quail, C.. c_. japonlca: and ring-necked pheasant, £. colchlcus) can
consume dietary concentrations of 5000 ppm for 5 days without mortality.
The toxldty of aramlte to terrestrial flora was assessed by Gentile
and Gallagher (1972). Germination and growth of petunia pollen tubes were
Inhibited by concentrations of 1000 ppm of active Ingredient of the
pesticide, Aramlte 15% wp, 2-(p-tert-butylphenoxy)-l-methylethyl 2-chloro-
ethyl sulflte, added to agar medium.
The lack of adequate data regarding the toxldty of aramlte precluded
the development of freshwater or saltwater criteria by the method of
U.S.EPA/OWRS (1986).
Data regarding the pharmacoklnetlcs of aramlte are limited to a single
study of urinary metabolites of orally-treated rats (Truhaut et al., 1978).
The Identification of l-(p-tert-butylphenoxy) 2-propanol In the urine of
aramlte-dosed rats suggests that one of the sulflte ester bonds of aramlte
undergoes metabolic hydrolysis.
Data regarding the carclnogenlclty of aramlte 1n humans were not
located In the available literature dted 1n Appendix A. However, chronic
dietary exposure to aramlte caused neoplastlc nodules or tumors In the
v1
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livers and biliary tracts of several rat strains (FDRL, CFN and Wlstar)
(Oser and Oser. 1960; Truhaut et al. 1975; Popper et al., 1960), In the
livers of males of one mouse strain [(C57BL/6xC3H/Anf)F ] (Innes et al..
1969) and 1n the extrahepatlc biliary tract of dogs {Sternberg et al., 1960;
Oser and Oser, 1962). In addition, data from the three studies of FDRL rats
(Oser and Oser, 1960, 1962; Popper et a!.,I960) suggests a dose-duration
response for the carclnogenldty of aramlte, as well as a dose-related
Increase In the proportion of malignant tumors.
Long-term dietary exposure to aramlte also causes nonneoplastlc liver
effects. Degenerative liver changes (liver cord swelling, vacuolated
cytoplasm, occlusion bodies and portal flbrosls) were observed In dogs fed
1580 ppm aramlte for 1 year (Oser and Oser, I960). Rats fed 200 ppm dietary
aramlte for 2 years displayed liver hypertrophy (1n males) and degenerative
alterations that Included hydropic swelling, small focal areas of
centrolobular necrosis and passive congestion (Delchmann et al., 1967).
Aram1te-1nduced liver weight Increases were noted In dietary studies In
which FDRL and CFN rats were administered >100 ppm for <2 years (Popper et
al., 1960, Oser and Oser, 1960).
Aramlte also affects reproduction In rats. In a study of the chronic
toxlclty of dietary aramlte (Oser and Oser, 1960), pups of F_ rats fed
1580 and 5000 ppm displayed decreased body weights at weaning.
Survlvablllty of pups during lactation significantly decreased 1n FQ and
F rats fed 5000 ppm and 1n F_ rats fed all three concentrations (500,
1580 and 5000 ppm). Pregnancies failed to develop after five matings In
F- rats fed 5000 ppm, but Indices of fertility and reproduction were
otherwise unaffected 1n all three generations (Oser and Oser, 1960).
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Pertinent data regarding the toxldty of Inhalation exposure or the
teratogenlclty of aramHe were not located 1n the available literature cited
In Appendix A. Pertinent data regarding the mutagenlclty of aramHe were
restricted to one negative dominant lethal assay with mice (Epstein et al.,
1972).
An oral L05Q of 3.9 g/kg aramHe was determined for rats, and this
dose was lethal to guinea pigs (Oser and Oser, 1960).
AramHe was assigned to U.S. EPA Group B2, probable human carcinogen,
on the basis of positive results In cancer studies using rats (Oser and
Qser, 1960, 1962; Popper et al., 1960; Truhaut et al., 1975), mice (Innes et
al., 1969) and dogs (Sternberg et al., 1960). A slope factor (q *) of
2.45xlO~2 (mg/kg/day)'1 was derived for both oral and Inhalation
exposure from the Increased Incidence of benign and malignant liver
neoplasms In rats In the dietary study by Popper et al. (1960). A
cancer-based RQ of 100 was also assigned based on these data.
An RfD for chronic oral exposure to aramHe of 0.05 mg/kg/day was
derived by applying an uncertainty factor of 100 to the NOAEL of 5 mg/kg/day
for noncancer liver effects In rats In the dietary study by Popper et al.
(1960) and Oser and Oser (1962). The chronic oral RfD was also adopted as
the subchronlc oral RfD. An RQ of 1000 for chronic (noncancer) toxldty was
based on decreased survival In suckling pups 1n the reproduction study In
rats by Oser and Oser (1960).
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. CHEMICAL AND PHYSICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 3
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.2. WATER 4
2.2.1. Hydrolysis 4
2.2.2. Photolysis 4
2.2.3. Mlcroblal Degradation 5
2.2.4. Volatilization 5
2.2.5. Adsorption 5
2.3. SOIL 5
2.4. SUMMARY 6
3. EXPOSURE 7
3.1. HATER 7
3.2. FOOD 7
3.3. INHALATION 7
3.4. DERMAL 7
3.5. SUMMARY 7
4. ENVIRONMENTAL TOXICOLOGY 9
4.1. AQUATIC TOXICOLOGY 9
4.1.1. Acute Toxic Effects On Fauna 9
4.1.2. Chronic Effects On Fauna 10
4.1.3. Effects On flora 10
4.1.4. Effects On Bacteria 10
4.2. TERRESTRIAL TOXICI1Y 10
4.2.1. Effects On Fauna 10
4.2.2. Effects On Flora 12
4.3. FIELD STUDIES 12
4.4. AQUATIC RISK ASSESSMENT 12
4.5. SUMMARY 14
1x
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TABLE OF CONTENTS (cont.)
Page
5. PHARMACOKINETICS 16
5.1. ABSORPTION...' 16
5.2. DISTRIBUTION 16
5.3. METABOLISM 16
5.4. EXCRETION 16
5.5. SUMMARY 17
6. EFFECTS 18
6.1. SYSTEMIC TOXICITY 18
6.1.1. Inhalation Exposure 18
6.1.2. Oral Exposure 18
6.1.3. Other Relevant Information 21
6.2. CARCINOGENICITY 22
6.2.1. Inhalation 22
6.2.2. Oral 22
6.3. HUTAGENICITY 31
6.4. TERATOGENICITY 31
6.5. OTHER REPRODUCTIVE EFFECTS 31
6.6. SUMMARY 32
7. EXISTING GUIDELINES AND STANDARDS 34
7.1. HUMAN 34
7.2. AQUAT 1C 34
8. RISK ASSESSMENT 35
8.1. CARCINOGENICITY 35
8.1.1. Inhalation 35
8.1.2. Oral 35
8.1.3. Other Routes 36
8.1.4. Weight of Evidence 36
8.1.5. Quantitative 37
8.2. SYSTEMIC TOXICITY 7 39
8.2.1. Inhalation Exposure 39
8.2.2. Oral Exposure 40
9. REPORTABLE QUANTITIES 43
9.1. BASED ON SYSTEMIC TOXICITY 43
9.2. BASED ON CARCINOGENICITY 43
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TABLE OF CONTENTS (cont.)
Page
10. REFERENCES 49
APPENDIX A A-l
APPENDIX B B-l
APPENDIX C C-l
APPENDIX D D-l
X1
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LIST OF TABLES
No. Title Page
6-1 Incidence of Tumors In FDRL Rats Treated with
Aramlte In the Diet 23
6-2 Incidence of Tumors In FDRL and CFN Rats Treated with
Aramlte In the Diet 24
6-3 Incidence of Tumors In Hale Ulstar Rats Treated with
Aramlte 1n the Diet 26
6-4 Incidence of Tumors In Mice Treated with
Aramlte In the Diet 28
6-5 Incidence of Tumors In Dogs Treated with
Aramlte In the Diet 29
9-1 Toxlclty Summary for Aramlte 44
9-2 Composite Scores for Aramlte 45
9-3 Aramlte. Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 46
9-4 Derivation of Potency Factor (F) for Aramlte 48
xll
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LIST OF ABBREVIATIONS
AEL Adverse effect level
BCF Bloconcentratlon factor
BOD Biological oxygen demand
CAS Chemical Abstract Service
CBI Confidential Business Information
CS Composite score
E0-|o Effective dose to 10% of recipients
PEL Frank effect level
GMAV Genus mean acute value
GMCV Genus mean chronic value
Koc Octanol/water partition coefficient
Kow Soil sorptlon coefficient
LCso Concentration lethal to 50% of recipients (and all other
subscripted concentration levels)
1059 Dose lethal to 50% of recipients (and all other subscripted dose
levels)
LOAEL Lowest-observed-adverse-effect level
MTD Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
UV Ultraviolet
wp Wettable powder
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Aramlte 1s the common name for the chemical known as sulfurous add, 2-
chloroethyl 2-[4-(d1methylethyl)phenoxy]-l-methylethyl ester by the 9th
Collective Indices of the Chemical Abstract Service and as sulfurous add, 2-
(p-tert-butylphenoxy)-l-methylethyl 2-chloroethyl ester by the 8th Collective
Indices of the CAS. Aramlte 1s also known as Acaradde, Aradde, Aratron,
butylphenoxylsopropyl chloroethyl sulflte, cyanoethyl sucrose, CES,
N1agaram1te, Ortho-MHe, 2-(p-t-butylphenoxy)-l-roethylethyl 2-chloroethyl
sulflte and 2-{p-t-butylphenoxy)-l-1sopropyl 2-chloroethyl sulflte (SANSS,
1989). The structure, molecular weight, empirical formula and CAS number for
aramlte are as follows:
CH3 0
CH3-C-
CH3
Molecular weight: 334.87
Empirical formula: C-js Hj3 CL 04 S
CAS Registry number: 140-57-8
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Aramlte 1s a colorless liquid when pure, although the technical material
1s a dark amber liquid (Spencer, 1968). It 1s practically Insoluble In water
but mlsdble 1n most organic solvents. Solubility In petroleum oils decreases
rapidly with decreasing temperature (Spencer, 1968; IARC, 1974). Selected
physical properties of aramlte are as follows:
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Melting point: -31.7°C Wlndholz, 1983
Boiling point: 200-210T Wlndholz, 1983
(at 7 mm Hg)
Specific gravity: 1.145-1.62 Spencer, 1968
(technical grade
20/20°C)
Water solubility: 0.1 mg/J, Nalshteln, 1964
Vapor pressure:
at 175°C 0.1 mm Hg Spencer, 1968
Log Kow: no data
Being an ester, aramHe 1s hydrolyzed by alkalies (Spencer, 1968).
Technical aramlte, which may contain 5-10% b1s-2(4-tert-butylphenoxy)-l-
methylethyl sulflte, decomposes 1n sunlight and develops an ordor of sulfur
dioxide. PhotodecomposUlon can be stabilized by adding polypropylene
glycol (Spencer, 1968; IARC, 1974). AramHe Is Incompatible with alkaline
materials such as lime or Bordeaux mixture (mixture made by adding slaked
dim to a copper sulfate solution) (Spencer, 1968).
1.3. PRODUCTION DATA
The U.S. International Trade Commission (formerly U.S. Tariff Com-
mission) has not reported the production of aramlte In the United States
since 1970, when the only producer listed was Unlroyal (USTC, 1972).
Worthing and Walker (1987) 11st aramlte as a pesticide with little current
commercial Interest. AramHe Is not listed 1n the 1977 U.S. EPA TSCA
production file. It was made by the reaction of 2-chlorethyl chloro-
sulflnate with l-(p-tert-butylphenoxy) propanol-2 (IARC, 1974). No
available data Indicate that aramlte Is currently Imported Into the United
States.
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1.4. USE DATA
Aramlte Is a mltlclde used to control certain phytophagous mites
(Spencer, 1968). In 1970, aramlte was registered for use on only 20 crops,
<*
which were fruits and nuts. Usage was restricted by U.S. EPA to postharvest
applications or nonbearlng trees (IARC, 1974). Aramlte was used extensively
on citrus until Federal restrictions were Imposed after extended animal
feeding studies Indicated potential carcinogenic properties (Jeppson and
Gunther, 1970).
1.5. SUMMARY
AramUe 1s the common name for the chemical known as sulfurous acid, 2~
chloroethyl 2-[4-(d1methylethyl)phenoxy]-l-methylethyl ester by the 9th
Collective Indices of the CAS. AramUe Is a pesticide (mltldde) and has
been known by the trade names Acarlclde, Aratron, Nlagaramlte and Ortho-
Mite (SANSS, 1989). It Is a colorless liquid when pure, although the
technical material Is a dark amber liquid. It Is practically Insoluble In
water but Is mlsclble in most organic solvents. Being an ester, aramlte 1s
hydrolyzed by alkalies and Is Incompatible with alkaline materials, such as
lime (Spencer, 1968). The United States International Trade Commission
(formerly United States Tariff Commission) has not reported the production
of aramlte In the United States since 1970. Aramlte Is currently listed as
a pesticide with little Interest (Worthing and Walker, 1987). It is not
listed 1n the 1977 U.S. EPA TSCA production file. No available data
Indicate that aramlte Is currently Imported Into the United States. AramUe
was used as a mitlcide on various fruits, nuts and trees, but Us use on
trees bearing fruits and nuts has been restricted since 1970 (Spencer, 1968;
IARC, 1974).
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Aramlte has been described as nonvolatile (Mitchell, 1961). Its vapor
pressure of 0.1 mm Hg at 175°C (Spencer, 1968) also suggests low volatility;
therefore, aramlte emitted to the atmosphere probably exists In the aerosol/
participate phase rather than the vapor phase. A typical example of
emission to the atmosphere 1s spraying of trees to control mites. In the
absence of any known chemical or photolytlc reaction, aramlte aerosol
released by spraying Is expected to be removed from air primarily by dry and
wet deposition.
2.2. WATER
2.2.1. Hydrolysis. Aramlte 1s hydrolyzed by alkalies (Spencer, 1968). A
rate constant for the aqueous hydrolysis of aramlte was not located;
therefore, the Importance of hydrolysis 1n environmental media Is not
known. Aramlte residues were observed In subcutlcular areas of citrus
fruits >30 days after no residue was detected In extracutlcular parts
(Jeppson and Gunther, 1970), suggesting that aramlte 1s relatively stable In
addle media.
2.2.2. Photolysis. Aramlte 1n hexane solution does not absorb UV light
>290 nm (Gore et a!., 1971), Indicating that aramlte will not directly
photolyze 1n sunlight. Mitchell (1961) found little or no degradation of
aramlte by spotting It on a chromatographlc paper and exposing H to a
germlddal lamp of 253.7 nm maximum "wavelength for 30 minutes and developing
the spot In aqueous and nonaqueous solvents. Although germlddal lamps
produce wavelengths shorter than sunlight, the paper chromatography tests
demonstrate aramlte's stability to direct photolysis.
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Technical aramHe reportedly decomposes In sunlight, developing a sulfur
dioxide odor (Spencer, 1968). Technical aramlte Is only =90% pure and may
contain 5-10% b1s-2(4-tert-butylphenoxy)-l-methylethyl sulfHe (Spencer,
1968; IARC, 1974) and other Impurities. Based upon the photolysis data
discussed previously, the reported photodecomposltlon of technical aramlte
Is probably due to photodecomposltlon of the Impurities rather than of
aramlte Hself.
2.2.3. M1crob1al Degradation. Pertinent data regarding the microblal
degradation of aramHe were not located 1n the available literature cited 1n
Appendix A; therefore, the Importance of blodegradatlon In the environment
Is not known. Nalshteln (19&4) reported that aramlte, at concentrations of
0.01 mg/s. to several mg/l, does not affect the BOD of water. This
Indicates that low concentrations of aramHe are not toxic to aquatic
microbes.
2.2.4. Volatilization. Aramlte 1s a relatively nonvolatile compound (see
Section 2.1) and significant volatilization from water Is not expected.
2.2.5. Adsorption. Based upon an estimated K of 15.500 (Section 2.3),
aramlte may partition significantly from the water column to sediment and
suspended material. The bulk of aramlte released to the aquatic environment
may become associated with sediment material.
2.3. SOIL
The following regression-derived equation can be used to estimate the
K of organic compounds (Lyman, 1982): log K = -0.55 log water
oc oc
solubility (In ppm) + 3.64. Using the water solubility of 0.1 mg/l
(section 1.2), the KQC for aramlte Is an estimated 15,500. Since this has
not been verified by experimental data, H may not be accurate. A K
oc
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value of this range of magnitude, however, suggests that a compound Is
generally Immobile In soil systems (Swann et al., 1983) and Is not expected
to leach Into groundwater.
Pertinent data regarding the degradation of aramlte 1n soil were not
located In the available literature cited In Appendix A. Aramlte 1s
hydrolyzed by alkalies (Spencer, 1968); therefore, aramlte may be
susceptible to hydrolysis In alkaline soils. The rate at which alkaline
hydrolysis may occur 1n soil Is not known.
2.4. SUMMARY
Environmental fate data pertaining to aramlte are limited. Insufficient
data are available to predict the relative Importance or occurrence of
chemical or biological degradation of aramlte In soil or water. Although
aramlte Is hydrolyzed by alkalies (Spencer, 1968), rate constant data are
not available to determine hydrolysis rates In alkaline soil or water.
Experimental studies Indicate that aramlte 1s not susceptible to direct
photolysis (Gore et al., 1971; Mitchell, 1961). Based upon a reported water
solubility of 0.1 mg/i. (Na1shte1n, 1964), the K for aramlte Is an
estimated 15,500 from a regression-derived prediction equation (Lyman, 1982)
which Indicates that aramlte Is Immobile 1n soil (Swann et al., 1983). The
estimated K value suggests that aramlte may partition significantly from
the water column to sediment and suspended material; therefore, the bulk of
aramlte released to the aquatic environment may become associated with
sediment material. Aramlte Is nonvolatile (Mitchell, 1961) and 1s not
expected to volatilize significantly from water or soil. Aramlte aerosol
released to the atmosphere during spraying of the mltldde Is expected to be
removed from air by dry and wet deposition.
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3. EXPOSURE
3.1. WATER
Pertinent monitoring data regarding the levels of aramlte In surface
water, groundwater or drinking water were not located In the available
literature cited 1n Appendix A. No water monitoring data pertaining to
aramlte were available from the U.S. EPA STORET data base.
3.2. FOOD
Pertinent monitoring data regarding food exposure of aramlte were not
located In the available literature cited In Appendix A. Citrus residue
studies using araralte found that =3/4 of Initial applications become
cutlcular or subcutlcular residue within 3 days, with all residues becoming
subcutlcular within 25 days (Jeppson and Gunther, 1970).
3.3. INHALATION
Pertinent monitoring data regarding Inhalation exposure of aramlte were
not located In the available literature cited In Appendix A. It 1s possible
that workers Involved In spraying or other applications of aramlte as a
mltldde are subject to Inhalation and dermal exposure.
3.4. DERMAL
Pertinent monitoring data regarding levels of aramlte In water, food and
air were not located 1n the available literature cited 1n Appendix A.
3.5. SUMMARY
Pertinent monitoring data regarding water, food, Inhalation, and dermal
exposure of aramlte were .not located 1n the available literature cited In
Appendix A; therefore, H 1s Impossible to estimate Inhalation, Ingestlon
and dermal exposure to this chemical. Workers Involved 1n spraying or other
5996H -7- 08/03/89
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applications of aramite as a mitkide are probably subject to inhalation and
dermal exposure. Consumption of fruits and nuts sprayed with this pesticide
is also a likely source of exposure for the general population.
5996H
-8-
06/15/89
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects On Fauna. Clemens and Sneed (1959) tested the
static acute tox1c1ty of aramlt-e (15%) to channel catfish, Ictaluruj
punctatus. Ten fingerllngs, 2-3 Inches long, were placed 1n 4-gallon
aquaria and tested at each of 10 concentrations at 20°C. The LDQ, LD5Q
and LD for periods <24 hours were >100 ppm.
A concentration of 5.0 mg/l of aramlte was lethal within 10 hours to
larval sea lampreys, Petromyzon marlnus. rainbow trout, Sal mo galrdneM. and
blueglll sunflsh, Lepomls macrochlrus, In static acute tests performed by
Applegate et al. (1957). LeBlanc (1984) reported a 96-hour LC5Q of 0.35
mg/s. from static acute toxlclty tests with blueglll sunflsh, L.
macrochlrus.
Static acute toxlclty tests conducted with aramlte and the water flea,
Daptinla magna. yielded a 48-hour LC5Q of 0.16 mg/l (LeBlanc, 1984;
Sanders and Cope, 1966). A 26-hour LD5Q of 0.069 mg/i was calculated by
Frear and Boyd (1967) from 10 definitive, well controlled assays with D.
magna. Ten daphnlds, <24 hours In age, were added to 100 ml solutions of
aramlte In 4-ounce bottles to which 1 ml of acetone was added to enhance
the solubility. Controls were subjected to acetone/water solutions.
Sanders and Cope (1966) assessed the static acute toxlclty of aramlte at
16°C to the cladoceran, Slmocephalus serrulatus. The 48-hour EC&0 was
0.18 mg/a.
The acute toxlclty of aramlte to the scud, Gammarus lacustrls. was
tested by Sanders (1969). Ten 2-month-old scuds were placed In 1.5-gallon
glass aquaria containing 4 I of test water and submerged 1n temperature-
5996H -9- 08/03/89
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controlled water baths. The 24-, 48- and 96-hour LC50 values reported at
70+1°C were 0.35, 0.10 and 0.06 mg/^, respectively.
^i* Data regarding the static acute toxicity of aramite to saltwater species
were not located in the available literature cited in Appendix A.
4.1.2. Chronic Effects On Fauna.
4.1.2.1. TOXICITY — Pertinent data regarding the effects of chronic
exposure of aquatic fauna to aramite were not located in the available
literature cited in Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION — Pertinent data regarding
the bioaccumulation/bioconcentration potential of aramite in aquatic fauna
were not located in the available literature cited in Appendix A.
4.1.3. Effects On Flora.
4.1.3.1. TOXICITY -- Pertinent data regarding the toxic effects of
exposure of aquatic flora to aramite were not located in the available
literature cited 1n Appendix A.
4.1.3.2. BIOCONCENTRATION — Pertinent data regarding the bioconcen-
tration potential of aramite in aquatic flora were not located in the
available literature cited in Appendix A.
4.1.4. Effects On Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to aramite were not located In the available
literature cited In Appendix A.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects On Fauna. Hill and Camardese (1986), H111 et al. (1975)
and Heath et al. (1972) investigated the toxicity of aramite to young birds
during 8-day tests that included 5 days of treated diet followed by 3 days
of untreated diet. Ten incubator-hatched offspring from breeding colonies
5996H . -10- 06/20/89
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were tested at each exposure, along with equal numbers of controls fed
untreated diets. Ten-day-old bobwhites, Collnus virglnianus. were tested
with concentrations ^5000 ppm of aramite. Twenty percent mortality was
noted at this level, and 10% mortality was reported at 2500 ppm aramite.
Fourteen-day-old Japanese quail, Coturnix c. japon i c a, and ring-necked
pheasant, Phasianus colchicus. fed concentrations ^5000 ppm suffered no
mortality. The researchers reported LC50s of >5000 ppm for these species.
Streu (1972) assessed the toxicity of aramite to young female twospotted
spider mites, Tetranychus urficae. and reported an LCSO of 0.90 ppm.
Citrus red mites, Panonychus citri, reared in captivity were exposed to
the commercial product, Aramite (2-p-tert-butylphenoxy> isopropyl 2-chlor-
ethyl sulfite, an acaricide, in the laboratory (Oeppson et al., 1969).
Mites held ventral-side up on sticky tape were sprayed with concentrations
ranging from 0.01-0.07%, resulting in mortality levels ranging from 20-98%.
An LC50 of 0.017% may be estimated from the dose-response curve provided
by this study. The comparative lethality of direct contact with spray and
with residue of this acaricide was also evaluated by these researchers.
Lemon fruit and rootings were sprayed with varied concentrations and
Infested with mites. The LC50 for nymphs of this species from contact
exposure was =0.01% of the acaricide and, from exposure to residue only,
0.02%. Adults were slightly less sensitive. The percent aramite content of
the test substance was not reported.
Eldefrawi et al. (1965) evaluated the toxicity of several acaricides to
the mite, Tetranychus cinnabarinus. Laboratory tests of Aramite
(2-p-tert-butylphenoxy) isopropyl 2-chloroethyl sulfite identified LC50
concentrations (calculated on the basis of active ingredient) of 33.5 ppm by
5996H . -11- 06/20/89
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the slide dip method and 164 ppm by the leaf spray method for adult mites.
The LC5Q for the egg stage of T. clnnabaMnus was 224 ppm.
4.2.2. Effects On Flora. Gentile and Gallagher (1972) assessed the toxl-
cUy of the commercial product, Aramlte 15% wp, 2-(p-tert-butylphenoxy)-
1-methyl-ethyl 2-chloroethyl sulfHe, to petunia pollens, "Blue Lagoon" and
"White Cascade" varieties, grown under greenhouse conditions. Pollen was
obtained from dehiscing anthers of young flowers and germinated on discs of
agar medium treated either with 1000 ppm active Ingredient of the pesticide
or with distilled water (controls). The percent germination was derived
from random counts of 100 pollen grains from each of five test discs.
Average length of the pollen tube was derived from measurement of 10
tubes/disc at 150x with an ocular micrometer. Treated pollen showed 12.25%
germination as compared with 82.3% among controls. Average length of
treated pollen tubes was 0.18 mm, compared with 0.33 mm among controls.
4.3. FIELD STUDIES
Pertinent data regarding the effects of aramlte on flora and fauna 1n
the field were not located In the available literature cited In Appendix A.
4.4. AQUATIC RISK ASSESSMENT
The lack of adequate data regarding exposure of aquatic fauna and flora
to aramlte precluded the development of a freshwater criterion (U.S.EPA/
OWRS, 1986) (Figure 4-1). Available data Indicate that acute toxic effects
can occur at concentrations >0.35 mg/i In fish and >0.06 mg/8, 1n aquatic
Invertebrates. Additional, data required for the development of a fresh-
water criterion Include the results of acute assays with a salmonId fish
species, another fish species or an amphibian, an Insect, a nonarthropod and
nonchordate species, and an Insect or species from a phylum not previously
5996H
-12-
08/03/89
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F a rn i 3. y
ttl
(.;hor dat e ( Sa i rnon i d — f i sh >
; . hordate t warrnwater fish)
#3
C.hordate (fish or amphibian)
#4
Lr u5t acean ( p 1 ankt on i c )
1*5
f-~r ust aceari ( bent hie)
ttfa
I nsect an
#7
r • o r < — A r t h r o p o d / — C h o r- d a t G>
New I nsect an or phylum
representative .
#3
a 1 g a t-
#10
Vascular plant
•UH^Not Available; «"26-h LCa <,
cr.irus; • 46-h ECS o for the wat
; the Ec-ud, GanirnaruE lacustr
TEST TYPE
BMftV- BMCV BCF-
(rnc)/L) (rng/L)
Nft N« Nfl
0. 35" Nft NA
Ntt Nft Nft
0. 1BB Nft NA
0. 06" Nfl NA
NM NA NA
NPi NA Nft
NA NA NA
XXXXXXXXXXXX
XXXXXXXXXXXX NA NA
XXXXXXXXXXXX
XXXXXXXXXXXX NA Nft
for blueqill sunqish. Lepornis rnacro-
er flea, Dajp_hnia rnaqna; * 96-h LCS o
as.
FIGURE 4-1
GMAVs, GMCVs and BCFs Required to Derive Numerical Water Quality
Criteria (U.S. EPA/OMRS, 1986) to Protect Freshwater Aquatic Life from
Aramite Exposure.
5996H
-13-
06/20/89
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represented. The development of a freshwater criterion would also require
data from chronic toxlclty tests with two species of fauna, one species of
algae or vascular plant and at least one bloconcentratlon study.
The lack of adequate data regarding exposure of aquatic fauna and flora
to aramlte precluded the development of a saltwater criterion (U.S.EPA/OWRS,
1986). Available data Indicate that acute toxic effects can occur at
concentrations >10 ppm. Additional data required for the development of a
saltwater criterion Include the results of acute assays with two chordate
species, a nonarthropod and nonchordate species, a mysld or panaeld
crustacean, two additional nonchordate species and one other species of
marine fauna. The development of a saltwater criterion would also require
data from chronic toxlclty tests with two species of fauna, one species of
algae or vascular plant and at least one bloconcentratlon study.
4.5. SUMMARY
Static acute toxlclty data on aramlte have been reported for four
species of freshwater fish and one saltwater fish (Applegate, 1957; Clemens
and Sneed, 1959; LeBlanc, 1984). Lethality was noted at concentrations
>0.35 mg/8. 1n blueglll sunflsh, L. macrochlrus (LeBlanc, 1984). This
concentration 1s the only 96-hour LCfi for fishes In the available
literature; data for other species were collected from shorter-duration
tests.
Frear and Boyd (1967) reported a 26-hour LD5Q of 0.069 for the water
flea, I), maqna. which 1s. a lower -concentration than the 48-hour ECcn of
bu
0.16 mg/a reported by LeBlanc (1984) and Sanders and Cope (1966). The
48-hour EC50 of 0.18 mg/i reported by Sanders and Cope (1966) for the
cladoceran, S. serrulatus. Indicates similar sensitivity for these two
5996H -14- 08/03/89
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crustaceans. The scud, G. lacustrls. was slightly more sensitive than
either of the other crustaceans, with a 96-hour LC50 of 0.06 mg/^.
Data regarding the toxic effects- of aramite to saltwater species were
not located in the available literature cited in Appendix A.
Acute toxic effects of aramite in terrestrial fauna have been assessed
in birds (Hill and Camardese, 1986; Hill et al., 1975; Heath et al., 1972)
and in mites (Streu, 1972; Jeppson et al., 1969; Eldefrawi et al., 1965).
These data indicate that acute toxic effects can occur at concentrations
^0.90 ppm in mites, but that young birds (bobwhites, C. virqinlanus;
Japanese quail, C. c. japonica; and ring-necked pheasant, P. colchicus) can
consume dietary concentrations of 5000 ppm for 5 days without mortality.
The toxicity of aramite to terrestrial flora was assessed by Gentile and
Gallagher (1972). Germination and growth of petunia pollen tubes were
inhibited by concentrations of 1000 ppm of active ingredient of the
pesticide, Aramite 15% wp, 2-(p-tert-butylphenoxy)-l-methylethyl 2-chloro-
ethyl sulfite, added to agar medium.
The lack of adequate data regarding the toxicity of aramite precluded
the development of freshwater or saltwater criteria by the method of
U.S.EPA/OWRS (1986).
5996H • -15- 06/20/89
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5. PHARHACOKINETICS
5.1. ABSORPTION
Pertinent data regarding the extent and rate of absorption of aramHe
were not located In the available literature cited In Appendix A. A number
of studies have provided Indirect evidence for the gastric absorption of
aramlte, however, by demonstrating that chronic feeding of aramlte-dosed
food to rodents (Oser and Oser, 1960; Popper et al.f 1960; Innes et a!.,
1969; Truhaut et al.t 1975) and to dogs (Sternberg et a!,, 1960} causes
toxic and cancerous effects of the liver and biliary tract.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of aramlte were not located 1n
the available literature cited In Appendix A.
5.3. METABOLISM
Truhaut et al. (1977) examined urinary metabolites of rats given acute
(2 g/kg In olive oil by gavage) and chronic (400 mg/kg/day in diet) oral
doses of aramlte. Although aramlte was not detected In the urine of treated
animals, two compounds were Identified that were absent In the urine of
control rats. One of these metabolites was Identified as l-(p-tert-butyl-
phenoxy) 2-propanol. Thus, aramlte was apparently metabolized by hydrolysis
of one of Its sulfHe ester bonds. Neither the extent nor the site of
metabolism was examined. Other data regarding the metabolism of aramHe
were not located 1n the available literature cited In Appendix A.
5.4. EXCRETION
Pertinent data regarding the rate or extent of excretion of aramlte were
not located 1n the available literature cited In Appendix A.
5996H -16- 08/03/89
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5.5. SUMMARY
Data regarding the pharmacokinetics of aramite are limited to a single
study of urinary metabolites of orally-treated rats (Truhaut et al., 1978).
The identification of l-(p-tert-butylphenoxy) 2-propanol in the urine of
aramite-dosed rats suggests that one of the sulfite ester bonds of aramite
undergoes metabolic hydrolysis.
5996H • -17- 06/15/89
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Pertinent data regarding the subchronlc and
chronic toxldty of aramUe from Inhalation exposure were not located In the
available literature cited In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC ORAL — Oser and Oser (1960) fed groups of
young male and female mongrel dogs sex diets supplemented with 0, 500 and
1580 ppm aramlte for 1 year. All treated dogs survived. Body weights were
unaffected at 500 ppm, but at 1580 ppm, reduced terminal body weights were
associated with reduced food Intake. After 1 year, no treatment-related
changes were noted In blood Indices (total and differential white cell
counts, blood sugar and hemoglobin), although slightly diminished red cell
counts were measured In most dogs. H1stolog1cal examination of the major
organs and tissues revealed no treatment-related changes except In the
liver. Degenerative liver changes were noted at the 1580 ppm level.
Changes Included "Hver cord swelling, vaeuolated cytoplasm and occasional
occlusion bodies In two dogs and a slight degree of portal flbrosls In one
dog at the 1580 ppm level. At 500 ppm, the authors observed cloudy swelling
and rarefactions of the liver cells with some focal cell necrosis, but
stated that these changes were comparable In degree with those seen 1n the
control dogs.
6.1.2.2. CHRONIC ORAL — Oser and Oser (1960) also examined the
chronic toxldty of dietary aramlte In FDRL rats. Groups of 10 weanling
rats of both sexes were fed diets containing 0, 500, 1580 or 5000 ppm
aramlte for 2 years. Animals were mated and, after weaning, F and F
5996H -18- 08/03/89
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offspring were fed diets Identical to those of their parents. Blood and
urine from F_ rats were collected and examined periodically, but the
nature of the urAnalysis was unspecified. Body weights were evaluated
periodically 1n F_. F and F_ rats. Post-mortem hlstologlcal
examinations were made of the livers and kidneys of all rats and of the
other major organs In > two rats/sex/concentratlon. Reproductive Indices of
all three generations were evaluated and are discussed In Section 6.5.
In the F rats (as well as 1n the F and F rats), growth through
the first 12 weeks of treatment was affected only at the 5000 ppm level.
The difference In growth, however, could be attributed to reduced food
Intake. Survival significantly decreased In the FQ groups fed the highest
concentration In the first year of feeding (10 and 2054 survival for females
and males vs. 75 and 90% for the respective control groups). In the second
year, however, all aramHe-treated groups displayed significantly decreased,
concentration-related survival relative to the control group. No rats
survived 96 weeks of treatment at the highest concentration. After 104
weeks of treatment, survival for females and males of the remaining groups
were 0 and 18% for 1580 ppm, 10 and 60% for 500 ppm and 50 and 70% for
controls, respectively.
Examination of several blood Indices (sugar and hemoglobin levels,
erythrocyte and leukocyte counts) Indicated no significant difference
between treated and control rats (Oser and Oser, 1960). H1stopatholog1cal
examinations of the major, organs and tissues of rats that died or were
sacrificed at termination of the experiment revealed no treatment-related
changes except In the liver. At the 1580 and 5000 ppm levels, pathological
liver changes were reported ("varying from focal hyperplasla and
5996H -19- 08/03/89
-------
inflammatory reactions to malignancy"), but details of the Incidence of
these changes were limited to lesions, which were diagnosed as malignant or
precancerous (Section 6.2.2). The histology of the livers of the 20 rats
fed 500 ppm did not differ from that of the controls, except for the
occurrence of a hyperplastk nodule 1n the liver of one rat.
Diets containing 0, 100, 200 or 400 ppm aramlte were provided for 2
years to three strains of rats (FDRL, Sprague-Dawley and CFN and two strains
of mice (C3H and C57BL). Rat data were reported by Popper et al. (1960) and
Oser and Oser (1962), and mouse data by Oser and Oser (1962). Groups of 100
animals of each strain (50/sex) were fed aramlte-dosed diets. For each
strain, control groups contained 200 animals (100/sex). Major organs and
tissues of moribund animals and survivors at 2 years were examined for gross
changes. All livers were examined microscopically, but other organs were
examined microscopically only If macroscopic changes were apparent.
Neither growth nor survival was affected by aramlte treatment 1n any of
the strains of rats or mice (Popper et al., 1960; Oser and Oser, 1962).
Survival of the Sprague-Dawley and CFN rats was significantly reduced (=40
and 70%, respectively) relative to that of FDRL rats (*90%) because of
respiratory Infections which were not treatment-related. The extremely high
mortality of the Sprague-Dawley rats, which occurred predominantly 1n the
ninth and tenth months, precluded evaluation of liver effects after 2 years
of aramlte treatment. Liver weights were not measured for the mice, but
significantly Increased absolute and-relative liver weights were observed at
the highest concentration (400 ppm) In both sexes of the FDRL and CFN rats.
At the 100 and 200 ppm levels, significant absolute and relative liver
weight Increases were seen only 1n FDRL rats. Gross abnormalities of
5996H -20- 08/03/89
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various organs were observed In all strains of both species, but the authors
stated that the severity and Incidence were not treatment-related except for
the Increased Incidence of liver abnormalities In rats. Rat liver
i
abnormalities were cancerous or precancerous and are described In Section
6.2.2. Hlstologlcal changes In the livers of treated mice were not
remarkable (Oser and Oser, 1962).
Delchmann et al. (1967) fed groups of 60 Osborne-Mendel rats
(30/sex/group) diets containing mixtures of DDT, methoxychlor, aldrln,
thlourea and 200 ppm aramlte, diets containing Individual pesticides
(aramlte at 200 ppm), or a non-supplemented basal diet. Treatment periods
were 24-27 months. Body weights and hematologlcal Indices {hematocrU,
hemoglobin, erythrocytes and leukocytes) were measured periodically, and all
tumors and major organs were examined hlstologlcally. Aramlte, when fed
alone at 200 ppm, did not affect weight gain, hematologlcal Indices or
survival of the rats, but Increased absolute and relative liver weights In
male rats (but not 1n females). Aramlte treatment was associated also with
hlstologlcal changes of the liver (hydropic swelling, granular cytoplasm,
slight fatty metamorphosis, small focal areas of centrolobular necrosis and
passive congestion). Evidence for additive or synerglstlc toxlcologlcal
effects was not provided by the treatments with pesticide mixtures.
6.1.3. Other Relevant Information. Oser and Oser (1960) determined an
oral L05Q value for aramlte of 3.9 g/kg In rats. In this study, aramlte
(1n a 2% aqueous gum tragacanth solution) was administered by stomach tube
to rats of both sexes (five animals/sex/dose). A single dose of aramlte
(3.9 g/kg) was administered by gavage to 10 guinea pigs, and within 2 weeks,
five of the animals died, thus Indicating that aramlte's acute toxldty 1n
5996H -21- 08/03/89
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guinea pigs 1s similar to that 1n rats. Attempts to determine oral LD5Q
values for dogs were unsuccessful because dogs regurgitated doses of aramHe
Immediately after administration.
6.2. CARC1NOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhalation exposure to aramHe were not located 1n the available literature
cited In Appendix A.
6.2.2. Oral. There 1s evidence of carclnogenlclty of chronic oral
exposure to aramHe 1n rats (Oser and Oser, 1960; Popper et al., 1960; Oser
and Oser, 1962; Truhaut et al., 1975), 1n dogs (Sternberg et al., 1960) and
1n mice (Innes et al., 1969).
In the chronic feeding study by Oser and Oser (1960) described In
section 6.1.2.2, six of 20 rats (10 male and 10 female FDRL Hlstar) fed 5000
ppm aramHe had lesions described as hepatomas or cholanglomas. Two of 21
rats fed 1580 ppm aramHe had hepatocellular lesions described as malignant,
and one of 20 rats fed 500 ppm had a hyperplastlc nodule In the liver. The
authors did not report the Incidence of hyperplastlc nodules at the two
highest doses (Table 6-1).
Studies of the chronic toxlclty of food dosed with aramHe at lower
concentrations (0, 100, 200 and 400 ppm) showed that AramHe caused
Increased Incidences of tumors In rats but not 1n mice (Popper et al., 1960,
Oser and Oser, 1962). Experimental details for these studies were described
1n Section 6.1.2.2. Significantly Increased Incidences of hyperplastlc
Hver nodules were noted at the 400 ppm level 1n both FDRL and CFN rats
(Table 6-2). Significantly Increased Incidences of nodules also were
observed In CFN rats fed 200 ppm, but Incidences In FDRL rats fed 200 ppm
and In both strains fed 100 ppm were virtually Identical to control
5996H -22- 10/02/89
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incidences (see Table 6-2). In FDRL rats fed 400 ppm, two liver carcinomas
and five bile duct adenomas were identified. The authors stated that the
animals with carcinomas also had hyperplastic nodules, but did not specify
if animals with bile duct adenomas also had hyperplastic liver nodules or
carcinomas. In CFN rats, low nonsignificant incidences of bile duct
adenomas were identified in all three groups of aramite-treated rats. The
authors did not specify, however, whether or not animals with adenomas also
had hyperplastic nodules. No other treatment-related neoplastic alterations
were observed in the livers of treated rats.
Data from the two studies of FDRL rats (see Tables 6-1 and 6-2) suggest
a dose-related response for the carcinogenicity of aramite, as well as a
dose-related increase in the proportion of malignant tumors.
The carcinogenicity of chronic oral exposure to aramite is further
indicated by a study in which male Wistar rats were fed diets containing 0
or 5000 ppm aramite for 56 weeks (Table 6-3) (Truhaut et al., 1975).
Thirty-three animals were fed aramite-dosed diets, and 20 rats served as
controls. The authors estimated the daily intake of aramite as 400
mg/kg/day. Data from this study were also presented in two later reports
(Blanc et al., 1978 and Truhaut et al., 1978). Aramite-treated rats
displayed significantly decreased body weight gain and terminal body weights
(not attributable to decreased food intake) and increased absolute and
relative liver weights .(Truhaut et al., 1975; Blanc et al., 1978). Nineteen
of 33 treated rats survived 56 weeks of treatment. Liver tumors (neoplastic
proliferation of parenchyma cells) were evident in all treated animals
surviving to 56 weeks. Information regarding survival and incidences of
neoplasms in the control group was not reported.
5996H . -25- 06/20/89
-------
TABLE 6-3
Incidence of Tumors in Male Wistar Rats Treated with Aramite in the Diet'
Dose
(ppm)
0
5000
Duration of
Treatment
(weeks)
56
56
Target
Organ
1 iver
liver
Tumor
Type
liver tumors
liver tumors
Tumor
Incidence
NR°
19/19C
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
QUALITY OF EVIDENCE
Relevant route of exposure; adequate numbers of treated
animals
Only one sex of one species; only one dose level; tumor
incidence for controls not reported; dose appeared to
be above MTD
Inadequate for quantitative risk assessment
"Source: Truhaut et al., 1975
"Twenty control animals were included, but incidence of liver tumors in
these animals was not specified.
Nineteen of 33 rats fed aramite-dosed food survived to 56 weeks of
treatment; liver tumors (neoplastic proliferation of liver parenchyma cells)
were identified in all 19.
NR = Not reported
6164H
-26-
06/20/89
-------
Innes et al. (1969) administered dally doses (464 mg/kg/day) of aramlte
In 0.5% gelatin by stomach tube to groups of (C57BL/6xC3H/Anf)F and
(C57BL/6xAkR)F mice of both sexes (16 mlce/sex/straln). Gavage treatment
began 7 days after birth and continued until the mice were weaned at 4
weeks. After weaning, aramlte was provided In the diet at a concentration
of 1112 ppm for =80 weeks. Examination of necropsled animals revealed an
Incidence of tumors In male (C57BL/6xC3H/Anf)F1 mice (6/16) significantly
(p=0.01) larger than the Incidence 1n control mice (Table 6-4). The tumors
were predominantly liver tumors described as hepatomas and were considered
potentially malignant by the authors. Incidences of tumors In female
(C57BL/6xC3H/Anf)F1 mice and In both sexes of (C57BL/6xAkR)F] mice did
not differ significantly from those 1n controls.
Chronic oral exposure of dogs to aramlte causes cancer; however, the
primary site In dogs has been Identified as the biliary tract rather than
the liver (Sternberg et al., 1960) (Table 6-5). Forty mongrel dogs of both
sexes (17 male and 23 female) were fed diets containing aramlte for 462-1220
days (Sternberg et al., 1960) (see Table 6-5). The dogs were divided Into
three groups of 12, 12 or 16 animals receiving aramlte concentrations of 0,
500 or 828-1420 ppm, respectively. The control dogs and five of the
low-dose animals were not autopsled and examined for tumors, although all of
these dogs appeared outwardly healthy throughout the experiment. The
remaining 7 dogs of the low-dose group and 12 dogs of the high-dose group
appeared moribund (or died) during "the treatment period and were examined
for hlstologlcal changes In the liver and biliary tract. In 14 of the 19
autopsled dogs, >1 adenocarclnoma was Identified In the examined areas (see
Table 6-5). Five dogs died before 811 days (short duration of treatment);
one had a neoplastlc nodule of the liver. The other 14 autopsled dogs who
5996H . -27- 10/02/89
-------
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6163H
-29-
08/03/89
-------
lived 811 days or longer had the following tumors: 7 had adenocarclnoma of
the gall bladder and extrahepatlc biliary duct), mainly dogs of the high-
dose group}; 2 had adenocarclnoma of the hepatic biliary duct only; 1 had
adenocarclnoma of the gall bladder only; 1 had adenocarclnoma of the gall
bladder and Intrahepatlc biliary duct; and 3 had adenocarclnoma of the
extra- and Intrahepatlc biliary duct. No calculi were present In the gall
bladder or biliary ducts. Neoplastlc nodules In the liver parenchyma and
adenocarclnomas of liver bile ducts were also observed In some of the
animals that had adenocarclnomas of the extrahepatlc biliary tract.
In a series of 2-year feeding experiments with Osborne-Hendel rats,
Radomskl et al. (1965) and Delchmann et al. (1967) administered aramlte
Individually at two concentrations (BO and 200 ppm) and In mixtures with
other pesticides at three concentrations (50, 80 and 200 ppm}. Groups of
sixty rats (30/sex/group) received the 80 ppm (Radomskl et al., 1965) and
200 ppm (Delchmann et al., 1967) treatments, and a group of 100
(50/sex/group) received the 50 ppm treatment (Radomskl et al., 1965). Tumors
detected by gross examination of major organs and tissues were examined
h1stolog1cally. Incidences of tumors In any of the groups treated with
aramlte alone were not significantly different from Incidences of tumors In
control groups. Furthermore, the data from experiments with mixtures did
not provide evidence for synerglstlc carcinogenic effects among the
pesticides.
Single subcutaneous .Injectlonr of aramlte Into C3H/Anf mice (10
mg/mouse; 50 mice/sex) were not carcinogenic within periods of observation
ranging from 273-575 days postappHcatlon. Weekly applications of aramlte
(0.1 mg or 10 mg In acetone) were applied to the skin of the same strain of
mice for periods ranging from 44-74 weeks. Weekly visual observations of
the skin were recorded. At the end of the exposure period, mice were
5996H -30- 10/02/89
-------
subjected to gross autopsy. Sections of the skin were prepared and examined
microscopically for hlstologlc alteration. Mice treated at either dose
showed no evidence of skin tumors as revealed by macroscopic and microscopic
examination (Hodge et al., 1966).
6.3. MU1AGENICITY
Pertinent data regarding the mutagenldty of Aramlte were restricted to
one negative dominant lethal assay In mice (Epstein et al., 1972). Single
IntraperHoneal doses of 200 and 500 mg/kg aramlte were administered to
groups of seven and nine male ICR Ha Swiss mice, respectively. The treated
males were then mated during sequential weekly periods with groups of
untreated virgin females. The number of early fetal deaths and prelmplanta-
tlon losses associated with the treated groups were not different from
control values.
6.4. TERATOGENICITY
Pertinent data regarding the teratogenldty of aramlte were not located
In the available literature cited In Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of aramlte were
restricted to the chronic oral study by Oser and Oser (1960) described 1n
Section 6.1.2.2. FQ rats were mated >7-8 times during their llfespans,
but FI and F2 generations were restricted to the production of only two
litters. The authors did not specify the duration of exposure before the
first mating. Indices of fertility (number of pregnancies/mating) and
reproduction (number of Utters/pregnancies) were not affected by chronic
feeding of aramlte-dosed food 1n any of three generations, except that
pregnancies failed to result after the fifth mating In the FQ rats at 5000
ppm. Pups of FQ rats fed 1580 and 5000 ppm displayed decreased average
body weights at weaning. Survlvablllty of pups during lactation (number of
5996H . -31- 10/02/89
-------
pups weaned/number of pups born) decreased significantly In FQ and FI
rats fed the highest dose (5000 ppm) and In F_ generations at all dose
levels (500, 1580 and 5000 ppm). At 5000 ppm. none of the F_ generation
lived through the lactation period.
6.6. SUMMARY
Data regarding the carclnogenlclty of aramlte In humans were not located
In the available literature cited In Appendix A. However, chronic dietary
exposure to aramlte caused neoplastU nodules or tumors In the livers and
biliary tracts of several rat strains (FDRL, CFN and Wlstar) (Oser and Oser,
1960; Truhaut et al. 1975; Popper et al., 1960), 1n the livers of males of
one mouse strain [(C57BL/6xC3H/Anf)f^] (Innes et al., 1969) and In the
extrahepatlc biliary tract of dogs (Sternberg et al., 1960; Oser and Oser,
1962). In addition, data from the three studies of FDRL rats (Oser and
Oser, 1960, 1962; Popper et al.,1960) suggest a dose-duration response for
the carclnogenlclty of aramlte, as well as a dose-related Increase 1n the
proportion of malignant tumors.
Long-term dietary exposure to aramlte also causes nonneoplastlc liver
effects. Degenerative liver changes (liver cord swelling, vacuolated
cytoplasm, occlusion bodies and portal flbrosls) were observed 1n dogs fed
1580 ppm aramlte for 1 year (Oser and Oser, 1960). Rats fed 200 ppm dietary
aramlte for 2 years displayed liver hypertrophy (1n males) and degenerative
alterations that Included hydropic swelling, small focal areas of
centrolobular necrosis and passive- congestion (Delchmann et al., 1967).
Aram1te-1nduced liver weight Increases were noted 1n dietary studies In
which FDRL and CFN rats were administered >100 ppm for <2 years (Popper et
al., 1960, Oser and Oser, 1960).
5996H
-32-
10/02/89
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AramHe also affects reproduction In rats. In a study of the chronic
tox1c1ty of dietary aramHe (Oser and Oser, I960), pups of F» rats fed
1580 and 5000 ppm displayed decreased body weights at weaning. Survlva-
i
bllHy of pups during lactation significantly decreased In FQ and F,
rats fed 5000 ppm and In F« rats fed all three concentrations (500, 1580
and 5000 ppm). Pregnancies failed to develop after five matlngs 1n Ffl
rats fed 5000 ppm, but Indices of fertility and reproduction were otherwise
unaffected 1n all three generations (Oser and Oser, 1960).
Pertinent data regarding the toxlclty of Inhalation exposure or the
teratogenlclty of aramHe were not located In the available literature cited
In Appendix A. Pertinent data regarding the mutagenlclty of aramHe were
restricted to one negative dominant lethal assay In mice (Epstein et al.,
1972).
An oral LD,n of 3.9 g/kg aramHe was determined for rats, and this
dose was lethal to guinea pigs (Oser and Oser, 1960).
5996H
-33-
10/02/89
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7. EXISTING GUIDELINES AND STANDARDS
Current guidelines and standards regarding Aramite were not located in
the available literature cited in Appendix A.
7,2. AQUATIC
Aramite has been identified and listed as a hazardous constituent (U.S.
EPA, 1981).
5996H
-34-
06/15/89
-------
8. RISK ASSESSMENT
Statements concerning available literature in this document refer to
published, quotable sources and are in no way meant to imply that CBI, which
this document could not address, do not exist. From examination of the
bibliographies of the CBI data, however, it was determined that CBI data
would not alter the approach to risk assessment or the risk assessment
values presented herein.
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenicity of
inhalation exposure to aramite were not located in the available literature
cited in Appendix A.
8.1.2. Oral. As discussed in Section 6.2.2., positive results were
available for the carcinogenicity of chronic oral exposure to aramite in
rats (Oser and Oser, 1960; Popper et al., 1960; Truhaut et al., 1975), in
dogs (Sternberg et al., 1960) and in mice (Innes et al., 1969).
Two of 21 rats fed 1580 ppm aramite and 6 of 20 rats fed 5000 ppm
aramite had liver tuirors. in the 2-year study by Oser and Oser (1960) (see
Table 6-1). In another 2-year feeding study (Popper et al., 1960),
significantly increased incidences of hyperplastic nodules were observed in
rats fed diets containing 200 or 400 ppm aramite (see Table 6-2). Nineteen
of 33 male Nistar rats fed 5000 ppm aramite survived 56 weeks of treatment
(Truhaut et al., 1975); liver tumors were identified in all surviving rats
(see Table 6-3). In a group of 24 dogs provided diets containing ^500 ppm
aramite for 462-1220 days (Sternberg et al., 1960), 14 had adenocarcinomas
in their bile ducts or gall bladder (see Table 6-5). A significantly
increased incidence of liver tumors (see Table 6-4) was observed also in
5996H . -35- 06/15/89
-------
o
male (C57BL/6xC3H/Anf)F1 mice given aramHe by gavage at 464 mg/kg/day for
3 weeks during suckling, followed by 1112 ppra In the diet for 80 weeks
(Innes et a!., 1969).
8.1.3. Other Routes. Neither single subcutaneous Injections nor weekly
skin-painting applications of aramlte were tumorlgenlc 1n mice (Hodge et
al., 1966). Additional data regarding the cardnogenlclty of Aramlte by
other routes of exposure were not found.
8.1.4. Weight of Evidence. There are no data regarding the cardno-
genlclty of aramlte In humans. Information regarding aramHe's mutagenldty
Is limited to a single report that aramlte did not cause dominant lethal
mutations 1n mice (Epstein et al., 1972).
Qualitative and quantitative evidence exists for the cardnogenlclty of
aramlte In three species of animals. Chronic dietary exposure to aramlte
caused statistically significant Increased Incidences of liver tumors or
neoplastlc nodules In three strains of rats (Oser and Oser, 1960; Popper et
al., 1960; Oser and Oser, 1962; Truhaut et al., 1975) and males of one
strain of mice (Innes et al., 1969). Chronic dietary exposure was
associated with a high Incidence of tumors In the extrahepatlc biliary
system of dogs (Sternberg et al., 1960); however, lack of examination of
control dogs precluded statistical analysis of the data (see Table 6-5).
Three of the rat studies Indicate that Increases In the Incidences of liver
neoplasms and proportions of malignant liver tumors were related to dose
(Oser and Oser. 1960, 1962; Popper ei al., 1960)
The available data In several species provide sufficient evidence for
cardnogenlclty of aramlte In animals and Indicate a potential for aramlte
to cause cancer In humans. Because there 1s sufficient evidence for the
5996H -36- 08/03/89
-------
earelnogenlcUy of aramUe 1n animals but no human data, aramlte 1s
classified In U.S. EPA Group B2 -- Probable Human Carcinogen (U.S. EPA,
1986a).
8.1.5. Quantitative.
8.1.5.1. INHALATION — Pertinent data regarding the cardnogenlcHy of
Inhaled aramlte were not located In the available literature cited In
Appendix A. A tentative quantitative estimate of carcinogenic risk
*
(q-j) that Is due to Inhalation exposure to aramlte can be derived from
oral exposure data, assuming that aramlte Is carcinogenic following any
route of exposure and that there are no route-specific differences 1n
pharmacoklnetlcs such as differences between routes In absorption
efficiencies. Support for the first assumption Is provided by
demonstrations that orally administered aramlte Induces tumors at sites
distant from the gastrointestinal tract (In the liver and extrahepatlc
biliary system). The lack of pharmacoklnetlc data for aramlte underscores
the tentative nature of this estimate.
From the oral q * of 2.45xl(T2 (rag/kg/day)"1 (calculated In
Section 8.1.5.2.), the concentrations of aramlte In air associated with
Increased lifetime risk of cancer at risk levels of 10~5, 10"* and
10"7 are calculated to be 1.43xl(T8, 1.43x10"* and 1.43xlO~5
mg/m3, respectively. These concentrations were calculated by dividing a
given risk level by the q * multiplying by the reference human body
weight (70 kg) and dividing by 20- mVday, the reference Inhalation rate
for humans (U.S. EPA, 1986b).
8.1.5.2. ORAL — Three dietary studies with rats and mice (Oser and
Oser, 1960; Popper et a!., 1960; Innes et al., 1969) provided data suitable
for calculation of quantitative estimates of cancer risk (q,*s). From
5996H -37- 08/03/89
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these data, four q,*s were derived using the multistage model of Howe and
Crump (1982). Data used 1n the derivations are presented In Appendix B.
The Incidences of liver hyperplastlc nodules and tumors In FDRL rats
from the Popper et al. (I960) and Oser and Oser (1962) studies {see Table
*
6-2) provide the highest quality data upon which to base an oral q, for
aramHe. The experiment was well designed, with more than adequate, numbers
of animals, a duration of exposure equal to the rat's llfespan and a high
dose level that appeared to be only slightly below the MTD. Furthermore,
the occurrence of liver carcinomas at the highest dose Indicates that there
was a progression from benign hyperplastlc liver nodules to malignancy. The
data for CFN rats from the same study (see Table 6-2) Is of similar quality,
but there Is no evidence of progression from hyperplastlc nodules to
malignancy.
The study of FDRL Wlstar rats by Oser and Oser (1960) demonstrated a
statistically significant Increased Incidence of liver tumors at high
dietary doses (1580 and 5000 ppm) (see Table 6-1). The data of the highest
dose group was dropped from consideration In the Howe and Crump (1982) model
(Appendix B), since this group was exposed to aramlte for a shorter duration
of time than the other two dose groups 1n the study. Also, a limitation of
this study Is that Incidences of hyperplastlc liver nodules were
Incompletely reported.
Although the data for male (CB57BL/6xC3H/Anf)F^ mice from Innes et al.
(1969) Indicate that dietary aramHe can cause liver tumors In mice (see
Table 6-4), there was only one treatment level and no Indication of
progression from benign to malignant tumors.
*
The available rat and mouse data support a q-j based upon rat data
rather than one based upon mouse data. The available data for
tumorlgenlclty 1n mice are largely negative. In the study by Innes et al.
5996H -38- 10/03/89
-------
(I960), negative responses were obtained for female mice of the
(CB57BL/6xC3H/Anf)Fl strain and both sexes of the (CB57/6xAkr)F1 strain.
As Indicated above, treatment-related tumors occurred only 1n male
*»
(CB57BL/6xC3H/Anf)Fl mice In this study. Oser and Oser (1962) provided
dietary aramlte at concentrations <400 ppm and found no Increased Incidence
of tumors In treated mice of two other strains (C3H and CB57BL).
Additionally, carcinomas were Induced In rats (Popper et a!., 1960), but not
In mice (Innes et al., 1969). Aramlte-lnduced tumors have been observed
more consistently 1n rats; positive results exist for all three rat strains
examined In two Independent studies (Popper et al., 1960; Truhaut et al.,
1975).
The q1 of 2.45xlO~r (mg/kg/day)"1 from the FDRL rat data from
Popper et al. (1960) (Appendix B), therefore, Is the most appropriate
quantitative estimate of cancer risk for aramlte. The concentrations of
aramlte 1n drinking water associated with Increased lifetime risks of cancer
are 1.43xlO~*, 1.43xlO~3 and 1.43x10"* mg/i at risk levels of
10~5, 10~* and 10~7, respectively. These concentrations were
*
calculated by dividing a given risk level by the q,, multiplying by the
body weight for humans (70 kg) and dividing by the reference dally water
consumption for humans (2 l) (U.S. EPA, 1986b).
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure -- Pertinent data regarding the subchronlc or
chronic toxldty of 1nha-led aramlte were not located 1n the available
literature cited In Appendix A.
5996H . -39- 10/02/89
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8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC ORAL) — Data for
the subchronlc systemic toxlclty of aramlte are limited to the 1-year
feeding study by Oser and Oser (1960) In which dogs were fed aramlte at
concentrations of 0. 500 and 1580 ppm. A LOAEL of 1580 ppm was Identified
for degenerative liver changes Including liver cord swelling, vacuolated
cytoplasm and portal flbrosls (rec #8). In dogs fed 500 ppm, liver changes
were observed and described as cloudy swellings and rarefactions of liver
cells with some focal cell necrosis and occasional occlusion bodies (rec
#9). These changes were comparable with those seen 1n control dogs;
therefore, 500 ppm has been designated a NOAEL. Because limited numbers of
animals (three/concentration) were used and additional subchronlc data are
not available, confidence In this study and the data base Is low.
Nevertheless, a subchronlc RfD (of low confidence) can be derived from the
NOAEL In this study. Assuming that dogs consume 0.025 kg food/kg body
weight/day (U.S. EPA, 1986b), the treatment concentrations for the LOAEL and
NOAEL correspond to 39.5 and 12.5 mg/kg/day, respectively. An oral
subchronlc RfD of 0.125 mg/kg/day Is derived by dividing the NOAEL by an
uncertainty factor of 100 (10 to extrapolate from animals to humans and 10
to provide additional protection for unusually sensitive Individuals).
Given the limitations of the subchronlc data base and those of the key
study from which the subchronlc oral RfD was derived, 1t may be preferable
to adopt the value of the chronic oral RfD (0.05 mg/kg/day) for the
subchronlc RfD. As explained 1n the next section, confidence 1s medium In
the chronic value because of an adequate data base and a suitably designed
key study.
5996H -40- 08/03/89
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8.2.2.2. CHRONIC EXPOSURES (ORAL) — Three rat studies provide
Information suitable for derivation of a chronic oral RfD for aramlte. The
rat study by Oser and Oser (1960) demonstrated reduced survival of the
suckling offspring of F_, F_ and F generations fed dietary aramlte.
In this study, Fn rats were mated >7-8 times throughout a 2-year exposure
period. F and F rats were provided the same dietary concentrations as
their parents but were allowed to produce only two litters. Reduced survival
of pups of the F_ generation was significant at all three of the provided
concentrations (500, 1580 and 5000 ppm) (rec #5, 6 and 7, respectively).
Thus, 500 ppm represents the lowest PEL for this effect In rats, and a NOAEL
was not Identified.
Liver weight Increases were measured 1n FDRL rats provided dietary
aramlte at 100 (rec #1), 200 and 400 ppm (rec #2) for 2 years (Popper et
al., 1960; Oser and Oser, 1962). Because other nonneoplastlc, hlstologlcal
effects of the liver were not observed 1n this rat strain, all three of
these levels are NOAELs. In the same study, CFN rats fed 400 ppm had
Increased liver weights (rec #3), but those fed 100 and 200 ppm did not.
Other noncancerous liver effects In the CFN rats were not revealed by
hlstopathologlcal examination. Thus, 400 ppm Is the highest NOAEL for liver
effects In this study (rec #3).
In the study by Delchmann et al. (1967), Osborne-Mendel rats fed diets
containing 200 ppm aramlte displayed degenerative liver changes (hydropic
swelling, small focal areas of cervtrolobular necrosis and passive conges-
tion). The 200 ppm concentration, therefore, represents a LOAEL for
degenerative liver changes In Osborne-Hendel rats (rec #4). A NOAEL cannot
be Identified because additional levels were not tested.
5996H -41- 08/03/89
-------
The lowest LOAEL among these dietary studies, 200 ppm [10 mg/kg/day,
assuming rats consume 0.05 kg food/kg body weight/day (U.S. EPA, 1980)], Is
for degenerative liver effects In Osborne-Hendel rats (Delchmann et a!.,
1967) (rec #4). Although this study did not Identify a NOAEL or NOEL for
liver effects In Osborne-Hendel rats, nonadverse liver effects (Increased
liver weights without nonneoplastU alterations) (rec #1) were observed In
FDRL rats at a lower dietary concentration, 100 ppm (5 mg/kg/day} (Popper et
al., 1960; Oser and Oser, 1962). The NOAEL of 5 mg/kg/day Is, therefore,
selected as the basis for the chronic oral RfD. A chronic oral RfD of 0.05
mg/kg/day Is derived by dividing the NOAEL by an uncertainty factor of 100
(10 to extrapolate from animals to humans and 10 to provide additional
protection for the most sensitive Individuals). Confidence In the key study
1s medium because, although more than adequate numbers of animals were
provided with three treatment levels and all livers were examined
microscopically, tissues other than the liver were examined microscopically
only If macroscopic abnormalities were apparent. Confidence Is medium also
In the data base and the RfD. Two adequately designed, Independent studies
of rats provided data regarding liver effects that were due to chronic
feeding of aramlte 1n three different strains. In addition, Information was
available concerning the reproductive effects of dietary aramlte. The data
base could be Improved with Information regarding teratogenlclty, effects at
sites other than the liver and systemic toxldty In other species.
5996H -42- 08/03/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Data regarding the systemic toxldty of aramHe were discussed 1n
Section 6.1. Dose-response data appropriate for derivation of CSs are
summarized In Table 9-1. Inhalation studies for aramHe were not avail-
able. Degenerative liver changes were noted by Oser and Oser (1960) where
dogs were provided dietary aramHe at concentrations of 1580 ppm (39.5
mg/kg/day) for 1 year. In chronic feeding studies with rats, Increased
liver weights were observed at dietary concentrations >100 ppm (5 mg/kg/day}
(Popper et al., 1960; Oser and Oser, 1962), and degenerative liver changes
occurred at dietary concentrations of 200 ppm (10 mg/kg/day) (Delchmann et
al., 1967). Oser and Oser (1960) also reported decreased survival In the
suckling offspring of f~ rats fed dietary concentrations >500 ppm (25
mg/kg/day).
Table 9-2 derives candidate CSs for the human equivalent doses
associated with the effects presented In Table 9-1. Since Oser and Oser
(1960, 1962), Popper et al. (1960) and Delchmann (1967) reported effects on
the liver that may have been related to carclnogenesls, these studies are
not further considered for the derivation of an RQ based on systemic
toxldty; however, CSs of these studies are provided 1n Table 9-2 for
comparlslon. Decreased survival of suckling pups, noted by Oser and Oser
(1960), had a CS of 20, which corresponds to an RQ of 1000. This 1s
selected as the RQ for Aramlte based on systemic toxldty (Table 9-3).
9.2. BASED ON CARCINOGENICHY
As discussed In Chapter 6. aramHe caused hyperplastlc nodules or tumors
In rat livers (see Tables 6-1, 6-2 and 6-3), In the extrahepatlc biliary
system of dogs (see Table 6-4) and In mouse livers (see Table 6-5). Aramlte
5996H -43- 08/03/89
-------
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6157H
-45-
08/03/89
-------
TABLE 9-3
Aramite
(CAS NO. 140-57-8)
Minimum Effective Dose (MED) and Reportafale Quantity (RQ)
Route:
Species/sex:
Dose*:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
oral
rat/male and female
301 mg/day
two matings (preceded by treatment of two preceding
generations)
decreased survival of suckling pups of F, generation
2
10
20
1000
Oser and Oser, 1960
*Human equivalent dose
6158H
-46-
06/20/89
-------
Is classified as a U.S. EPA Group B2 chemical, because sufficient evidence
of carclnogenlclty 1n animals and lack of human data were presented. The
data for aram1te-1nduced liver tumors In FDRL rats (Popper et a!., 1960;
Oser and Oser, 1962} provided the most appropriate oral q-j* with a value
of 2.5xlO~2 (mg/kg/day)"1, as discussed In Chapter 8. According to the
model of Howe and Crump (1982), the ED1Q Is 14.13 mg/kg/day. Inversion of
this value, followed by an adjustment to extrapolate from animals to humans.
leads to an F factor of 4.512xl(Tl (mg/kg/day)'1 for aramHe (Table
9-4). Aramlte Is, therefore, assigned to Potency Group 3, and, because of
Its assignment to Group B2, 1s given a low hazard ranking, which corresponds
to a cancer-based RQ of 100.
5996H -47- 08/03/89
-------
o
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or
physical State:
Body weight:
Duration of
treatment:
TABLE 9-4
Derivation of Potency Factor (F) for Aramlte
Popper et al., 1960; Oser and Oser, 1962
oral, diet
rat
FDRL
male and female
food
0.270 kg
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental dose/
exposure (ppm):
Transformed dose
(mg/kg/day):
Tumor Incidence:
Unadjusted l/ED-)o-
Adjusted 1/ED10*:
RQ:
104 weeks
104 weeks
104 weeks
liver
hyperplastlc nodules and carcinomas
0 100 200
0 5 10
2/193 2/93 3/100
7.077xlO"2 (mg/kg/day T1
4.512X10'1 (mg/kg/day)"1
100
400
20
25/90
Calculated by multiplying the unadjusted l/ED-|(j by the cube root of the
ratio of the reference human body weight by the average experimental animal
body weight (U.S. EPA, 1980)
6159H
-48-
10/02/89
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10. REFERENCES
Applegate, V.C., J.H. Howe 11, A.E. Hall Jr. and M.A. Smith. 1957. Toxicity
of 4346 chemicals to larval lampreys and fishes. Spec. Sci. Rep. Fish. No.
207, Fish Wildl. Serv. U.S.D.I., Washington, DC. p. 1-9; 22.
Blanc, F., V. Ngoc-Huyen, 3.M. Warnet, J.R. Claude and R. Truhaut. 1978.
Carcinogenic effect of an insecticide aramite on the rat liver. Toxiol.
Eur. Res. 1(1): 13-22.
Clemens, H.P. and K.E. Sneed. 1959. Lethal doses of several commercial
chemicals for fingerling channel catfish. Spec. Sci. Rep. Fish. No. 316,
FishNildl. Serv. U.S.D.I., Washington, DC. p. 1-10.
Crockett, P.W., B. Kilian, K.S. Crump and R.B. Howe. 1985. Descriptive
Methods for Using Data from Dissimilar Experiments to Locate a No-Adverse-
Toxic-Effects Region in the Dose-Duration Plane. Prepared by K.S. Crump and
Company, Inc., under Contract No. 6807-007 for Environmental Criteria and
Assessment Office, Cincinnati, OH.
Deichmann, W.B., M. KepUnger, F. Sala and E. Glass. 1967. Synergism among
oral carcinogens. IV. The simultaneous feeding of four tumorigens to
rats. Toxicol. Appl. Pharmacol. 11(1): 88-103.
Durkin, P. and H. Meylan. 1988. User's Guide for DZPlot. A Program for
Dose/Duration Graphs. Prepared by Chemical Hazard Assessment Division,
Syracuse Research Corporation under Contract No. 68-C8-0004 for Environ-
mental Criteria and Assessment Office, Cincinnati, OH.
5996H • -49- 06/15/89
-------
Eldefrawi, M.E., A.H. Hosny, A. Toppozada and S. Hassan. 1965.
Susceptibility to acaricldes of the mite Tetranychus dnnabarinus Infesting
cotton in Egypt. J. Econ. Entomol. 58: 1106-1110.
Epstein, S.S., E. Arnold, J. Andrea, W. Bass and Y. Bishop. 1972. Detec-
tion of chemical mutagens by the dominant lethal assay in the mouse.
Toxicol. Appl. Pharmacol. 23: 288-325.
Frear, D.E.H. and J.E. Boyd. 1967. Use of Daphnia magna for the
microbioassay of pesticides. I. Development of standardized techniques for
rearing Daphnia and preparation of dosage mortality curves for pesticides.
J. Econ. Entomol. 60: 1228-1236.
Gentile, A.G. and K.J. Gallagher. 1972. Pollen germination and tube
elongation in petunia inhibited or reduced by commercial formulations of
pesticides in vitro. J. Econ. Entomol. 65: 488-491.
Gore, R.C., R.W. Hannah, S.C. Pattacini and T.J. Porro. 1971. Infrared and
ultraviolet spectra of seventy-six pesticides. J. Assoc. Anal. Chem. 54:
1040-1082.
•
Heath, R.G., J.W. Spann, E.F. Hill and 3.F. Kreitzer. 1972. Comparative
dietary toxicities of pesticides to birds. Fish Wildl. Serv., Bur. Sport
Fish. Wildl. Spec. Sci. Rep. Wildl. No. 152. U.S.D.I. 57 p.
5996H ' -50- 06/15/89
-------
Hill, E.F. and M.B. Camardese. 1986. Lethal dietary toxicities of
»i
environmental contaminants and pesticides to Coturnix. Fish Wildl. Serv.
FishWildl. Tech. Rep. 2. U.S.D.I. 0: 1-147.
Hill, E.F., R.G. Heath, J.W. Spann and J.O. Williams. 1975. Lethal dietary
toxicities of environmental pollutants to birds. U.S.. Fish Nildl. Serv.
Spec. Sci. Rep. Wildl. No. 191. Washington, DC. 63 p.
Hodge, H.C., E.A. Maynard, W.L. Downs, J.K. Ashton and L.L. Salerno. 1966.
Tests on mice for evaluating carcinogenicity. Toxicol. Appl. Pharmacol.
9(3): 583-596.
Howe R.B. and K.S. Crump. 1982. Global 82. A computer program to
extrapolate quantal animal toxicity data to low doses. Prepared for the
Office of Carcinogen Standards. Occupational Safety and Health
Administration. U.S. Department of Labor Contract 41USC252C3.
IARC (International Agency for Research on Cancer). 1974. IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Humans. IARC, Lyons,
France. 5: 39-46.
Innes, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli, L. Fishbein, E.R.
Hart, et al. 1969. Bioassay of pesticides and industrial chemicals for
tumorigenicity in mice: A preliminary note. J. of the Nat. Cancer Instit.
42(6): 1001-1114.
5996H -51- 06/15/89
-------
Jeppson L.R., W.E. Westlake and F.A. Gunther. 1969. Toxicity control and
residue studies with DO-14 (2-(p-tert-butylphenoxy)cyclohexyl 2-propynyl
sulfite) as an acaricide against the citrus red mite. J. Econ. Entomol.
62: 531-536.
Jeppson, L.R. and F.A. Gunther. 1970. Acaricide residues on citrus foliage
and fruits and other biological significance. Res. Rev. 33: 101-136.
LeBlanc, G.A. 1984. Interspecies relationships in acute toxictty of
chemicals to aquatic organisms. Env. Tox. Chem. 3: 47-60.
Lyman, N.J. 1982. Adsorption coefficient for soils and sediments. |n:
Handbook of Chemical Property Estimation Methods, Lyman, W.J., W.F. Reehl
and D.H. Rosenblatt, Eds. McGraw-Hill Book Co., New York, NY. p. 4-9.
Mantel, N. and M.A. Schneiderman. 1975. Estimating "safe" levels, a
hazardous undertaking. Cancer REs. 35: 1379-1386.
Mitchell, L.C. 1961. The effect of ultraviolet light <2537A) on 141
pesticide chemicals by paper chromotography. J. Assoc. Off. Agr. Chem. 44:
643-653.
Naishtein, S.Y. 1964. Sanitary protection of water bodies from pollution
with industrial waste waters from synthesis of analogs and derivatives of
DDT. Vopr. Gigieny Naselen, Mest, Kiev, SB. 5: 34-37. (Taken from Chem.
Abstr. 64: 15563f)
5996H ' -52- 06/20/89
-------
(her, B.U and M. Oser. 1960. 2-(p-tert-8ulylphenoxy) Uopropyl 2-chloro-
ethyl sulflte (aramlte). I. Acute, subacute and chronic oral toxlclty.
Toxlcol.
Appl. Pharmacol. 2: 441-457.
Qser, B.I. and H. Oser. 1962. 2-(p-tert-Bulylphenoxy)1sopropyl
2-chloroethyl sulfHe (aramHe) II. Carclnogenlclty. Toxlcol. and Appl.
Pharmacol. 4: 70-88.
Popper, H., S.S. Sternberg, B.L. Oser and M. Oser. 1960. The carcino-
genic effect of aramHe In rats. Cancer. 13(5): 1035-1046.
Radomskl, J.L., W.B. Delchmann, W.E. HacDonald and E.M. Glass. 1965.
Synerglsm among oral carcinogens. I. Results of the simultaneous feeding
of four tumorlgens to rats. Toxlcol. Appl. Pharmacol. 7(5): 652-656.
0
Sanders, H.O. 1969. Toxlclty of pesticides to the crustacean Gammarus
lacustrls. Bur. Sport F1sh. W1ldl. Fish Hlldl. Serv. Tech. Paper No. 25.
18 p.
Sanders. H.O. and O.B. Cope. 1966. Toxldtles of several pesticides to two
species of cladocerans. Trans. Am. Fish. Soc. 95: 165-169.
•
SANSS (Structure and Nomenclature Search System). 1989. Chemical
Information System (CIS) computer data base.
5996H -53- 08/03/89
-------
Spencer, E.Y. 1968. Guide to the chemicals used In crop protection.
Publication 1093, 5th ed. Canada Department of Agriculture, Research
Branch, p. 49.
Sternberg, S.S., H. Popper, B.L. Oser and M. Oser. 1960. Gallbladder and
bile duct adenocardnomas In dogs after long term feeding of aramlte.
Cancer. 13: 780-789.
Streu, H.T. 1972. Two spotted spider mite. Its biology and control
(acerlna: tetranychldae). Proc. Ohio State Hor. Soc. 125: 83-85.
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. VanderKuy and H.O. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Residue Reviews. 85: 17-28.
Truhaut, R., J.R. Claude, V.N. Huyen, J.M. Warnet and F. Blanc. 1975.
Primary liver carclnogenesls 1n rats after feeding of a pesticide 2,4-tert
butylphenoxy-l-methylethyl-2-chloroethyl sulflte aramlte. C.R. Hebd Seances
Acad. Sc1. Ser. Scl. Nat. 281(9): 599-604.
Truhaut, R., J.R. Claude and F. Blanc. 1977. The metabolism of aramlte, a
pesticide Inducing liver tumors. .In: Proc. European Soc. Toxlcol. 18:
326-328.
5996H
-54-
OB/03/89
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Truhaut, R., 3.R. Claude, J.H. Harriet, Vu Ngoc Huyen and P. Blanc-Habets.
1978. Aramlte: Experimental cancerogenldty and metabolism. Meded. Fac.
Landbouwwet. RljksunW. Gent. 43(2}: 1225-1231.
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1981. Identification and Listing of Hazardous Waste. 40 CFR
261. App. VIII.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic loxldty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986b. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
5996H -55- 08/03/89
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U.S. EPA/OWRS (U.S. Environmental Protection Agency/Office of Hater
Regulations and Standards). 1986. Guidelines for Deriving Numerical
National Water Quality Criteria for the Protection of Aquatic Organisms and
Their Uses. U.S. EPA, Washington, DC. 106 p.
USTC (United States Tariff Commission). 1972. Synthetic Organic
Chemicals. Unites States Production and Sales, 1970. TC Publication 479.
U.S. Tariff Commission. Washington, DC. p. 203.
Windholz, M., Ed. 1983. Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NO. p. 112.
Worthing, C.R. and S.B. Walker. 1987. The Pesticide Manual.. 8th ed.
British Crop Protection Council, Croydon, England, p. 862.
5996H ' -56- 06/20/89
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APPENDIX A
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXL1T
TOXLIT 65
RTECS
OHM TADS
STORE!
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted In April, 1989. and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices. 5th ed. Cincinnati. OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton. Ed. 1981. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 2A. John Wiley and Sons,
NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 2B. John Wiley and Sons,
NY. 2879-3816 p.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 2C. John Wiley and Sons,
NY. 3817-5112 p.
5996H A-l 08/03/89
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Grayson, H. and D. Eckroth, Ed. 1978-84. Klrk-Othmer Encyclopedia
of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23 Volumes.
Hamilton, A. and H,L. Hardy. 1974. Industrial Toxicology. 3rd ed.
Publishing Sciences Group, Inc., MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Humans. IARC,
Lyons, France: WHO.
Jaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA-600/6-84-010. (NTIS PB84-243906) Menlo Park, CA: SRI Inter-
national.
NTP (National Toxicology Program). 1988. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials. 6th
edition. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Stanford, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (United States International Trade Commission). 1986.
Synthetic Organic Chemicals. U.S. Production and Sales, 1985, USITC
Publication 1892. Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals. 2nd edition. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M. Ed. 1983. The Merck Index. 10th ed. Merck and Co.,
Inc., Rahway, NJ.
5996H A-2 08/03/89
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In addition, approximately 30 compendia of aquatic toxicity data were
reviewed, including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria Data
Book. Volume 3. Effects of Chemicals on Aquatic Life. Selected
Data from the Literature through 1968. Prepared for the U.S. EPA
under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Finley. 1980. Handbook of Acute Toxicity of
Chemicals to Fish and Aquatic Invertebrates. Summaries of Toxicity
Tests Conducted at Columbia National Fisheries Research Laboratory.
1965-1978. United States Dept. Interior, Fish and Wildlife Serv.
Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. 2nd ed.
Prepared for the Resources Agency of California, State Water Quality
Control Board. Publ. No. 3-A.
Pimental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
5996H
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05/12/89
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APPENDIX B1
CANCER DATA SHEET FOR DERIVATION OF q*
Compound: aramHe
Reference: Oser and Oser, 1960
Species, strain, sex: rat, FDRL, male and female
Tumor site and type: liver tumors
Route, vehicle: oral, diet
Dietary concentration
(ppm): 0 SOO 1580
Transformed animal dose3
(mg/kg/day): 0 25 79
Duration of exposure
(weeks): 104 48 48
Measured body weights
(kg):
Human equivalent dosageb:
Incidence (Number Responding/
Number tested
or examined):
0.300
0
0/20
0.285
0.392
0/20
0.280
1.230
2/21
Human q* : 0.6861 (mg/kg/day"1 )c
Estimated using rat food factor of 0.05 (U.S. EPA, 1980).
^Transformed animal dose multiplied by: (1) cube root of the ratio of
animal body weight: reference human body weight and 2) cube of the ratio of
the duration of the experiment (I.e., duration of treatment) to the
Hfespan of the rat (U.S. EPA, 1980)
C0ata from the high-dose group (5000 ppm) were dropped from analysis 1n
order to fit the data to the model.
6166H . B-l 10/03/89
-------
APPENDIX B2
CANCER DATA SHEET FOR DERIVATION OF A qf
Compound: aramlte
Reference: Popper et al., 1960; Oser and Oser. 1962
Species, strain, sex: rats, FDRL, male and female
Body weight: 0.270 (measured)
Length of exposure (le) = 104 weeks
Length of experiment (Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: hyperplastlc liver nodules and carcinomas
Route, vehicle: oral, diet
Dietary Incidence
Concentrations Transformed Animal Dosea (number responding/number
(ppm) (mq/kq/day) tested or examined)
0 0
100 5
200 10
400 20
2/193
(0 carcinomas)
2/93
(0 carcinomas)
3/100
(0 carcinomas)
25/90
(2 carcinomas)
Unadjusted q* = 3.8485xlO~3 mg/kg/day"1
Human q* = 2.454xlQ~2 (mg/kg/day'1}&
aAssumed: rats consume 0.05 kg food/kg body weight/day (U.S. EPA, 1980)
DHuman q* was calculated by dividing the unadjusted qf by the
cube root of the ratio of the reference human body weight (70 kg, U.S. EPA,
1986b) to the experimental time-weighted average animal body weight (0.270
kg).
6167H . B-2 10/02/89
-------
APPENDIX B3
CANCER DATA SHEET FOR DERIVATION OF A qj
Compound: aramUe
Reference: Popper et al., 1960; Oser and Oser, 1962
Species, strain, sex: rats, CFN, male and female
Body weight = 0.278 (measured)
Length of exposure (le) = 104 days
Length of experiment {Le) = 104 days
LUespan of animal (L) = 104 days
Tumor site and type: hyperplastlc liver nodules and carcinomas
Route, vehicle: oral, diet
Incidence
Experimental Doses Transformed Animal Dose3 (number responding/number
or Exposures (mq/kq/day) tested or examined)
0
100
200
400
0
5
10
20
5/180
(0 carcinomas)
3/93
(0 carcinomas)
10/90
(0 carcinomas)
22/96
(0 carcinomas)
Unadjusted qf = 0.121xlO"2 mg/kg/day-1
Human q* = 7.64xlO~3 (mg/kg/day~l)b
Assuming that rats consume 0.05 kg food/kg body weight/day (U.S. EPA,
1980)
DCalculated by the following equation: human qf = (unadjusted
qf) (cube root of HBW divided by ABW) (L/le) where HBM Is the
reference human body weight, 70 kg (U.S. EPA, 1986b), ABW 1s the
experimental animal body weight (0.278 kg), L Is the llfespan of rats (104
weeks) and le 1s the duration of exposure of the rats (104 weeks).
6167H . 8-3 10/02/89
-------
APPENDIX B4
CANCER DATA SHEET FOR DERIVATION OF A q*
Compound: aramlte
Reference: Innes et al., 1969
Species, strain, sex: mice, (C57BL/6xC3H/Anf)F), male
Body weight = 0.03 kg (reference value: U.S. EPA, 1980)
Length of exposure (le) = 80 weeks
Length of experiment (Le) = 80 weeks
LUespan of animal (L) = 104 weeks
Tumor site and type: liver hepatoma
Route, vehicle: oral, gavage for first 3.5 weeks followed by diet for
remainder of study
Dietary Incidence
Concentration Transformed Animal Dose3 (number responding/number
(ppm) (mq/kq/day) tested or examined)
0
112
0
14.6
8/73
6/16
Unadjusted q* = 5.20648x1O"2 mg/kg/day"1
Human qf = 1.51717 (mg/kg/day~Mb
aAssum1ng that mice consume 0.13 kg food/kg body weight/day (U.S. EPA,
1986b)
bTo calculate the human q-j*, the unadjusted qf was multiplied by
the cube root of the ratio of the reference body weight for humans (70 kg)
to the reference body weight for ttte mice (0.03 kg) and ratio of the animal
llfespan (104 weeks) to the length of the experiment (80 weeks) (U.S. EPA,
1980).
6167H . B-4 10/02/89
-------
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-------
APPENDIX 0
DOSE/DURATION RESPONSE GRAPHS FOR ORAL EXPOSURE TO ARAMITE
D.I. DISCUSSION
Dose/duration-response graphs for oral exposure to aramite generated by
the method of Crockett et al. (1985) using the computer software by Durkin
and Meylan (1988) developed under contract to ECAO-Cincinnati are presented
In Figures D-l and D-2. Data used to generate these graphs are presented in
Section D-2. In the generation of the figures all responses are classified
as adverse (FEL, AEL or LOAEL) or non-adverse (NOEL or NOAEL) for plotting.
For oral exposure, the ordinate expresses dosage as human equivalent dose.
The animal dosage in mg/kg/day is multiplied by the cube root of the ratio
of the animal:human body weight to adjust for species differences in basal
metabolic rate (Mantel and Schneiderman, 1975). The result is then
multiplied by 70 kg, the reference human body weight, to express the human
equivalent dose as mg/day for a 70 kg human.
The Boundary for Adverse Effects (solid line) is drawn by identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point, an infinite
line is extended upward, parallel to the dose axis. The starting point is
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or
concentration equal to or lower than the previous one. This process is.
continued to the lowest adverse effect dose or concentration. From this
point, a line is extended to the right, parallel to the duration axis. The
Region of Adverse Effects lies above the Adverse Effects Boundary.
Using the envelope method, the Boundary for No Adverse Effects (dashed
line) is drawn by Identifying the highest no adverse effects dose or
6183H
D-l
06/13/89
-------
o
\
3)
tf
V)
0
9
Z
lee -t-
10
T I i t ! i
F7
J i 1 ;
1 _l_l
a.
B.B81 0.01 6.1
HUNAN EQUIU DURATION (fraction lifespan)
ENVELOP METHOD
1 2
Key: F = PEL
L - LOAEL
N - NOAEL
Solid line = Adverse Effects Boundary
Dotted line « No Adverse Effects Boundary
FIGURE D-l
Dose/Duration - Response Graph for Oral Exposure to Aramite
Envelope Method
6183H
D-2
06/13/89
-------
t
\
Si
0
A
I
z
i
10880 -~
1800 - -
100 --
10 +
e.0001
i Exposure)
F7
"1.8
\ F6
\
v T-5.
0.001 0.01 0.1
HUMAN EQUIU DURATION (fraction lifes^an)
CENSORED DATA METHOD
n3
Key: F = PEL
L = LOAEL
N - NOAEL
Solid line - Adverse Effects Boundary
Dashed line » No Adverse Effects Boundary
FIGURE 0-2
Dose/Duration - Response Graph for Oral Exposure to Aramite
Censored Data Method
6183H
D-3
06/13/89
-------
concentration. From this point, a line parallel to the duration axis is
extended to the dose or concentration axis. The starting point is then
connected to the next lower or equal no adverse effect dose or concentration
at a longer duration of exposure. When this process can no longer be
continued, a line is dropped parallel to the dose or concentration axis to
the duration axis. The No Adverse Effects Region lies below the No Adverse
Effects Boundary. At either ends of the graph between the Adverse Effects
and No Adverse Effects Boundaries are Regions of Ambiguity. The area (if
any) resulting from intersection of the Adverse Effects and No Adverse
Effects Boundaries is defined as the Region of Contradiction.
In the censored data method, all no adverse effect points located in the
Region of Contradiction are dropped from consideration, and the No Adverse
Effects Boundary is redrawn so that it does not intersect the Adverse
Effects boundary and no Region of Contradiction is generated. This method
results in the most conservative definition of the No Adverse Effects Region.
The Adverse Effects Boundary for oral exposure to aramite is defined by
five data points in Figures D-l and D-2. Starting from the upper left of
each figure, these points represent: the lethal dose for guinea pigs
-------
et al., 1960; Oser and Oser, 1962). In Figure D-2, the latter of these
points is censored and the Region Of Contradiction is absent. The right
side of the No Adverse Effects Boundary is then defined by the lowest NOAEL
(rec #1) for liver effects in rats (Popper et al., 1960; Oser and Oser,
1962), which provided the basis for the chronic oral RfD derived in Section
8.2.2.2.
D.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS FOR ORAL EXPOSURE
TO ARAMITE
Chemical Name: Aramite
CAS Number: 140-57-8
Document Title: Health and Environmental Effects Document for Aramite
Document Number: pending
Document Date: pending
Document Type: HEED
RECORD #1:
Species: Rats
Sex: Both
Effect: NOAEL
Route : Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose:
Durat
Durat
100
NR
WGTIN
LIVER
4
5.000
104.0 weeks
104.0 weeks
Comment: Experimental doses: 0, 100, 200, 400 ppm in diet.
Transformed doses: 0, 5, 10, 20 mg/kg/day. FDRL
rats. No adverse, non-neoplastic liver histology,
• even at highest dose.
Citation: Popper et al., 1960; Oser and Oser, 1962.
6183H
D-5
06/20/89
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RECORD #2:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 20.000
Duration Exposure:
Duration Observation;
100
NR
WGTIN
LIVER
4
104.0 weeks
104.0 weeks
Comment: See previous record.
Citation: Popper et al., 1960; Oser and Oser, 1962.
RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Food
Dose: 20.000
Duration Exposure:
Duration Observation:
104.0 weeks
104.0 weeks
Number Exposed: 100
Number Responses: NR
Type of Effect: WGTIN
Site of Effect: LIVER
Severity Effect: 4
Comment: Experimental details as per rec #1, except that
CFN rats were studied. No adverse, non-cancerous
liver effects were observed in histological
examinations.
Citation: Popper et al., 1960; Oser and Oser, 1962
6183H
0-6
06/20/89
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RECORD #4:
RECORD #5:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Food
Dose: 10.000
Duration Exposure:
Duration Observation:
104.0 weeks
104.0 weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
60
NR
DEGEN
LIVER
6
30
NR
WGTIN
LIVER
4
Comment: Experimental concentration: 200 ppm in diet.
Osborne-Mendel rats. Liver histology: hydropic
swelling, granular cytoplasm, centrolobular
necrosis, passive congestion. Liver weight
increase only in males.
Citation: Deichmann et al., 1967
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 25.000
Duration Exposure:
Duration Observation:
NR
NR
DEATH
BODY
10
17.0 weeks
17.0 weeks
Comment: Experimental concentrations: 0, 500, 1580, 5000
ppm. More than 7-8 matings/dose for F0; 2
matings/dose for F, and F2. Decreased survival
during lactation of F3 at 500, 1580 and 5000 ppm
and of F,, fz at 5000 ppm. Exposure duration
roughly estimated from parents' exposure at an
assumed time of first mating. Pregnancies failed
after fifth mating at 5000 ppm in FB.
Citation:. Oser and~0ser, 1960
6183H
D-7
06/20/89
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RECORD #6:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 79.000
Duration Exposure:
Duration Observation:
NR
NR
DEATH
BODY
10
Comment: As per rec #5.
Citation: Oser and Oser, 1960
17.0 weeks
17.0 weeks
RECORD #7:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Food
Dose: 250.000
Duration Exposure:
Duration Observation:
17.0 weeks
17.0 weeks
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Comment: As per rec #5, except that decreased survival
during lactation was also noted in F, and F2
generations at this dose level.
Citation: Oser and Oser, 1960
6183H
D-8
06/20/89
-------
RECORD #8:
Species:
Sex:
Effect:
Route:
Dogs
Both
LOAEL
Food
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 39.500
Duration Exposure: 52.0 weeks
Duration Observation: 52.0 weeks
3
3
DEGEN
LIVER
6
Comment: Experimental concentrations: 0, 500,
Liver cord swelling, vacuolated
occlusion bodies, slight degree
fibrosis.
Citation: Oser and Oser, 1960.
1580 ppm.
cytoplasm,
of portal
RECORD #9:
Species:
Sex:
Effect:
Route:
Dogs
Both
NOAEL
Food
Dose: 12.500
Duration Exposure:
Duration Observation:
52.0 weeks
52.0 weeks
Number Exposed: 3
Number Responses: 3
Type Of Effect: DEGEN
Site of Effect: LIVER
Severity Effect: 6
Comment: See previous record,
this level.
Citation: Oser and Oser, 1960.
No adverse liver effects at
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
Both
FEL
Gavage
Dose: 3900.000
Duration Exposure:
Duration Observation:
~
1 .0 days
14.0 days
Number Exposed: 10
Number Responses: 5
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Comment: LDso value.
Citation: Oser and Oser, 1960
61.83H
D-9
06/20/89
-------
RECORD #11:
Species:
Sex:
Effect:
Route:
Guinea
Both
FEL
Gavage
Pigs
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10
5
DEATH
BODY
10
Dose: 3900.000
Duration Exposure: 1.0 days
Duration Observation: 14.0 days
Comment: One dose tested.
Citation: Oser and Oser, 1960.
6183H
D-10
06/20/89
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