-------
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
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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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6162H
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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
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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
-------
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
-------
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
-------
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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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
-------
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
-------
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
-------
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
-------
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
-------
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
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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
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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
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06/20/89
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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
-------