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In the NCI (1977) study, both rats (50/sex/group) and mice (50/sex/
group) were maintained on diets containing chlordane (71.7% dst 23.1%
trans, 0.3% heptachlor, 0.6% nonachlor, 1.1% hexachlorocyclopentadlene and
0.28% chlordene) for 80 weeks, followed by an observation period. Because
the dose levels were changed during the experiment, the dosage listed \r\
Table 3-2 Is a TWA as calculated by the NCI (1977). Rats received higher
dose levels In mg/kg bw than mice 1n this study. Female rats appeared to be
more sensitive than male rats, as evidenced by Increased mortality In
females 1n both treated groups. High-dose females, but not males, had
tremors after 44 weeks of treatment. In mice, a dose-related significant
Increase In mortality occurred 1n both treated groups of males.
Velslcol Chemical Corporation (1983a) fed ICR mice diets containing 0,
1, 5 or 12.5 ppm technical grade chlordane, resulting 1n approximate dosages
of 0, 0.15, 0.71 or 1.79 mg/kg bw/day for 2 years. Liver effects, Including
Increased SGOT and SGPT, hepatocellular swelling and necrosis, and Increased
liver weight occurred 1n the 5 and 12.5 ppm groups. No effects were
observed at 1 ppm.
In a Velslcol Chemical Corporation (1983b) study, Fischer 344 rats were
fed diets containing 0, 1, 5 or 25 ppm chlordane (Isomers not specified}
(-0, 0.05, 0.25 or 1.25 mg/kg bw/day) for 130 weeks. Liver weights of
females receiving 5 or 25 ppm were Increased at 26 and 52 weeks but not at
130 weeks. Hale liver weights were Increased at 130 weeks but not at 26 and
52 weeks. There was an Increased Incidence of hepatocellular swelling and
necrosis 1n treated males. The 1 ppm level was considered a LOEL for liver
effects In male rats.
In a study by Wazeter (1968), dogs exposed orally to chlordane (type not
specified) developed enlarged livers with hlstopathologlcal changes.
0023H -9- 07/13/88
-------
A scientific review panel of WHO/FAO examined this study and concluded that
a dose of 3 rag/kg diet was a NOEL (Vettorazzl, 1975). No further
Information was available.
3.2.2. Inhalation. Pertinent data regarding the chronic tox1c1ty of
Inhaled chlordane were not located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Ingle (1952) Investigated the effect of chlordane-contaml-
nated diets at dose levels of 5, 10, 30, 150 and 300 ppm on the fetus .In.
utero and on the newborn while nursing. Two female Osborne-Mendel rats from
each dose level were mated after 24 and 48 weeks of chlordane exposure. No
effect on fetal mortality and health or on litter size was reported. After
birth, three pups remained with their chlordane-treated dams, while three
others were placed with foster dams that had not been exposed to chlordane.
Pups nursed by dams exposed to chlordane levels of 150 and 300 mg/kg diet
developed toxic effects, such as hyperexcHabUHy, tremors, decreased body
weight and death. Toxic effects developed 1n the pups that were nursed by
dams treated with chlordane-contamlnated (>150 ppm) diets, whether or not
they had been exposed .In. utero; however, the pups whose mothers were exposed
to high levels of chlordane (>150 ppm) during pregnancy did not develop
toxic effects when they were nursed by foster dams exposed to low levels (5,
10 and 30 ppw) of chlordane.
Delchmann and KepHnger (1966) reported decreased viability of offspring
of mice that ate a diet containing 100 ppm chlordane for 4 months. Chlor-
dane was also found to decrease fertility 1n male and female rats (Ambrose
et al., 1953a) and 1n female mice (Welch et al., 1971). There was decreased
survival among offspring of rats fed 640 and 1280 ppm chlordane (Ambrose et
al., 1953b).
0023H -10- 07/13/RR
-------
3.3.2. Inhalation. Pertinent data regarding the teratogenldty or
fetotox1c1ty of chlordane Inhalation were not located In the available
literature.
3.4. TOXICANT INTERACTIONS
Intraperltoneal Injection of phenobarbltal 1n neonatal Sprague-Oawley
rats reduced the LD5Q of chlordane Injected 1ntraper1toneally (Harbison,
1975). Pretreatment of rats with chlordane potentiated the hepatocellular
necrosis produced by carbon tetrachloMde (Stenger et al., 1975). Male
weanling Wlstar rats (Boyd and Taylor, 1969) on a low-protein diet (3.5%)
for 28 days had a much lower LQ.Q (137+30 mg/kg bw) than a group of wean-
ling rats that ate commercial rodent food (LD50=311 mg/kg bw).
0023H -11- 07/13/88
-------
4. CARCINOGENICITY
4.1. HUNAN DATA
4.1.1. Oral. No data were located In the literature search conducted for
purposes of this document.
4.1.2. Inhalation. Host Inhalation exposure to chlordane occurs as work-
related exposure either 1n the manufacturing or application of chlordane.
Exposure to several chemicals 1n addition to chlordane often confounds
evaluation of the human data. Aplastlc and refractory megoblastlc anemia,
as well as acute stem cell, acute lymphoblastlc and acute myelomonocytlc
leukemia, have been reported to result from chlordane exposure, primarily
through Inhalation (Infante et al., 1978; Klemmer et al., 1977; FuMe and
Trubowltz, 1976). A retrospective mortality study of 1403 white male
workers employed for >3 months 1n the manufacture of chlordane and hepta-
chlor Indicated that the observed Incidences of all types of cancer except
lung cancer were less than expected (Wang and MacMahon, 1979). The
Increased Incidence of lung cancer was not statistically significant. U.S.
EPA (1986a) concluded that Insufficient population size, exposure duration
and follow-up periods, exposure characterization, confounding factors such
as other chemical exposures and smoking 1n this and other studies (Alvarez
and Hyman, 1953; OHraglla et al., 1981; F1shbe1n et al., 1964; Prlnd and
Spurbeck, 1951; Klemmer et al., 1977) preclude definitive conclusions
regarding the effects of human occupational exposure. The studies as a
group were considered Inadequate ep1dem1olog1c evidence.
4.2. BIOASSAYS
4.2.1. Oral. In the unpublished report by the IRDC (1973) reviewed by
Epstein (1976), the liver lesions produced during chlordane treatment were
originally diagnosed as preneoplastlc lesions. A subsequent redlagnosls of
-------
hepatocellular carcinoma was made by Reuber (1978) and other pathologist;
(Epstein, 1976). The results of this revaluation are presented 1n
Table 4-1.
In the NCI (1977) study, the dose levels were changed during the experi-
ment for both mice and rats. The TWA dose levels calculated by the NCI
(1977) are given 1n Table 4-1. Mice 1n the NCI (1977) study developed a
dose-related Increase In the Incidence of hepatocellular carcinoma. As 1n
the IROC study (Epstein, 1976), the male mice appeared more sensitive. Rats
1n the NCI (1977) study developed miscellaneous neoplasms; these occurred
spontaneously In the control groups as well as 1n the treated rats. The
only significant dose-related Increase In tumors was In fibrous hlstlo-
cytomas In male rats. These tumors were discounted as biologically signifi-
cant since the Incidence 1s known to vary greatly. The Incidence of thyroid
tumors was not consistently significant or dose-related. One of the two
hepatocellular carcinomas occurred 1n a low-dose male; the other occurred 1n
one of the pooled control animals.
In what appears to be another reporting of the Velslcol Chemical
Corporation (1983a) study, RIASBT (1983a) described a study 1n which groups
of 80 male and 80 female ICR mice were fed diets containing 0, 1, 5 or 12.5
ppm technical grade chlordane for 24 months. There was a significant
(p<0.001) Increase In the Incidence of hepatocellular adenoma and hemangloma
of the liver 1n 12.5 ppm males dying between 19 and 24 months or at terminal
sacrifice. There were no other treatment-related effects on tumor Incidence.
In what appears to be another reporting of the Velslcol Chemical
Corporation (1983b) study, RIASBT (1983b) described a study In which groups
of 80 male and 80 female Fischer 344 rats were fed diets containing 0, 1, 5
or 25 ppm chlordane for 130 weeks. The Incidence of hepatic adenomas was
0023H -13- 02/29/88
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reported to be significantly (p<0.001) Increased 1n males given 25 ppm (9/64
vs. 1/64 1n controls). No other significant treatment-related effects on
tumor Incidence were found.
Becker and Sell (1979) correlated elevated levels of alpha-fetoproteln
with primary hepatocellular carcinoma In mice exposed for 36 weeks to diets
containing 25 or 50 ppm of chlordane. Hepatocellular carcinomas were found
1n 27% of the survivors.
Ambrose et al. (1953a) did not observe treatment-related tumors In
groups of 3-5 rats fed diets containing 10-1280 ppm chlordane for 400 days.
Liver lesions occurred at >80 ppm. Ingle (1952) exposed groups of 20 male
and female Osborne-Hendel rats to diets containing 0, 5, 10, 30, 150 or 300
ppm chlordane for 2 years. "High tox1c1ty" occurred at 150 and 300 ppm, but
no treatment-related tumors were observed.
4.2.2. Inhalation. Pertinent data regarding the Inhalation cardnogen-
Idty of chlordane were not located 1n the available literature.
4.3. OTHER RELEVANT DATA
Chlordane did not cause reverse mutations In nine strains of Salmonella
typhlmurlum or 1n two strains of Escherlchla coll with or without metabolic
activation (Probst et al., 1981; Gentile et al., 1982); unscheduled DNA
synthesis 1n rat, mouse or hamster primary hepatocyte cultures (Probst et
al., 1981; Maslansky and Williams, 1981); or dominant lethal mutations In
CD-I mice following 1ntragastr1c or 1ntraper1toneal administration (Arnold
et al., 1977). Positive results were obtained for mltotlc gene conversion
assays 1n Saccharomyces cerevlslae only after metabolic activation (Gentile
et al., 1982), and for unscheduled DNA synthesis 1n SV-40 transformed human
flbroblasts only In the absence of metabolic activation (Ahmed et al., 1977).
0023H -16-
-------
U.S. EPA (1986a) summarized the available mutagenldty data for chlor-
dane and concluded that chlordane Is apparently not mutagenlc In bacterial
assays, 1n Jji vitro DNA repair assays and 1n mouse dominant lethal assays.
Positive results were obtained 1n some but not all mammalian cell assays.
The available data were Insufficient, however, to assess definitively the
mutagenlc potential of chlordane.
4.4. WEIGHT OF EVIDENCE
U.S. EPA (1986a) reviewed the available Information concerning chlorjlane
carclnogenlclty and concluded that a number of Independent laboratory animal
studies demonstrated that oral exposure to chlordane causes liver cancer In
mice and rats. U.S. EPA (1986a) classified chlordane as a probable human
carcinogen, Group 62, using the Agency's guidelines for carcinogen risk
assessment (U.S. EPA, 1986b).
0023H -17- 08/20/87
-------
5. REGULATORY STANDARDS AND CRITERIA
A tolerance of 0.3 mg/kg has been established by the U.S. EPA (1976) for
residues of chlordane 1n or on ~50 fruit and vegetable crops. The ACGIH
(1986) has adopted a TLV of 0.5 mg/m3 and an STEL of 2 mg/m3. OSHA
(1985) lists a PEL of 0.5 mg/m3. U.S. EPA (1985b) calculated an RfD for
oral exposure for chlordane based on the Velslcol Chemical Corporation
(1983b) 30-month study 1n rats. The RfD was calculated from the LOAEL of 1
ppm 1n the diet (0.045 mg/kg/day), which caused a significant Increase 1n
Incidence of hepatocellular necrosis 1n males. U.S. EPA (1985b) applied an
uncertainty factor of 1000 to this LOAEL to derive an RfD of 5xlO~5
mg/kg/day.
0023H -18- 07/13/88
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
Chlordane 1s a chemical for which a carcinogenic potency has been calcu-
lated and that may be carcinogenic 1n humans. Based upon the guidelines for
this document series, H 1s Inappropriate to calculate an oral or Inhalation
RfDs for chlordane.
6.2. REFERENCE DOSE (RfO)
Chlordane 1s a chemical for which a carcinogenic potency has been calcu-
lated and that may be carcinogenic 1n humans. Calculation of an RfD 1s
therefore outside the scope of this document series. Existing approaches
are described 1n Chapter 5.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. Chlordane treatment was associated with significant
Increases In hepatocellular carcinomas In treated mice of both sexes In the
IROC (1973) and NCI (1977) studies. The RIASBT (1983b) study also showed a
significant Increase 1n liver tumors 1n treated male rats compared with
controls. The Office of Pesticide Programs 1s currently 1n the process of
Devaluating this study. U.S. EPA (1986a) fitted the linearized multistage
model to each of these data sets to obtain estimates of carcinogenic
potency. These potency estimates (human q * values) are presented In
Table 6-1. The geometric mean of the potency estimates for mice was 1.3
(mg/kg/day)'1, which was consistent with the potency estimate from the
single rat data set, 1.1 (mg/kg/day)'1. U.S. EPA (1986a) concluded that
mice were the more sensitive tested species, and because humans may be as
sensitive as the most sensitive animal species, adopted 1.3 (mg/kg/day)"1
as the potency estimate for the general population. This value has been
verified by CRAVE and 1s available on IRIS (U.S. EPA, 1987).
0023H -19- 07/14/88
-------
TABLE 6-1
Human Potency Estimates for Chlordane*
Species/Strain
Mice/CD-I
Mice/CD-I
M1ce/B6C3Fl
M1ce/B6C3Fl
Rats/F344
Sex
M
F
M
F
M
Tumor Site/Type
liver,
liver.
liver,
liver,
liver,
carcinoma
carcinoma
carcinoma
carcinoma
adenoma
Potency
(mg/kg/day)'1
4
2
0
0
1
.74
.98
.76
.25
.11
Reference
IRCD
IRDC
NCI,
NCI,
, 1973
, 1973
1977
1977
RIASBT, 1983b
and carcinoma
*Source: U.S. EPA, 1986a
0023H
-20-
02/29/88
-------
6.3.2. Inhalation. Inhalation data were not available for estimation of
carcinogenic potency; however, U.S. EPA (1986a) used the potency estimate
for oral exposure to calculate a unit risk 1n air. Thus, U.S. EPA (1986a)
supports the position that chlordane 1s equally carcinogenic by either the
oral or Inhalation routes. Therefore, the oral q,* of 1.3 (mg/kg/day)'1
1s adopted as the Inhalation q * for the purposes of this document. This
value has been verified by CRAVE and 1s available on IRIS (U.S. EPA, 1987).
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Threshold Limit Values for Chemical Substances 1n the Work Environment
Adopted by ACGIH, Cincinnati, OH. p. 14.
Ahmed, F.E., R.W. Hart and N.J. Lewis. 1977. Pesticide-Induced DNA damage
and Us repair 1n cultured human cells. Mutat. Res. 42: 161-174. (Cited
1n U.S. EPA, 1985a)
Aldrlch, P.O. and J.H. Holmes. 1969. Acute chlordane Intoxication In a
child. Arch. Environ. Health. 19: 129-132. (Cited 1n U.S. EPA, 1985a)
Alvarez, W.C. and S. Hyman. 1953. Absence of toxic manifestations In
workers exposed to chlordane. Arch. Ind. Hyg. Occup. Med. 8: 480-483.
(Cited 1n U.S. EPA, 1985a)
Ambrose, A.M., H.E. ChMstensen, D.J. Robblns and L.J. Rather. 1953a.
Toxlcologlcal and Pharmacological studies on chlordane. Ind. Hyg. Occup.
Med. 7: 197-210. (CHed In U.S. EPA, 1986a)
Ambrose, A.M., H.C. Chrlstensen and D.J. Robblns. 19535. Pharmacological
observations on chlordane. Fed. Proc. Am. Soc. Exp. B1ol. 12: 298. (CHed
In U.S. EPA, 1986a)
0023H -22- 07/13/88
-------
Arnold. D.W., G.L. Kennedy, Jr., M.L. KepHnger, J.C. Calandra and C.J.
Calo. 1977. Dominant lethal studies with technical chlordane, HCS-3260 and
heptach1or:heptachlor epoxlde. J. Toxlcol. Environ. Health. 2: 547-555.
(CHed 1n U.S. EPA, 1985a)
Atlas, E., R. Foster and C.S. G1am. 1982. A1r-sea exchange of high molecu-
lar weight organic pollutants: Laboratory studies. Environ. Sd. Technol.
16: 283-286.
Barnett, J.R. and H.W. Dorough. 1974. Metabolism of chlordane 1n rats. J.
Agrlc. Food Chem. 22: 612-619. (Cited 1n U.S. EPA, 1985a)
Becker, F.F. and S. Sell. 1979. Alpha-fetoproteln levels and hepatic
alterations during chemical cardnogenesls In C57B1/6N mice. Cancer Res.
39: 3491. (CHed In U.S. EPA, 1985a)
Bldleman, T.F., W.N. Billings and W.T. Foreman. 1986. Vapor-particle
partitioning of semlvolatlle organic compounds: Estimates from field collec-
tions. Environ. Sd. Technol. 20: 1038-1043.
Bopp, R.F., H.J. Simpson, C.R. Olsen, R.M. Trier and N. Kostyk. 1982.
Chlorinated hydrocarbons and radlonucUde chronologies In sediments of the
Hudson River and esterary, New York. Environ. Sc1. Technol. 16: 666.
Boyd, E.M. and F.I. Taylor. 1969. The acute oral toxldty of chlordane 1n
albino rats. Ind. Med. 38: 42-49. (Cited In U.S. EPA, 1985a)
0023H -23- 07/13/88
-------
Curley, A. and L.K. Garrettson. 1969. Acute chlordane poisoning. Arch.
Environ. Health. 18: 211-215. (CHed 1n U.S. EPA, 1985a)
Delchmann, W.B. 1981. Halogenated cyclic hydrocarbons. ln_: Patty's Indus-
trial Hygiene and Toxicology, 3rd rev. ed., Vol. 28, G.D. Clayton and F.E.
Clayton, Ed. John Wiley and Sons, Inc., NY. p. 3603-3769.
Delchman, W.B. and M.L. KepHnger. 1966. Effect of combinations of pesti-
cides on reproduction of mice. Toxlcol. Appl. Pharmacol. 8: 337-338.
(CHed 1n U.S. EPA, 1986a)
DeLong, D.W. and P. Ludwlg. 1954. Hazards Involved when animals are
exposed to organic 1nsect1c1dal residues. J. Econ. Entomol. 47: 1056.
(CHed 1n U.S. EPA, 1985a)
DHraglla, D., D.P. Brown, T. Namekata and N. Iverson. 1981. Mortality
study of workers employed at organochlorlne pesticide manufacturing plants.
Scand. J. Work Environ. Health. 7(Suppl. 4): 140-146. (CHed 1n U.S. EPA,
19853)
Epstein, S.S. 1976. CardnogenlcHy of heptachlor and chlordane. Sd.
Total Environ. 6: 103-154. (Cited 1n U.S. EPA, 1985a)
F1shbe1n, W.I., J.V. White and H.J. Isaacs. 1964. Survey of workers
exposed to chlordane. Ind. Med. Surg. 33: 726-727. (Cited In U.S. EPA,
1985a)
-------
Furle, B. and S. Trubowltz. 1976. Insecticides and blood dyscraslas:
Chlordane exposure and self-limited refractory megaloblastlc anemia. J. Am.
Med. Assoc. 235: 1720-1722. (Cited 1n U.S. EPA, 1985a)
Gentile, J.M., G.J. Gentile, J. Bultman. R. Sechrlest, E.D. Wagner and M.J.
Plewa. 1982. An evaluation of the genotoxlc properties of Insecticides
following plant and animal activation. Mutat. Res. 101(1): 19-29. (Cited
1n U.S. EPA, 1985a)
Harbison, R.D. 1975. Comparative toxldty of selected pesticides 1n
neonatal and adult rats. Toxlcol. Appl. Pharmacol. 32: 443-446. (Cited 1n
U.S. EPA, 1985a)
IARC (International Agency for Research on Cancer). 1979. Chlordane. in:
Some Halogenated Hydrocarbons. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans. IARC, WHO, Lyons, France. Vol.
20, p. 45-66.
Infante, P.P., S.S. Epstein and W.A. Newton, Jr. 1978. Blood dyscraslas
and childhood tumors and exposure to Chlordane and heptachlor. Scand. J.
Work Environ. Health. 4: 137-150. (Cited 1n U.S. EPA, 1985a)
Ingle, L. 1952. Chronic oral toxldty of Chlordane to rats. Arch. Ind.
Hyg. Occup. Med. 6: 357-367. (Cited In U.S. EPA, 1986a)
IRDC (International Research and Development Corporation). 1973. Unpub-
lished report to Velslcol Chemical Corporation, Eighteen Month Oral Carcino-
genic Study 1n Mice, December 14, 1973. (Cited 1n U.S. EPA, 1985a)
0023H -25- n7/i3/flft
-------
Klemmer, K.U., A.M. Budy, W. Takahasdhl and T.J. Haley. 1977. Human tissue
distribution of cyclodlene pesticides Hawaii 1964-1973. CUn. Toxlcol.
11(1): 71-82. (Cited 1n U.S. EPA, 1985a)
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw H111 Book Co., New York. p. 4-9, 15-20.
Maslansky, C.J. and G.M. Williams. 1981. Evidence for an eplgenetlc mode
of action 1n organochloMne pesticide hepatocardnogenlcUy: A lack of
genotoxlclty 1n rat, mouse and hamster hepatocytes. J. Toxlcol. Environ.
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0023H -27- 07/13/88
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0023H -28- 07/13/88
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0023H -29- 07/14/88
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0023H -31- 07/13/88
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