METHOXYCHLOR JMPR 1977
Explanation
This pesticide was evaluated for acceptable daily intake by the Joint
Meeting in 1965 (FAO/WHO 1965 ). Additional studies on biochemistry,
long term studies in animal species other than the rat and
reproduction studies were required.
Since the previous evaluation new data on acute toxicity and
teratogenicity, have been presented and are summarized in the
following monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
In mice, labelled methoxychlor given orally was eliminated to the
extent of 98.3% within 24 hours.
2-(p-hydroxyphenyl)-2-(p-methoxyphenyl)-1,1,1-trichloroethane
and 2,2 bis(p-hydroxyphenyl)-1,1,1-trichloroethane were, identified
(Metcalf et al., 1970).
TOXICOLOGICAL STUDIES
Special study on teratogenicity
Groups of pregnant rats received oral closes of methoxychlor at dose
levels of 0, 34.6, 138, 242 and 346 mg/kg from gestation day 6 through
15. The number of resorptions in animals at 242 and 346 mg/kg, was
increased in comparison with the control. With the exception of the
242 mg/kg group foetal weight was decreased. No abnormalities by
external, visceral and skeletal examination wore observed (Ravert and
Parke, 1976).
Special studies on carcinogenicity
In their evaluation of 4 oral feeding studies in rats and of 2 studies
in mice with skin painting and with subcutaneous application a group
of experts convened by IARC, concluded.
Methoxychlor was tested by the oral route only in the rat. Three
experiments, including one employing dietary levels of up to 1600 ppm
(equivalent to about 80 mg/kg bw/day), provided no evidence of
carcinogenicity. Because of inadequate reporting, conclusions cannot
be drawn from the results of a fourth experiment in which some liver
tumours were observed in rats fed up to 2000 ppm in the diet
(equivalent to about 100 mg/kg bw/day). Data from these four
experiments do not allow an evaluation of the carcinogenicity of
methoxychlor to be made at the present time.
No tumours were reported in limited skin application and subcutaneous
injection (simple-dose) studies (IARC, 1974).
Since then further studies have become available:
2 groups of 50 male B6C3F1 mice were administered in the diet 1750 and
3500 ppm methoxychlor while 2 groups of 50 female mice received 1000
and 2000 ppm for 78 weeks. The animals were then kept on basal diet
for another 15 weeks. 2000 ppm was the maximum tolerated dose. 20
animals of each sex served as controls. A close-related body weight
depression of 15-20% was observed only in females, however no effect
on survival was detected.
For males the actual survival was adequate, as 69 percent of the high
dose, 58 percent of the low dose, and 45 percent of the control mice
survived over 81 weeks. For females the actual survival was high, as
98 percent of the high dose, 90 percent of the low dose, and 85
percent of the control mice survived until the end of the test.
No treatment-related organ lesions occurred. The tumour incidence was
similar in all groups. In males, hepatocellular carcinomas were found
in 23% of the controls, 8% of the low and 19% of the high dose group.
In females no liver carcinomas were found in the control and high dose
group, whereas the incidence in the low dose group was 6%. Thus, the
study did not provide any evidence of the carcinogenicity of
methoxychlor in B6C3P1 mice (NCI, 1977).
2 groups of 50 male Osborne-Mendel rats were administered in the diet
360 -500 and 720 -1000 ppm methoxychlor for 78 weeks. This was
followed by a period of 33 weeks on the basal diet. 2 groups of 50
female rats received 750, and 1500 ppm for 78 weeks. 20 rats of each
sex served as controls.
Weight gain was reduced in both groups by 5 -25%. No effect on
survival was recorded: 86% of the high dose males, 74% of the low dose
and 85% of the controls lived at least 100 weeks. In all female groups
more than 90% survived 100 weeks.
Inflammatory, degenerative and proliferative lesions as seen in the
control and treated animals were similar in number and kind to
spontaneous lesions occurring in aged Osborne-Mendel rats. In regard
to neoplasms, hemangiosarcomas were the only tumours observed at
unusually high incidences.
The hemangiosarcomas occurred in the spleen of 1/20 control males,
6/44 low dose males, 2/42 high dose males, and 1/20 control females.
Hemangiosarcomas also occurred as subcutaneous masses in 2/50 low dose
males and as an abdominal tissue mass in 1/50 low dose male rats.
Thus, there was an increased incidence of hemangiosarcomas at all
sites in male rats receiving methoxychlor (9 low dose and 2 high dose)
as compared to a single control male and a single control female with
these tumours.
With the exception of a hemangiosarcoma in the spleen of one control
female there were no unusual tumours or any unusual incidences of
spontaneous tumours in the female rats. The occurrence of these
tumours was not statistically significant.
Acute Toxicity
Species Sex Route LD50 References
Rat F Oral 3460 Terrell & Parke, 1976
COMMENTS
Several new studies were examined by the Meeting.
Methoxychlor is mainly degraded by hydrolysis of the methyl ether
leading to a polar phenol which is rapidly excreted.
Methoxychlor does not exhibit a teratogenic potential in rats.
Several carcinogenicity studies in rats and mice at dose levels up to
3500 ppm were negative. Therefore the ADI for humans established in
1965 remains unchanged.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 200 mg/kg in the diet, equivalent to 10 mg/kg bw
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR HUMANS
0-0.1 mg/kg bw
REFERENCES
FAO/WHO. (1965) Evaluation de la toxicité de résidues pesticides dans
les denrées alimentaires. WHO/Food. Add./27.65.
IARC. (1974) Monographs on the evaluation of carcinogenic risks of
chemicals to man. Vol. 5, 193. International Agency for Research on
Cancer.
Metcalf, R.L., Kapoor, I.P., Nystrom, R.F. and Sangha, G.K. (1970)
Comparative metabolism of methoxychlor, methioclor and DDT in mouse,
insects and in a model ecosystem. J. agric. Ed Chem. 18, 1145.
NCI. (1977) Bioassay of Methoxychlor for Possible Carcinogenicity,
Carcinogenesis Testing Program, Division of Cancer Cause and
Prevention. National Cancer Institute, National Institutes of Health.
(Unpublished Report).
Ravert, J. and Parke, G.S.E. (1976) Investigation of teratogenic and
toxic potential of methoxychlor in rats. Unpublished report from
Cannon Laboratories Inc.
Terrell, Y. and Parke, G.S.E (1976) Acute oral toxicity in rats of
technical methoxychlor. Unpublished report from Cannon Laboratories,
Inc.
See Also:
Toxicological Abbreviations
Methoxychlor (ICSC)
Methoxychlor (FAO Meeting Report PL/1965/10/1)
Methoxychlor (IARC Summary & Evaluation, Volume 5, 1974)
Methoxychlor (IARC Summary & Evaluation, Volume 20, 1979)