PESTICIDE RESIDUES IN FOOD - 1984 Sponsored jointly by FAO and WHO EVALUATIONS 1984 The monographs Data and recommendations of the joint meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues Rome, 24 September - 3 October 1984 Food and Agriculture Organization of the United Nations Rome 1985 DIMETHOATE Explanation Dimethoate was evaluated by the Joint Meetings in 1965, 1966 and 1967 (FAO/WHO, 1965, 1967 and 1968). The ADI (0.02 mg/kg bw/day was derived from a study in humans where the NEL of 0.2 mg/kg bw/day was based on plasma cholinesterase depression. Animal studies comprised essentially short-term studies (rat, 15 weeks and 6-12 months; dog, 13 weeks), and a three-generation, two-litter per generation, reproduction study in mice. Several studies have been obtained through open literature and are summarized in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Effects on Enzymes and Other Biochemical Parameters Dimethoate significantly inhibited the active transport of glucose though the isolated intestine of the mouse (Guthrie, Shah & Moreland, 1980). TOXICOLOGICAL STUDIES Special Studies on Reproduction Mice Five generations of CD-1 mice were maintained on a diet containing 60 ppm of Dimethoate in drinking water. Dimethoate treatment significantly altered reproductive performance as indicated by reduced mating success and longer gestation period. At birth, litter size or weight were not reduced, but pup mortality increased significantly with treatment. Growth rate of the pups was generally lower than that observed for controls. Dimethoate did not show teratologic potential or adverse effects on organ weights or histology (Budreau & Singh, 1973). Special Studies on Teratogenicity Rat Groups of pregnant female rats were administered 0, 3, 6, 12 or 24 mg/kg bw of Dimethoate daily from days 6 to 15 of gestation. The dams were killed on day 22 of gestation; the uterine content was removed, the carcass weighed, the number of corpora lutea was determined, and the animals were necropsied. The foetuses were weighed and examined for viability and external malformations. Live foetuses were studied for skeletal development and visceral anomalies. Maternal weight decreased significantly in the 24 mg/kg group. Clonic spasms and muscular tremors were seen in females treated with 24 mg/kg. Mean foetal weight was not reduced in treated groups. Dimethoate treatment (12 and 24 mg/kg) was associated with an increased number of litters with abnormal foetuses and foetuses with wavy ribs. No effect was seen at a dose of 6 mg/kg bw of formulated product, equal 2.84 mg/kg of Dimethoate (Khera, et al., 1979). Cat Teratogenic effects were studied in four groups of 17 cats each, which were mated and treated with Cygon-4E, a commercial insecticide containing 47.3 percent Dimethoate, in single daily doses of 0, 3, 6 or 12 mg/kg bw on days 14 to 22 of pregnancy. The cats were necropsied on day 43 of pregnancy. Foetuses were removed, weighed, and examined for external malformations. The total number of anomalous foetuses in the 12 mg/kg group was higher, but not statistically different from that of controls. The only treatment-related malformation observed at this dose was forepaw polydactyly in eight of the 39 foetuses. A dose relationship was not established, due to the limited response and the common occurrence of this anomaly in the cat population. It is suggested that 6 mg/kg of Cygon-4E, or 2.84 mg/kg of Dimethoate be considered a no-effect level (Khera 1979). Special Studies on Mutagenicity See Table 1. Special Studies on Carcinogenicity Mouse Groups of B6C3F1 mice (50 males and 50 females/group) were fed diets containing Dimethoate (technical grade, 90-100 percent purity) at levels of 250 or 500 ppm for 60 to 80 weeks. Following the exposure period, mice were returned to control diets until they were sacrificed at 94 weeks. The matched control group consisted of seven male and ten female mice. The doses were selected after 1 000 and 500 ppm, used in a preliminary study, appeared too toxic. All animals were observed for signs of toxicity and body weights recorded. Tissues and organs from almost all animals in the study were subjected to histopathological examinations. In the first year of the study the average weight gain in all groups except the low-dose female group was less than that of the matched controls. In the second year the average gain in weight in the treated groups was generally similar. Tremors and hyperexcitability were observed in both sexes. During the second year of the study adverse clinical signs were observed in all treatment groups. Animals surviving at termination were generally in very poor physical condition. The Dimethoate treatment had no apparent effect on survival rates. Several non- neoplastic proliferative or inflammatory conditions occurred with approximately equal frequency in control and Dimethoate-treated mice. TABLE 1 - Special Studies on Mutagenicity Test system Test object Concentration Purity Results Reference of dimethoate used 5-methyl tryptophan E. coli 1 - 6.10-3 M not indicated positive Mohn, 1973 resistant mutation during 60 min. assay host-mediated mouse; 3 equal oral doses of not indicated positive Rani, Reddi & Reddy, assay S. typhimurium 155 mg/kg body weight 1980 S. typhimurium injected, collected, and plated sister-chromatid Chinese hamster 0, 10, 20, 40, and 80 94% positive in SCE; Chen, et al.,1981 exchange; cell ovary cells µg/ml + 10 picograms/ml positive in cell cycle delay V79 of 5-bromo deoxyuridine cycle delay (BUdR) micronucleus test mouse; bone 2 equal oral doses of not indicated positive Rani, Reddi & Reddy, marrow 51.7 mg/kg b.w. at 1980 24-h interval human cells human Chang 50 - 500 µg/ml 99.8% cytotoxic in Gabliks & Friedman, in vitro liver and HeLa both cell lines; 1965 cells ID50 = 170 µg/ml (liver cells) ID50 = 200 µg/ml (HeLa cells) human cells human HeLa 2.0-300 µg/ml 99.8% cytotoxic in Gabliks, 1965a in vitro cells minimal toxic dose = 20 µg/ml human cells human HeLa 2.0 -300 µg/ml 99.8% treated cells Gabliks, 1965b in vitro (up to cells more susceptible 108 days exposure) to poliovirus infection The most commonly occurring neoplasm in male mice was hepatocellular carcinoma and malignant lymphoreticular tumours in female mice but there was no significant difference in the incidence of tumours among the Dimethoate-treated mice and their controls (Nat. Canc. Inst., 1976). Rat Groups of Osborne-Mendel rats (50 males and 50 females/group) were fed diets containing Dimethoate (technical grade, 90-100 percent purity) at time-weighted average levels of 155 or 310 ppm (male rates) and 192 or 384 ppm (female rats) for 80 weeks, and then returned to control diets until they were sacrificed at 114 weeks. The matched control group consisted of ten male and ten female rats. Pooled control groups from other studies were also considered. The initial treatment levels (250 or 500 ppm) were selected after a six-week study showed weight depression in male and female rats fed 250 or 500 ppm, while all rats receiving 1 000 ppm died. As the initial treatment levels were toxic, levels for treated rats were lowered for the varying treatment periods indicated in Table 2. All animals were observed for signs of toxicity and body weights were recorded. Tissues and organs of almost all animals in the study were subjected to histopathological examinations. Cholinergic signs of toxicity were evident in treated animals. Early in the study tremors and hyperexcitability were observed in both male and female rats. In general there appeared to be a dose-related depression in both low- and high-dose groups. Adverse clinical signs in all treatment groups were noted with frequent incidence during the second year of the study. Animals that survived to termination were generally in poor physical condition. At termination there appeared to be a dose-related mortality with Dimethoate (58 and 51 percent survival to 115 weeks for males and females, respectively). However the significance of this observation is not clear, since survival was lowest in the male matched and pooled control group. Numerous inflammatory, degenerative and proliferative lesions, commonly seen in aged rats, occurred with approximately equal frequency in treated and control animals. Several non-neoplastic lesions occurred more frequently in treated rats than in controls, but were generally not dose-related. The pituitary and thyroid were the most common primary sites of neoplasia in both treated and control rats but there was no significant increase in the incidence of tumours between the treated and control groups (Nat. Canc. Inst., 1976). Acute Toxicity The acute toxicity of Dimethoate to rats via oral and dermal routes is summarized in Table 3. TABLE 2. Design of Dimethoate Chronic Feeding Study in Rats and Mice Initial Dimethoate Time on Study Time-Weighted No. of in Diet Treated Untreated Average Dose Animals (ppm) (weeks) (weeks) (ppm) (a) (b) (c) (d) RATS Male Matched Control 10 0 0 114 Low 50 250 19 155 125 61 0 34-35 High 50 500 19 250 61 310 0 33-34 Female Matched Control 10 0 0 114 Low 50 250 43 125 37 192 0 33-34 MICE Male Matched Control 10 (e) 0 0 94 Low 50 250 69 250 0 24 High 50 500 60 500 0 34 Female Matched Control 10 0 0 94 Low 50 250 80 250 0 13 High 50 500 80 500 0 14 TABLE 2. (continued) (a) All animals were 35 days of age when placed on test. (b) Initially 1 000 and 500 ppm of Dimethoate were fed to mice of each sex; these doses were too toxic, however, and the mouse study was terminated and restarted as shown in the table. (c) When diets containing Dimethoate were discontinued, treated rats and their matched controls were fed plain feed diets (without corn oil) for 8 weeks, then control diets (2 percent corn oil added) for an additional 25 to 27 weeks. Mice received the control diet until termination. (d) Time-weighted average dose = Sigma (dose in ppm x no. of days at that dose) Sigma (no. of days receiving each dose) (e) Examination at necropsy subsequently revealed that 3 of 10 mice designated as male matched controls were females. TABLE 3. Acute Toxicity of Dimethoate in Animals Species Sex Route Purity LD50 Reference Rat m/f oral 97.6-99% 540-600 Dal Re & mg/kg Vola Gera 1980 Rat m/f dermal 97.6-99% >7 000 Dal Re & mg/kg Vola Gera 1976 COMMENTS The last evaluation of Dimethoate was conducted in 1967, when an ADI of 0-0.02 mg/kg bw was derived from a no-effect level in humans of 0.2 mg/kg/day for plasma cholinesterase. Since that time several studies on the toxicology of Dimethoate have been published and have now been reviewed to supplement the data on short-term rat and dog. toxicology studies and a mouse three-generation study used in previous toxicological evaluations. A five-generation study of Dimethoate in mice showed decreased success in mating, longer reproduction time and increased pup mortality, but no teratogenic potential. Teratogenicity studies with Dimethoate-formulated products enabled no-effect levels to be established for rats and cats (2.8 mg Dimethoate/kg bw). Dimethoate was shown not to be oncogenic in mouse and rat studies, but was mutagenic in a number of in vivo and in vitro short-term tests. The meeting was informed that several additional toxicological studies are in progress and will be available by 1987. In the absence of a complete data base for this compound the ADI was replaced by a temporary ADI at a lower level. Level Causing no Toxicological Effect Rats: 5 ppm in the diet, equivalent to 0.25 mg/kg bw Humans: 0.2 mg/kg bw/day Estimate of Temporary Acceptable Daily Intake for Humans 0 - 0.002 mg/kg bw FURTHER WORK OR INFORMATION Required (by 1987) 1. Submission of the on-going toxicological studies sponsored by the "Dimethoate Task Force". 2. A dog study of at least six months' duration. Desirable Observations in humans. REFERENCES Budreau, C.H. & Singh, R.P. Effect of Fenthion and Dimethoate on 1973 reproduction in the mouse. Toxicol. Appl. Pharmacol. 26: 29-38. Chen, H.H., Hsueh, J.L., Sirianni, S.R. & Huang, C.C. Induction of 1981 Sister-Chromatid exchanges and Cell Cycle Delay in cultured mammalian cells treated with eight organophosphorous pesticides. Mutat. Res. 88: 307-316. Dal Re, V. & Vola Gera, F. Determination of the acute dermal toxicity 1976 of technical Rogor. Report from Centro Ricerche Antiparassitari, Montedison, Italy, submitted by Farmoplant, Italy to WHO. (Unpublished) Dal Re, V. & Vola Gera, F. Acute oral toxicity of technical Rogor 1980 samples recently produced in albino rats. Report from Centro Ricerche Antiparassitari, Montedison, Italy, submitted by Farmoplant, Italy to WHO. (Unpublished) Gabliks, J. Responses of cell cultures to insecticides II. Chronic 1965a toxicity and induced resistance. Proc. Soc. Expt. Biol. Med. 120: 168-171. Gabliks, J. Responses of cell cultures to insecticides III. Altered 1965b susceptibility to Poliovirus and Diptheria toxin. Proc. Soc. Expt. Biol. Med. 120: 172-175. Gabliks, J. & Friedman, L. Responses of cell cultures to insecticides 1965 I. Acute toxicity to human cells. Proc. Soc. Expt. Biol. Med. 120: 163-168. Guthrie, F.E., Shah, P.V. & Moreland, D.E. Effects of pesticides on 1980 active transport of glucose through the isolated intestine of the mouse. J. Agric. Food Chem. 22: 3. Khera, K.S. Evaluation of Dimethoate (Cygon 4E) for teratogenic 1979 activity in the cat. J. Environ. Pathol. Toxicol. 2: 1283-1288. Khera, K.S., Whalen, C., Trivett, G. & Angers, G. Teratogenicity 1979 studies on pesticidal formulations of Dimethoate, Diuron and Lindane in rats. Bull. Environ. Contam. Toxicol. 22: 522-529. Mohn, G. 5-methyl tryptophan resistance mutations in Escherichia Coli 1973 K-12. Mutat. Res. 20: 7-15. National Cancer Institute. Bioassay of Dimethoate for possible 1976 carcinogenicity. NCI-CG-TR-4 DHEW Publication No. (NIH) 77-80. Rani, M.V.U., Reddi, O.S. & Reddy, P.P. Mutagenicity studies involving 1980 Aldrin, Endosulfan, Dimethoate, Phosphamidon, Carbaryl and Ceresan. Bull. Environ. Contam. Toxicol. 25: 277-282.
See Also: Toxicological Abbreviations Dimethoate (EHC 90, 1989) Dimethoate (HSG 20, 1988) Dimethoate (ICSC) Dimethoate (FAO Meeting Report PL/1965/10/1) Dimethoate (FAO/PL:CP/15) Dimethoate (FAO/PL:1967/M/11/1) Dimethoate (JMPR Evaluations 2003 Part II Toxicological) Dimethoate (AGP:1970/M/12/1) Dimethoate (Pesticide residues in food: 1983 evaluations) Dimethoate (Pesticide residues in food: 1984 evaluations) Dimethoate (Pesticide residues in food: 1987 evaluations Part II Toxicology) Dimethoate (Pesticide residues in food: 1996 evaluations Part II Toxicological)