MONOCROTOPHOS First draft prepared by Dr. S. Caroldi, University of Padua, Padua, Italy EXPLANATION Monocrotophos was previously evaluated by the Joint Meeting in 1972 (Annex I, 18) when an ADI of 0.0003 mg/kg bw was allocated. Additional data submitted in 1975 (Annex I, 24) with respect to mutagenicity testing, biotransformation, and observations on man allowed the Meeting to increase the ADI to 0.0006 mg/kg bw. Since then, additional data have been generated, which have been evaluated by the 1991 FAO/WHO Joint Meeting. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOLOGICAL DATA Biochemical aspects Biotransformation Metabolic pathways of monocrotophos in mammals are depicted in Fig.1. Effects on enzymes and other biochemical parameters Thirty male and female (60 controls) Wistar-derived rats (5 weeks old at the beginning of the study) were fed monocrotophos (E isomer 78.7%) at dietary levels of 0, 0.1, 0.25, 0.5, 2.0 or 8.0 ppm for 8 weeks. Ten rats/sex/dose level (20 controls) were sacrificed at the end of the 8 week treatment. Ten rats/sex/dose level (20 controls) were fed control diet for 5 additional weeks (follow-up group) and remaining 10 rats/sex/dose level (20 controls) were continued on the same treatment as during the first 8 weeks for 5 additional weeks; these rats were killed after 13 weeks. No clinical symptoms or deaths due to treatment with mono-crotophos were observed. Trivial reduction of body weight occurred at 8 ppm in both sexes. A dose-related decrease of plasma, erythrocyte and brain cholinesterase activities was measured at all dose levels. Biologically significant inhibition of brain cholinesterase activity was observed at 2.0 and 8.0 ppm monocrotophos. The level of inhibition was similar in both sexes and after 8 or 13 weeks of treatment. Almost complete recovery of both brain and erythrocyte cholinesterase activities, from the biological point of view, was detected 5 weeks after the end of treatment with the test substance. No obvious signs of cumulative toxicity occurred nor that the observed changes were irreversible (Hend & Brown 1981). Toxicological studies Long-term carcinogenicity studies Mice Male and female CD mice (5 weeks old at the beginning of the study) were offered monocrotophos (E isomer 78.7%) at concentrations of 1, 2, 5 or 10 ppm in powdered diet for either 55 (12 animals/sex/dose), 78 (15 animals/sex/dose) or 104 weeks (50 animals/ sex/dose). Control animals were 24, 30 and 100 for the 55, 78 and 104 week sections, respectively. The content of trimethyl phosphate was below 0.5% and the content of the Z-isomer of monocrotophos was approximately 1.5%. Monocrotophos was incorporated in a nutritionally adequate diet; as significant decay was observed at room temperature but not at -4 °C, diets were prepared and stored at -4 °C until used. No food was allowed to remain in food hopper for more than 4 days. The actual content of monocrotophos in the diets was checked several times throughout the duration of the study and it was always shown to be within ± 10 % of nominal. The mice were observed daily for general health and appearance, body weights and food intake were measured weekly. Every three months groups of 10 mice/sex from the 0 and 10 ppm dose levels underwent ophthalmoscopic examination. At the scheduled times animals were killed and blood samples were taken for haematological examinations and cholinesterase activity determinations. Full necropsies were performed on all animals, major organs were weighed and tissues were examined histologically from all animals in the 104 week section of the study and from mice fed 0, 5 and 10 ppm monocrotophos in the 55 and 78 week sections. Body weight and food intake were not affected by treatment with monocrotophos. Convulsions were observed in animals in all groups including controls. The overall incidence of convulsions was increased in males from the 2 ppm dose level and in females from the 1 ppm dose level. No ocular abnormalities related to monocrotophos feeding were detected. No dose-related, biologically significant differences in hematological tests were observed. Mean plasma, erythrocyte and brain cholinesterase activities were significantly depressed in all treatment groups at all times sampled. Inhibition was dose-related, consistent throughout the duration of the study and no differences between sexes were apparent. In brain after 104 weeks of treatment, inhibition was approximately 20%, 30%, 50% and 65% at 1, 2, 5 and 10 ppm, respectively. At the end of the study the mortality rate was 60%, 56%, 60%, 62%, 62% in males and 51%, 50%, 58%, 46% and 54% in females at 0, 1, 2, 5, 10 ppm, respectively. Pathology did not show specific lesions attributable to treatment. Increased incidence of pulmonary neoplasms was found in males after 18 months of treatment at 5 and 10 ppm but this observation was not confirmed at the end of the study. There was no evidence of a treatment-related oncogenic effect of monocrotophos up to 10 ppm, the NOAEL for cholinesterase inhibition is below 1 ppm (Robinson & Brown 1982). Rats Male and female Wistar-derived rats (5 weeks old study) were offered monocrotophos (E isomer 78.7%) at concentrations of 0.01, 0.03, 0.1, 1.0 or 10 ppm in powdered diet for either 6 months (8 animals/sex/dose), 12 months (8 animals/sex/dose), 18 months (19 animals/sex/dose) and 24 months (50 animals/sex/dose). Control rats were 16, 16, 38 and 100 for the 6, 12, 18 and 24 month sections, respectively. The preparation, storage and presentation of the diets were the same as reported in the previous long-term study in mice. The actual content of monocrotophos in the diets was checked several times throughout the study and was always shown to be within ± 10 % of nominal. The rats were observed twice daily (daily on week-ends) for general health and appearance throughout the duration of the study. Body weights and food intake were measured weekly. Every three months groups of 10 rats/sex from the 0 and 10 ppm groups underwent ophthalmoscopic examination. At 6, 12, 18 and 24 months blood samples were taken and urine collected for haematological and clinical chemistry examinations, cholinesterase activity determinations and urinalysis. Full necropsies were performed on all animals, major organs were weighed and tissues was examined histologically. Body weight was significantly reduced between 5% and 10% in males fed 10 ppm monocrotophos. This difference was more apparent during the first year of the study and corresponds to lower food intake. Body weight and food intake were not affected by treatment with monocrotophos in males up to 1 ppm nor in females at any dose levels. General health and behaviour were not affected by monocrotophos. No ocular abnormalities related to monocrotophos feeding were detected. Mean plasma, erythrocyte and brain cholinesterase activities were significantly depressed in the 1 and 10 ppm dose groups. Inhibition was dose related (approximately 30-40% and 70-80% at 1 and 10 ppm, respectively), consistent throughout the duration of the study and not differences between sexes were detectable. The results of haematology, clinical chemistry and urinalysis yielded no consistent dose- nor time-related findings throughout the course of the study. At the end of the study, the mortality rate was 24%, 20%, 28%, 30%, 20%, 32% in males and 49%, 60%, 52%, 56%, 44% and 64% in females at 0, 0.01, 0.03, 0.1, 1.0 and 10 ppm, respectively. Organ weight variations among groups were of no toxicological relevance. Pathology showed that the incidences of patchy alopecia and ulcerative dermatitis of the tail were slightly higher in the 10 ppm groups of both sexes. Pituitary neoplasm incidence was increased at the end of the study in female but not in male rats fed 10 ppm monocrotophos. Because of the high incidence of this type of neoplasm (88% of females fed control diet for up to two years versus 96% of females fed 10 ppm monocrotophos), this observation was of no biological relevance. The NOAEL for cholinesterase inhibition was 0.1 ppm and there were no specific macro- or microscopic lesions and there was no evidence of a treatment-related oncogenic effect up to 10 ppm (Robinson et al., 1983). Reproduction studies Rats In a 1-litter 2-generation reproduction study, groups of 13 male and 26 female Wistar rats approximately 5 weeks old received monocrotophos (E isomer 78.7%) admixed in the diet at 0, 0.1, 1, 3 or 10 ppm. The preparation, storage and presentation of the diets was the same as previously reported in long-term studies in mice and rats. The actual content of monocrotophos in the diets was checked several times throughout the duration of the study and was always shown to be within ± 10 % of nominal. Rats were maintained on their respective diets for at least 15 weeks, then each male rat was allocated to two females of the same treatment group. The F1 generation was culled to the same number of rats as in F0 and animals were exposed to the appropriate test diet for 18 weeks before being bred to produce F2 generation. Body weights were recorded monthly for adult rats in the pre-mating phase and at 1, 4, 7, 14 and 21 days of age for F1 and F2 pups. Mating performance, fertility, litter size and viability were recorded. Pathology was performed on F0 and F1 adults, on selected F1 and F2 pups. Sperm head counts were made on the testes of F0 and F1 adult rats. Significantly lower body weights (6-9% reduction) were recorded in male but not in female rats fed 10 ppm monocrotophos for both F0 and F1 generations. No treatment-related toxic effects were observed in the F0 and F1 adults during the pre-mating phase. Faecal pellets produced by F0 and F1 rats fed 10 ppm monocrotophos were smaller and darker than dose produced by controls. There were no monocrotophos-related effects on sperm head counts of the F0 or F1 parent rats. Mating performance, fertility index and gestation index were not different among F0 groups. At 10 ppm the F1 male mating index was lower and fewer litters were produced compared to controls. The gestation lengths of F0 and F1 females at 10 ppm dose level were significantly greater than those of controls. Mean litter size, viability index and lactation index were significantly reduced at 10 ppm for both F1 and F2 generations. Viability index in the F2 generation was reduced also at 3 ppm. Mean pup weights were lower at 10 ppm for both F1 and F2 generations and at 3 ppm for the F2 generation. There were three total litter losses at 10 ppm of the F1 and F2 generations and one litter loss of the F2 generation at 3 ppm, probably due to lactation deficiency as suggested by poor mammary development observed in dams. Higher kidney and liver weights were observed for F2 female weanlings at 3 and 10 ppm. These finding were not related to any histopathological abnormalities. No pathological changes of any tissues (excluding poor mammary development mentioned above) could be related to monocrotophos exposure. One ppm was the NOAEL in this reproduction study (Dix & Thorpe, 1981). Special studies on delayed neurotoxicity Hens Fourteen adult Warren Studdler laying hens were treated orally with monocrotophos 60% w/v in acetone on two separate occasions 3 weeks apart. Monocrotophos was administered in gelatin capsules to supply 6.7 mg/kg of monocrotophos (equivalent to LD50 in domestic fowl). Hens were protected against cholinergic toxicity with atropine sulphate (17.4 mg/kg i.m.) and pralidoxime chloride (50 mg/kg i.m.). Positive controls received tri-O-tolyl phosphate (0.5 ml/kg undiluted, p.o.), negative controls did not received any treatment. Nine out of 14 birds died of acute cholinergic symptoms within 4 days of the first or second monocrotophos dose; the five animals which survived both monocrotophos doses did not develop clinical nor histopathological signs of delayed neurotoxicity. Positive controls gave the expected positive clinical and histopathological responses (Owen et al., 1978). Groups of 10 adult hens (COFAL/Marek) were dosed by gavage with technical monocrotophos (containing 77.4% of the active E-isomer of monocrot-ophos, 0.43% trimethyl phosphate) at concentrations of 0, 0.03, 0.1, 0.3 mg/kg for 96 days. A positive control group received tri-orthocresol phosphate (TOCP) at 7.5 mg/kg p.o. Because of lack of neurotoxic symptoms both the highest monocrotophos dose and TOCP dose were increased on day 79 to 0.5 mg/kg and 10 mg/kg, respectively. Monocrotophos was dissolved in acetone and pipetted into gelatin capsules half-filled with feed; the acetone was allowed to evaporate at room temperature. Stability of the test compound under these conditions was confirmed by analytical tests. Plasma cholinesterase activity was reduced in all groups, including the TOCP group. This reduction was dose-related and at the highest dose level ranged between 11.8% after the first dose and 46.9% after the final dose. No changes in erythrocyte cholinesterase activity and no clinical signs of the cholinergic type were observed. Body weights and egg-laying performance were not consistently affected throughout the duration of the study. Some of the hens dosed with TOCP showed clinical (3 out of 10 birds) and histopathological (7 out of 10 birds) signs of delayed neuropathy after raising the TOCP dose to 10 mg/kg. None of the monocrotophos-treated hens developed delayed neuropathy. Mono-crotophos is devoid of neurotoxic potential under the conditions of the study. However, the short-term study was performed at doses too low at which neither acute cholinergic nor delayed neurotoxic effects could have been detectable (Becci & Parent, 1981). Special studies on embryotoxicity and teratogenicity Rats Twenty-six female Charles River Crl:CD (SD) BR albino rats were treated with technical monocrotophos at concentrations of 0, 0.3, 1.0, or 2.0 mg/kg/day orally by gavage (5 ml/kg, dissolved in distilled water) on days 6 to 15 of gestation. The test chemical was supplied by Shell Chemical Company which also performed characterization, stability and chemical analysis of dosage formulations. The concentrations of all samples before and after dosing were within ± 10% of the nominal concentrations. A single female rat dosed with 2.0 mg/kg died on gestation day 15, it had a diffuse, red-black crusted exudate around both eyes and a thinned glandular stomach which lacked mucosal convolutions. The remaining females survived up to the final sacrifice. Mean body weights (from gestation day 12) and carcass weights were significantly reduced in animals dosed at 1.0 and 2.0 mg/kg bw. Carcass weights were also reduced at 0.3 mg/kg. No significant differences were noted for the gravid uterus weights. Muscle tremors and/or twitchings, listlessness, salivation, urine soaked fur and crusty eyes were observed in females dosed with 2.0 mg/kg, mainly within 4 hours of administration of the test substance. Pathological examination at final sacrifice did not show abnormalities which could be related to monocrotophos administration. There were no statistically significant differences noted in the mean numbers of corpora lutea, implantation sites, resorption sites, nor viable fetuses in treated animals. Reproductive percentages calculated for the treated dams were comparable to those of the control group. Mean body weight and crown-rump length data obtained for the 2.0 mg/kg fetuses were significantly lower than those of the control fetuses. Mean percent of runt fetuses per litter was increased in 1.0 and 2.0 mg/kg groups. The percentage of fetuses with non-ossified sternebra(e) was increased in litters of the 2.0 mg/kg group. The incidence (58.4%) was approximately doubled in comparison with control group and with the other groups at lower mono-crotophos dose levels but within the range of previous historical data (4.7% to 82.1%). Malformed and/or misshapen brain (malformed brain with subdural haemorrhage/encephalocoele) was observed in 1, 3, 2 and 2 fetuses at 0, 0.3, 1, 2 mg monocrotophos/kg, respectively. This malformation is uncommon in Sprague-Dawley rats; it appeared to be a progression of the same type of lesion which differed only in the degree of severity. These brain malformations may suggest a teratogenic effect of monocrotophos in rats (Borders et al., 1983). Table 1. Results of genotoxicity assays on monocrotophos Test system Test object Concentration of Purity Results Reference test substance In vitro Reversion assay (1) S. typhimurium 0-10 000 µg/plate Not given Positive with Moriya et al. (1983) TA98, TA100, dissolved in DMSO TA100 and TA1535, TA1537, WP2hcr (2) TA1538 E. coli WP2hcr Reversion assay (1) S. typhimurium 10-8000 µg/0.1 ml 78.4% Slight positive Hool & Arni (1986) TA98, TA100, dissolved in acetone with TA100 TA102, TA1535, (3) TA1538 L5178Y Tk +/- Mouse lymphoma 50-1200 µg/ml 58.4% Positive Jotz et al. (1980) mutation assay (1) cells dissolved in DMSO (4) Sister chromatid Human lymphoid 0-2 µg/ml in absolute Not given Positive Sobti et al. (1982) exchange assay cells (LAZ-007) ethyl alcohol (5) Sister chromatid Human lymphocytes 0.1-0.8 µg/8 ml 36% Positive Rupa et al. (1988) exchange assay culture x 24, 48, (6) 72 hr dissolved in DMSO Sister chromatid Chinese hamster CHO: 25-400 µg/ml 78% Positive Wang et al. (1987) exchange assay (1) ovary cells, RTE: 12.5-100 µg/ml (7) Rat tracheal dissolved in DMSO epithelial cells Table 1 (contd). Test system Test object Concentration of Purity Results Reference test substance Reverse mutation Saccharomyces 0.1-3% dissolved in 58.4% Positive Mortelmans et al. (1980) mitotic recombination cerevisiae D7 DMSO (8) gene conversion (1) Chromosome Human lymphocytes 0.01 µg/ml x 24, 48, 36% Positive Rupa et al. (1988) aberrations 72 hr dissolved in (6) DMSO Chromosome Human lymphocytes 10-4 - 10-9 M x 50 h 69% Positive Vaidya et al. (1982) aberrations in distilled water (9) Mitotic Saccharomyces 5% 55% Positive Simmon et al. (1977) recombination (1) cerevisiae D3 (10) DNA-repair Human fibroblast 0.0001-10 mM 55% Positive Simmon et al. (1977) (UDS) (1) cells (WI-38) (11) In vivo Chromosome study Chinese hamster 1.4, 2.8, 5.6 mg/kg 78.4% Negative Strasser & Arni (1986) (bone marrow) in distilled water (11) administered orally twice 24 h apart Chromosome study Swiss mouse 1, 1.5, 2 mg/kg 69% Positive Vaidya et al. (1982) (bone marrow) administered i.p. (8) twice 24 h apart in distilled water Table 1 (contd). Test system Test object Concentration of Purity Results Reference test substance Nucleus anomaly test Chinese hamster 1.4, 2.8, 5.6 mg/kg 78.4% Negative Strasser et al. (1986) (bone marrow) in distilled water (12) administered orally twice 24 h apart Micronucleus test Swiss mouse 2, 4, 8 mg/kg i.p. Not given Negative Kirkhart et al. (1980) (bone marrow) administered twice (13) 24 h apart Micronucleus test Swiss mouse 1, 1.5, 2 mg/kg i.p. 69% Positive Vaidya et al. (1982) (bone marrow) administered twice (8) 24 h apart Chromosome study Rat 0.5, 1, 2 mg/kg in Not given Equivocal Adhikari & Grover (1988) (bone marrow) DMSO administered (15) i.p. twice 24 h apart Dominant lethal Mouse 15, 30, 60 mg/kg of 55% Negative Simmon et al. (1977) diet x 7 weeks (16) Special studies on genotoxicity (1) Both with and without metabolic activation (2) Part of a study in which 228 pesticides were tested for mutagenicity in bacterial reversion-assay systems (3) The study was repeated three times at similar doses giving similar results. Positive control without activation: Daunorubicin HCl, 5-10 µg/0.1 ml; 4-nitroquinoline-N-oxide, 0.125-0.250 µg/0.1 ml; mitomycin-c, 0.5-1 µg/0.1 ml; sodium azide, 2.5-5 µg/0.1 ml; aminoacridine hydrochloride, 50-100 µg/0.1 ml gave expected positive responses. Positive control with activation: 2- aminoanthracene, 5-20 µg/0.1 ml; cyclophosphamide, 250 µg/0.1 ml gave the expected positive responses. (4) Positive control without activation: ethylmethane sulfonate, 500 µg/ml gave expected positive response. Positive control with metabolic activation: 3-methylcholantrene, 5 µg/ml gave expected positive response. The test substance gave positive response at 200 µg/ml and above and at 840 µg/ml and above with and without metabolic activation, respectively. (5) Monocrotophos was tested without metabolic activation. A dose-related statistically significant increase of sister chromatid exchange frequency was observed. (6) Positive control not run. (7) Monochrotophos was positive for sister chromatid exchange inductions in both CHO and RTE. (8) Positive control with and without metabolic activation: 1,2,3,4-diepoxybutane, 0.013% gave expected positive response. Monochrotophos induced mitotic crossing-over, gene conversion, and reverse mutation, with and without metabolic activation. (9) Positive control not run. (10) Positive control: 1,2,3,4,-diepoxybutane, 0.1% gave expected positive response. (11) Positive control without metabolic activation: 4-nitroquinoline-N-oxide, 0.05 mM gave expected positive response. Positive control with metabolic activation: Dimethylnitrosoamine, 50 mM gave expected positive response. (12) Positive control: cyclophosphamide, 64 mg/kg x 2 gave expected positive response. (13) Positive control: cyclophosphamide, 128 mg/kg x 2 gave expected positive response. (14) Positive control: trimethylphosphate, 1 g/kg x 2 gave expected positive response. (15) Positive control: ethyl methane sulfonate, 62.5-250 mg/kg x 2 gave expected positive response. Monochrotophos caused a dose-related increase of the frequency of aberrant cells, but the increase was significant only for the highest dose. (16) Positive control: triethylenemelamine, 0.2 mg/kg i.p. gave expected positive response. COMMENTS In a 13-week study in rats at dietary concentrations of 0, 0.1, 0.25, 0.5, 2, or 8 ppm, the NOAEL was 0.5 ppm, equivalent to 0.025 mg/kg bw/day, based on brain acetylcholinesterase inhibition at 2 ppm. In a 2-year study in mice at dietary concentrations of 0, 1, 2, 5 or 10 ppm a NOAEL could not be established because brain acetylcholinesterase inhibition was detected at the lowest dietary concentration (approximately 20% inhibition). There was no evidence of a treatment-related carcinogenic effect. In a 2-year study in rats at dietary concentrations of 0, 0.01, 0.03, 0.1, 1.0 or 10 ppm the NOAEL was 0.1 ppm, equivalent to 0.005 mg/kg bw/day, based on brain acetylcholinesterase inhibition at the next higher dose. Again, there was no evidence of carcinogenicity. Monocrotophos did not cause delayed neuropathy in hens. In a multigeneration reproduction study in rats at dietary concentrations of 0, 0.1, 1, 3, or 10 ppm, the NOAEL was 1 ppm, equivalent to 0.05 mg/kg bw/day, based on toxicity in pups seen in the F2 generation at 3 ppm. In a teratology study in rats at doses of 0, 0.3, 1 or 2 mg/kg bw/day, the NOAEL was 0.3 mg/kg bw/day for both maternal toxicity and teratogenicity. There was a slightly increased incidence of malformed and/or misshapen brain at all dose levels (0.3 mg/kg bw/day included). A dose-effect relationship for this uncommon malformation was lacking and historical control data were not available. Substantial variations in the purity of the test material used in the genetic toxicology studies hampered thorough evaluation for genotoxicity. When purity was at the level of technical grade monocrotophos (78%) there were significant responses in tests for mutagenicity in bacteria and sister chromatid exchange in Chinese hamster ovary cells; in vivo studies for clastogenic activity were negative. The Meeting concluded that the significance of the brain malformations observed in the teratology study in rats warranted clarification, as did the genotoxic potential of monocrotophos. Accordingly, the Meeting recommended that monocrotophos be reviewed in 1994. An ADI was allocated on the basis of the 2-year study in rats using a 100-fold safety factor. TOXICOLOGICAL EVALUATION Level causing no toxicological effect Mouse: < 1 ppm in the diet, equivalent to < 0.15 mg/kg bw/day Rat: 0.1 ppm in the diet, equivalent to 0.005 mg/kg bw/day Estimate of acceptable daily intake for humans 0-0.00005 mg/kg bw Studies which will provide information valuable in the continued evaluation of the compound 1. Genotoxicity studies, known to exist, with commercial and purified monocrotophos. 2. Historical control data on the incidence of brain malformations in rats at the relevant laboratory. REFERENCES Adhikari, N., Grover, I.S. (1988) Genotoxic effects of some systemic pesticides: in vivo chromosomal aberrations in bone marrow cells in rats. Environmental and Molecular Mutagenesis, 12: 235-242. Becci, P.J., Parent, R.A. (1981) Neurotoxicity evaluation of Azodrin insecticide: subchronic oral administration in hens. Unpublished Report 6535-II by Food and Drug Research Laboratories, Inc. Waverly, NY, USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Borders, C.K., Salamon, C.M., Mayhew, D.A. (1983) Technical Azodrin (SD 9129) teratology study in SD CD rats. Unpublished Report 450-1248 by Toxi-Genics Inc. USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Dix, K.M. & Thorpe, E. (1981) A reproduction study in rats fed Azodrin. Unpublished Report 1752 by Sittingbourne Research Centre, England. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Hend, R.W & Brown, V.K.H. (1981) A reversibility study of cholinesterase activity in rats fed Azodrin for 8 weeks. Unpublished Report 1720 by Sittingbourne Research Centre, Shell Toxicology Laboratory (Tunstall), Sittingbourne, England. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Hool, G. & Arni, P. (1986) Salmonella/mammalian-microsome mutagenicity test. C 1'414 tech. Unpublished Report 8508210 by CIBA-GEIGY Ltd Basle, Switzerland. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Kirkhart, B., Jones, D.C.L., Skinner, W.A. (1980) Micronucleus test on monocrotophos. Unpublished Report LSU 7558-19 by SRI International, Menlo Park, California, USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Jotz, M.M., Mitchell, A.D., Jones, D.C.L., Skinner, W.A. (1980) An evaluation of mutagenic potential of monochrotophos employing the L5178Y TK +/- mouse lymphoma assay. Unpublished Report LSU-7558 by SRI International, Menlo Park, California, USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Moriya, M., Ohta, T., Watanabe, K., Miyazawa, T., Kato K., Shirasu, Y. (1983) Further mutagenicity studies on pesticides in bacterial reversion assay systems. Mutation Research, 116: 185-216. Mortelmans, K.E., Shepherd, G.F., Jones, D.C.L., Skinner, W.A. (1980) In vitro detection of mitotic crossing-over, mitotic gene conversion and reverse mutation with Saccharomyces cerevisiae D7 for seven pesticides. Unpublished Report LSU-7558-20 by SRI International, Menlo Park, California, USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Owen, D.E., Butterworth, S.T.G., Brown, V.K.H., Thorpe, E. (1978) Toxicity of organophosphorus insecticide Azodrin: investigation of the neurotoxicity of Azodrin-5 to adult domestic hens. Unpublished Report TLGR 0066.78 by Shell Research Limited, Sittingbourne Res. Centre, England. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Robinson, J. & Brown, V.K.H. (1982) A two-year oncogenicity study in mice fed Azodrin. Unpublished Report 194/82 from Shell Research Limited. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Robinson, J., Gellatly, J.B.M. & Brown, V.K.H. (1983) A long-term feeding study with Azodrin in rats to investigate chronic toxicity and oncogenicity (6, 12, 18 and 24 month necropsies). Unpublished Report 194/82 from Shell Research Limited. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Rupa, D.S., Lakshaman, R.P.V., Reddy, P.P., Reddi, O.S. (1988) In vitro effect of monochrotophos on human lymphocytes. Bull. Environ. Contam. Toxicol., 41: 737-741 Simmon, V.F., Mitchell, A.D., Jorgenson, T.A., (1977) Evaluation of selected pesticides as chemical mutagens in vitro and in vivo studies. Unpublished Report EPA-600/1-77-028 by SRI International, Menlo Park, California, USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Sobti, R.C., Krishan, A., Pfaffenberger, C.D. (1982) Cytokinetic and cytogenetic effects of some agricultural chemicals on human lymphoid cells in vitro: organo-phosphates. Mutation Research, 102: 89-102. Strasser, F., Arni, P. (1986) Chromosome studies on somatic cells of Chinese hamster. Unpublished Report 850808 by CIBA-GEIGY Ltd Basle, Switzerland. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Strasser, F., Langauer, M., Arni, P. (1986) Nucleus anomaly test in somatic interphase nuclei of Chinese hamster. Unpublished Report 850809 by CIBA-GEIGY Ltd., Basle, Switzerland. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland. Vaidya, V.G., Patanakar, N. (1982) Mutagenic effect of monochrotophos - an insecticide in mammalian test systems. Indian J. Med. Res., 76, 912-917. Wang, T.C., Lee, T.C., Lin, M.F., Lin, S.Y. (1987) Induction of sister chromatid exchange by pesticides in primary rat tracheal epithelial cells and Chinese hamster ovary cells. Mutation Research, 188, 311-321.
See Also: Toxicological Abbreviations Monocrotophos (HSG 80, 1993) Monocrotophos (ICSC) Monocrotophos (WHO Pesticide Residues Series 2) Monocrotophos (WHO Pesticide Residues Series 5) Monocrotophos (Pesticide residues in food: 1993 evaluations Part II Toxicology) Monocrotophos (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)