CARBENDAZIM EXPLANATION Carbendazim was evaluated by the Joint Meetings of 1973, 1976, 1977, 1978 and 1983 (Annex 1, FAO/WHO, 1974a, 1977a, 1978a, 1979a, and 1984). A toxicological monograph was prepared by the Joint Meeting in 1973 (Annex 1, FAO/WHO, 1974b) and monograph addenda were prepared by the Joint Meetings in 1976 and 1983 (Annex 1, FAO/WHO, 1977b and 1985a). The Joint Meeting of 1983 estimated an acceptable daily intake (ADI) of 0-0.01 mg/kg b.w. for carbendazim but used a safety factor of 200 to reflect concern for the paucity of individual animal data for many of the studies evaluated. These data on individual animals used in the studies on carbendazim were recognized as desirable by the Meeting, and listed under the heading "Further Work or Information". Some additional data have been provided which permitted the Meeting to update the quality of a few studies previously reviewed. The results are summarized herein. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOLOGICAL DATA Toxicological studies Special study on reproduction Rat Sufficient individual animal and litter data were presented to confirm the absence of teratogenic or reproductive effects in the three generation two litter/generation study at doses up to and including 2000 ppm. The F3a offspring used specifically for teratogenic evaluation confirmed the absence of induction of malformations. In the four week toxicity study, using F3b offspring, although relative ovarian weights in all dose groups were reduced compared to controls, they were not decreased in a dose-related manner. Reduced relative spleen weights in males and females at 2000 ppm was also confirmed (Til et al., 1976a). Special Studies on Teratogenicity Rat Sufficient individual animal and litter data were provided to confirm the absence of teratogenic effects at dose levels of carbendazim in the diet up to and including 6000 ppm. However, ovarian weights were apparently reduced (compared to control) at > 2000 ppm. Litter data also confirmed the increase in misshapen and supernumery bones at > 6000 ppm, as well as the increased finding of delayed or absent ossification of the cervical vertebral bodies in all treatment groups. The finding of absent ossification of the cervical vertebral bodies increased in a dose-related manner (Koëter 1975a). Rabbit Sufficient individual animal and litter data were provided to confirm the absence of teratogenic effects at dose levels of carbendazim in the diet up to and including 6000 ppm. There were too few animals, litters, and foetuses in the 2000-ppm group for any useful evaluation of compound related effects. Visceral findings were made available on all dose groups, including control, and no compound related effects were evident. There was, however, compound related toxicity on the dams at 6000 ppm, With decreased ovarian weight and decreased body weight gain during treatment. There were more foetuses/litter at the high dose with supernumerary bones. The percentage of foetuses with incomplete ossification of sternebra and skull bones was increased, compared to controls, at all dose levels (i.e. > 600 ppm). The increased number of misshapen bones at the high dose was also confirmed with submission of additional data (Koëter 1975b). Special Study on Carcinogenicity (See also "Long-term Studies") Mouse Insufficient individual animal data were provided to confirm the results previously summarized. Individual animal data for gross pathological and microscopic examinations are needed to evaluate the carcinogenic potency of carbendazim in mice (Beems et al., 1976). Short-term Study Dog Individual animal data on macroscopic and microscopic observations confirmed the NOEL of 300 ppm (Til et al., 1972). Long-term Studies Rat Insufficient individual animal data were provided to confirm the results previously summarized. Common gross findings in all groups, including control, were pronounced lobular pattern in the liver, "suspected" tumor in lungs, and small testes (males). Individual histopathology data are needed to confirm the absence of a tumourigenic response in rats fed carbendazim for 2 years (Til et al., 1976b). Dog Additional data provided by the manufacturer included individual macroscopic and microscopic evaluations. However, severity of the response was still not identified, nor was it clear that each major organ in each dog had been subjected to a detailed microscopic evaluation. It would appear that all livers and kidneys were examined in each dose group, but beyond that the number of animals examined varied. In many cases no controls were reportedly examined, yet there were one or more dose group animals examined (e.g. trachea, spleen, gall bladder, urinary bladder, testes, uterus, pancreas, brain). Also, there was no indication the heart had been examined macroscopically or microscopically in any animal, other than for organ weight determinations. Of particular concern is the apparent paucity of pathological examination of the testes, with only one out of 16 male dogs reportedly examined. Relative testes weight for high dose males were increased over controls and other dose groups. One male in the high dose group had lower testes weight than the others, less than half the weight, but it similarly was the only male examined microscopically and found to have atrophic tubules and kidney. Therefore, with the exception of liver and kidney, very little can be said about compound related effects (present or absent) on other tissues/organs. Furthermore, data still had not been analysed according to sex/dose and these need to be separated in order to determine if there were any compound related effects on haematology, clinical chemistry or urine analyses by sex and dose. Available data do not support the previous finding of a NOEL in this study without further clarification (Reuzel et al., 1976). COMMENTS Additional data provided to the Meeting alleviated some of the concerns of the 1983 Joint Meeting regarding the reproduction and teratogenic studies on carbendazim. The NOEL of 2000 ppm was confirmed in the rat reproduction study. In separate rat and rabbit teratology studies additional individual animal data verified a NOEL for teratogenicity at 6000 ppm in both studies. The meeting also recognized that there are valid long-term feeding studies and carcinogenicity studies for carbendazim which were utilized in the estimation of the ADI in 1983. However, substantial questions still remain concerning the absence of adequate macroscopic/microscopic records of the pathological examinations in separate rat carcinogenicity (Til et al., 1976b), long-term dog (Reuzel et al., 1976) and mouse carcinogenicity (Beems et al., 1976) studies. In view of its continued concern over the lack of confirmatory laboratory data, the Meeting was unable to consider increasing the ADI. The Meeting reaffirmed the desirability of the additional data identified by the 1983 Joint Meeting. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Rat: 500 ppm in the diet, equivalent to 25 mg/kg b.w. Dog: 100 ppm in the diet, equivalent to 2.5 mg/kg b.w. ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.01 mg/kg b.w. FURTHER WORK OR INFORMATION DESIRED 1. Additional data/information are needed to clarify the apparent discrepancies between the macro- and microscopic findings in the long-term dog and carcinogenicity studies in rats and mice identified in the 1983 and 1985 evaluations. 2. Additional information to elucidate the mechanism of degenerative testicular effects in mammals. 3. Elucidation of the variability of the mutagenicity data. REFERENCES Beems, R.B., Til, H.P., & van der Heijden, C.A. Carcinogenicity study (1976) with carbendazim (99% MBC) in mice. Summary. Report No. R4936 of the Central Institute for Nutrition and Food Research (TNO), Submitted to WHO by BASF (Unpublished). Koëter, H.B.W.M. Effect of Hoe 17411 F (=BAS 3460F) on pregnancy of (1975a) the rat. Report from the Central Institute for Nutrition and Food Research (TNO), submitted by BASF to WHO (Unpublished). Koëter, H.B.W.M. Effect of Hoe 17411 (=BAS 3460F) on pregnancy of the (1975b) New Zealand white rabbit. Report from the Central Institute for Nutrition and Food Research (TNO), submitted by BASF to WHO (Unpublished). Reuzel, P.G.J., Hendriksen, C.F.M., & Til, H.P. Long-term (two-year) (1976) toxicity study with carbendazim in Beagle dogs. Report from the Central Institute for Nutrition and Food Research (TNO), submitted to WHO by BASF (Unpublished). Til, H.P., van der Meulen, H.C., Feron, V.T., Seinen, W. & de Groot, (1972) A.P. Sub-chronic (90-day) toxicity study with W17411 in beagle dogs. Report from Central Institute for Nutrition and Food Research, submitted by BASF to WHO (Unpublished). Til, H.P., Koëter, H.B.W.M., & van der Heijden, C.A. Multigeneration (1976a) study with carbendazim in rats. Report from the Central Institute for Nutrition and Food Research (TNO), submitted by BASF to WHO (Unpublished). Til, H.P., Köllen, C. & van der Heijden, C.A. Combined chronic (1976b) toxicity and carcinogenicity study with carbendazim in rats. Report from the Central Institute for Nutrition and Food Research (TNO), submitted by BASF to WHO (Unpublished).
See Also: Toxicological Abbreviations Carbendazim (EHC 149, 1993) Carbendazim (HSG 82, 1993) Carbendazim (ICSC) Carbendazim (WHO Pesticide Residues Series 3) Carbendazim (Pesticide residues in food: 1976 evaluations) Carbendazim (Pesticide residues in food: 1977 evaluations) Carbendazim (Pesticide residues in food: 1978 evaluations) Carbendazim (Pesticide residues in food: 1983 evaluations) Carbendazim (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental) Carbendazim (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental) Carbendazim (JMPR Evaluations 2005 Part II Toxicological)