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    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
    (KoŽter 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 (KoŽter 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).

    KoŽter, 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).

    KoŽter, 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., KoŽter, 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., KŲllen, 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 (PDS)
       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)