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).