THIOPHANATE-METHYL JMPR 1975
Explanation
This systemic fungicide of the benzimidazole group was evaluated
by the Joint Meeting in 1973 and an ADI of 0.08 mg/kg/day was
recommended (FAO/WHO, 1974). Because an uncertain proportion of
residues from thiophanate-methyl applications consist of
methyl-benzimidazole carbamate (MBC), for which an ADI has not been
established, only temporary tolerances could be recommended.
Recommendations were made for a number of vegetable food crops,
including some items for animal feeding purposes.
Further information on the nature and fate of thiophanate-methyl
in meat, milk and eggs was required before temporary tolerances could
be confirmed.
Since the previous evaluation, additional data have become
available and are summarized in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Tissue distribution, excretion in urine and faeces of
14C-labelled thiophanate-methyl (phenyl - 14C) were investigated in
female rats after administration of a dose level calculated to be
equivalent to 45 mg/kg in the diet during a period of 20 days. An
average of 89.60% of the 14C-TM radioactivity was excreted per day,
54.27% in urine and 35.38% in the faeces. After final administration
diminution of radioactivity was fairly rapid in all tissues with the
exception of thyroid, adrenal glands and liver in which organs it
temporarily persisted. In addition to thiophanate-methyl the main
metabolites or breakdown products identified in the faeces were
5-hydroxy methylbenzimidazole, 4-hydroxy thiophanate-methyl as well as
4-hydroxy-dimethyl-4,4'-O-phenylene bis-allophanate. In the urine the
main metabolite identified was 5-hydroxy methyl benzimidazole (Kosaka
et al., 1975).
TOXICOLOGICAL STUDIES
Special studies
On effect on male reproductive system
Thiophanate and thiophanate-methyl were administered by gastric
intubation over a 5-day period in doses of 0, 295, 192 mg/kg
respectively to groups of mature, male Swiss-Webter mice to
investigate the in vivo effects on sex: organs, adrenal glands as
well as the ability of the prostate gland to assimilate (3H)
testosterone. Upon sacrifice, body, testes, prostate, seminal
vesicles, and adrenal glands were weighed and the activity of
testosterone was measured in the prostate glands upon removal from
animals killed 5 minutes after a single dose of an intraperitoneal
injection of (1,2-3H) testosterone 24 hours after final dose of these
fungicides. The absolute weight of the adrenal glands was
significantly increased in both groups; absolute weight of prostate
was significantly increased in the group given thiophanate-methyl
while body weights were slightly increased. No effect upon weight of
the seminal vesicles was observed, The testes and adrenals / body
weight ratios were significantly increased in both groups, the
relative weight of prostate was significantly enhanced in the
thiophanate-methyl group, while the relative weights of seminal
vesicles were comparable to those of controls.
The uptake of (3H) testosterone and its metabolism to (3H)
dihydrotestosterone by the anterior prostate gland was not affected.
Histological examination of the testes revealed no effect on
spermatogenesis, and no evidence of sterile tubules or morphological
changes of the Leydig cells were observed (Thomas and Schein, 1974).
COMMENTS
New data on the metabolism and on affects on the male
reproductive system were submitted in response to the request for
further work set forth by the 1973 Meeting. It was noted that
thiophanate-methyl had no effect on the uptake and metabolism of
testosterone and spermatogenesis in male mice. Based on the new data
the previously allocated acceptable daily intake was reconfirmed.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Mouse: 160 ppm in the diet equivalent to 23 mg/kg bw.
Rat: 160 ppm in the diet equivalent to 8 mg/kg bw.
Dog: 50 mg/kg bw/day.
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.08 mg/kg bw.
RESIDUES IN FOOD AND THEIR EVALUATION
FATE OF RESIDUES
In chicken and eggs
New information on chicken feeding trials has been provided
(Nippon Soda Co., 1975), Laying white Leghorn chickens were fed
rations containing thiophanate-methyl at 10 mg/kg and 50 mg/kg levels
for 30 days. In addition the birds were treated with daily doses of
measured amounts of radioactive thiophanate-methyl, the amounts of
which were related to the amount of unlabelled thiophanate-methyl
through careful individual weighings and food consumption controls.
Excreta and eggs were collected throughout the experimental
period and analysed individually for total 14C-content. At the end of
the 30 days feeding period animals were sacrificed and samples of
muscle, fat, kidney and liver were obtained for radio-analysis. All
14C-activities were expressed as equivalent quantities of unaltered
thiophanate-methyl. Results are given in Table 1.
In no case had the treatment with thiophanate-methyl any
deleterious effects an either the chickens or the egg production
during the experiment.
Total residues of 14C-containing material in eggs reached a
plateau after three days of feeding, after which daily averages
corresponding to 0.035 and 0.115 mg/kg of thiophanate-methyl were
found in the two feeding groups. The highest levels in individual eggs
were 0.080 and 0.377 mg/kg, respectively.
Liver and kidney tissues from both test groups contained
detectable amounts of 14C-activity. The average contents at the 10
mg/kg feeding level were 0.31 mg/kg in liver and 0.14 mg/kg in kidney
and at the 50 mg/kg level 1.20 mg/kg and 0.72 mg/kg, respectively.
Muscle and fat from both groups contained no detectable 14C-activity.
It is noted that the excreta samples contained the majority of
the radioactivity detected. An average of 5.42 mg/kg was found in the
10 mg/kg feeding group and 23.9 mg/kg was found in the 50 mg/kg group.
TABLE 1. Thiophanate-methyl residues in eggs and chicken tissues
Residues, 14C expressed as mg thiophanate-methyl
per kg, from feeding level for 30 days of
Sample 10 mg/kg 50 mg/kg
Liver 0.31 (0.18-0.45) 1.20 (0.59-1.59)
Kidney 0.14 (0.10-0.20) 0.72 (0.42-1.22)
Muscle 0.00 (0.00-0.00) 0.00 (0.00-0.00)
Fat 0.035(0.023-0.054) 0.00 (0.00-0.00)
Eggs1 5.42 (2.93-8.99)2 0.115(0.050-0.187)2
Excreta1 - 23.87 (13.01-35.65)
1 Figures are averages from groups of five chickens.
2 Highest individual results for one egg were 0.080 at 10 mg/kg
feeding level and 0.377 mg/kg at the 50 mg/kg level.
APPRAISAL
New data on thiophanate-methyl residues in chicken tissues and
eggs have been made available. Feeding levels well above the maximum
rates which can be expected in practice were found not to give rise to
any detectable residues in meat and fat of chickens. In eggs residues
near to the limit of detection of conventional gas chromatographic
methods of analysis were found, while liver and kidneys showed
residues up to 0.45 mg/kg.
The latter residues may be expected to be eliminated after
withdrawal of the thiophanate-methyl feeding. However, the length of a
withdrawal period cannot be estimated owing to lack of experimental
details.
RECOMMENDATIONS
The recommendations made in 1973 are confirmed as being no longer
temporary and amended as follows:
MAXIMUM RESIDUE LIMITS
Commodity Limit
mg/kg*
Meat and fat of chicken 0.02**
* Measured as the sum of thiophanate-methyl and carbendazim and
expressed as the latter.
** At or about the limit of determination.
FURTHER WORK OR INFORMATION
No information required or desirable other than items listed in
1973 (FAO/WHO, 1974a, p. 41) with exception of items 1 and 2 of
desirable information.
REFERENCES
Kosaka, S., Fujino, A., Tanove, T. and Mitsui, B. (1975) The balance
and metabolic study of thiophanate-methyl on rats. Unpublished report
from the Nisso Institute for Life Science, Oiso, Kanagawa, submitted
to WHO by Nippon Soda Co.
Nippon Soda Company, Limited. (1975) Further work and information on
thiophanate-methyl for FAO/WHO JMPR 1975, July.
Thomas, J. A. and Schein, L. (1974) Effects of thiophanate and
thiophanate-methyl on the male reproductive system of the mouse.
Toxicol. Appl. Pharmacol., 30:129-133.