Pesticide residues in food — 2007: Toxicological ... - ipcs inchem

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can occur in untreated mice, including apoptotic-like bodies, degeneration, depletion and asynchrony
of spermatids, and tubular atrophy. Secondary to these testes effects, exfoliated germ cells and debris
were found in the epididymides at increased incidences only at the highest doses of 2000 ppm (28-
day study) or 6000 ppm (13-week study). The NOAEL for testes effects in mice after 13 weeks of
treatment was 1000 ppm, equivalent to 161 mg/kg bw per day.
No data were available to directly evaluate the potential for carcinogenicity of 1,2,4-triazole.
Available data on mutagenicity data were limited (Salmonella assays and a report of a study
of chromosomal aberration in rat bone-marrow cells), but they do not indicate any activity. A
large number of parent triazole-derivative pesticides had been classified as carcinogens (most
also are non-mutagenic), but the relevance of that finding to expected effects of free triazole may
be limited. The types of tumours associated with exposure to the parent chemicals were most
commonly hepatocellular adenomas/carcinomas in mice. None of the tumour types were clearly
associated with the proportion of free triazole formed in the available studies of metabolism
in rats and 1,2,4-triazole showed little or no effects in the livers of rats and mice in short-term
studies.
In a two-generation study of reproductive toxicity in rats, retardation of body-weight gain was
the most sensitive end-point in parent animals. At 250 ppm (equivalent to 16 mg/kg bw per day),
body weights of the F1 males were slightly but significantly lower than those of rats in the concurrent
control group. In some respects this is in contrast to the results of the two short-term studies of
toxicity in rats, where 500 ppm was a clear NOAEL with regard to body-weight reduction in males.
In females, body weights were lower only at 3000 ppm. Absolute brain weights were decreased in
males and females of the parental generation receiving 3000 ppm. At this dose also, microscopic
lesions such as mild to moderate degeneration and necrosis were evident in the cerebellum. The lesions
were identical to that observed in the short-term study of combined toxicity and neurotoxicity
in rats and are characterized by variable loss of Purkinje cells, white matter degeneration and gliosis.
The white matter tract degeneration presented as nerve fibre (axonal) swelling or fragmentation often
with digestion chambers containing debris and macrophages. No similar changes were noted in the
rats at 500 ppm.
In the two-generation study of reproduction, at a feed concentration of 500 ppm, all parameters
of reproduction were similar to those of rats in the control group through two generations. Fertility
was significantly decreased only at the highest feed concentration of 3000 ppm (equivalent to 218
mg/kg bw per day in females). Two out of 30 females delivered viable offspring (one pup each); there
were only three implantation sites compared with 265 in the control group. No effects were observed
on the length or the number of the estrous cycles. No treatment-related effects on sperm parameters
were observed at any dose, including the males at 3000 ppm. In parental females at 3000 ppm, the
number of total corpora lutea and the ovary weights were increased, and a dilatation of uterine horns
was found in some rats.
Two studies of developmental toxicity in rats (Renhof, 1988a, 1988b) demonstrated maternal
toxicity (retarded weight gain) at 100 mg/kg bw or higher, developmental toxicity (increased incidence
of runts, lower fetal and placental weights, and a higher incidence of minor skeletal deviations)
at 100 mg/kg bw or higher, and an increased incidence of malformations at 200 mg/kg bw. The maternal
and the developmental NOAEL in rats was 30 mg/kg bw per day.
In the study in rabbits (Hoberman, 2004), lower body-weight gain and clinical signs of systemic
toxicity such as excess salivation, hyperpnoea and ptosis were evident at 45 mg/kg bw per
day. Five out of 25 dams were sacrificed in a moribund condition at this dose. Developmental effects
included lower weights of fetuses at 45 mg/kg bw per day, and there were a few alterations of the
urogenital system which occurred in several fetuses at the maternally toxic dose of 45 mg/kg bw
per day. Similar to rats, the maternal and the developmental NOAEL was 30 mg/kg bw per day in
rabbits.
DIFENOCONAZOLE 201–272 JMPR 2007