Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

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In a study of prenatal developmental toxicity, groups of 20 naturally bred New Zealand white
[Hra:(NZW)SPF] rabbits were given technical-grade thiophanate-methyl (purity, 97.28–97.57%) at
a dose of 0, 5, 10, 20 or 40 mg/kg bw per day in 1% methylcellulose by gavage on days 6–28 of
gestation, the day of mating being considered to be day 0. The rabbits were sacrificed on day 29 of
gestation. The does were observed for viability, clinical signs, body weight, food consumption, and
the number of corpora lutea and the thoracic, abdominal, and pelvic viscera were examined. Their
uteri were excised and examined for the number and distribution of implantation sites, live and dead
fetuses and early and late resorptions. The fetuses were observed for sex, body weight and gross
external, visceral, brain and skeletal alterations.
At a dose of 20 mg/kg bw per day, there was a transient but significant reduction in maternal
body-weight gain and statistically significant reduced absolute and relative feed consumption. At a dose
of 40 mg/kg bw per day, faecal output was reduced, in conjunction with significantly reduced maternal
body-weight gain and absolute and relative feed consumption; however, body-weight gain and food
consumption recovered after the initial week of dosing. It is likely that the observed reduction in feed
consumption during this period contributed to the observed decreases in body weight, body-weight
gain and faecal output. There appeared to be an increased incidence of resorptions in rabbits treated
with 40 mg/kg bw per day, the numbers of litters with ≥ 20% resorptions per litter being 2 of 20 in the
controls, 2 of 17 at 5 mg/kg bw per day, 2 of 18 at 10 mg/kg bw per day, 0 of 17 at 20 mg/kg bw per
day, and 5 of 20 at 40 mg/kg bw per day. The historical control range for dead or resorbed conceptuses
per litter was 0–18.3%. In the fetuses, the dose of 40 mg/kg bw per day caused a significant increase in
the average for thoracic ribs (supernumerary ribs), with associated significant increases and decreases
in the averages for thoracic and lumbar vertebrae, respectively. In addition, fetal body weights were
slightly reduced (about 9%; not statistically significant) at the dose of 40 mg/ kg bw per day (Table 8).
The NOAEL for maternal toxicity was 10 mg/kg bw per day on the basis of reduced feed
consumption and reduced body-weight gain at 20 mg/kg bw per day and above. The NOAEL for
developmental effects was 20 mg/kg bw per day, on the basis of increased incidence of supernumerary
thoracic ribs and decreased fetal weights at 40 mg/kg bw per day, the highest dose tested. Thiophanatemethyl
was not selectively toxic to embryo or fetal viability, growth or morphology and was not
teratogenic (York, 1997b).
Table 8. Selected maternal and reproductive findings in a study of prenatal developmental
t oxicity in rabbits given thiophanate-methyl by gavage
Parameter
Body-weight gain
(kg), days 6–9
Body-weight gain
(kg), days 12–15
Body-weight gain
(kg), days 6–29
Feed consumption
(g/day), days 6–9
Feed consumption
(g/day), days 6–29
No. of dams
pregnant/with live fetuses
Mean No. of corpora
lutea/implantations
Dose (mg/kg bw per day)
0 5 10 20 40
0.08 0.07 0.09 0.06 –0.11**
0.09 0.11 0.08 0.04* 0.03**
0.41 0.44 0.44 0.36 c 0.10**
180.7 175.0 182.4 152.3 58.8**
159.0 160.6 160.9 140.7* 89.3**
20/19 a 17/17 19/18 b 17/17 20/19 a
10.3/9.3 9.4/8.9 9.9/9.7 8.6/7.6 9.9/9.2
THIOPHANATE-METHYL X-X JMPR 2006