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

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In New Zealand White rabbits, cyromazine produced severe maternal toxicity when administered
orally at a dose of at 60 mg/kg bw per day during gestation, as shown by clinical signs of toxicity, one
abortion, severe body-weight loss and decreased food consumption. Slight maternal toxicity (decreased
body-weight gain and feed consumption) was also observed at 30 mg/kg bw per day. As a result of the
severe maternal toxicity, postimplantation losses and resorptions increased at 60 mg/kg bw per day. At
this dose, the number of fetuses (litters) with external malformations (not considered to be treatmentrelated),
and the number of fetuses with vertebral anomalies were also increased. The NOAEL for
maternal toxicity was 30 mg/kg bw per day considering that body-weight loss was marginal at that
dose. The NOAEL for developmental toxicity was also 30 mg/kg bw per day (Nemec, 1985).
A study was undertaken in order to investigate the suspected deficiency in the male that sired
two fetuses with a rare malformation, cyclopia, in two groups in the previous study. A total of four
male New Zealand White (BUK:(CRL)NZWfBR) rabbits were used for artificial insemination, and
sperm morphology and semen quality were evaluated. The male that had been used in the previous
study of teratology was included to investigate whether this male would again produce fetuses showing
cyclopia and/or related head effects. Three groups of at least 56 female rabbits were inseminated.
Females in the ‘sham’ control group were ‘sham’ gavaged once daily from days 7 to 19 of gestation (a
stainless-steel dosing cannula was used, but no material was administered). The females in the other
two groups were not dosed. Clinical observations, body weights and food consumption were recorded
throughout the study. On day 29 of gestation, all dams were killed and uterine contents examined.
All fetuses were weighed, sexed and examined for external, skeletal and soft tissue anomalies and
developmental variations. The study was conducted according to the principles and practices of GLP
(with QA certificate).
Sixteen females died during the experimental period; 9, 5 and 2 from control group 1 (group
size, 56), control group 2 (group size, 59) and the ‘sham’ control group (group size, 56), respectively.
The cause of death for most of these animals was attributed to a suspected bacterial infection. There
were no differences in clinical observations between the groups. A total of 43, 48 and 45 gravid
females were available for examination at study termination from the control group 1, control group
2 and ‘sham’ control groups, respectively. There were no apparent differences between the groups in
maternal body-weight gain or food consumption. There were no group differences in reproductive
parameters.
Although cyclopia per se was not observed in this study, a number of rare and severe defects
of the head and related structures occurred (Table 34). These included hydrocephaly, acrania, cleft
palate (all observed in different fetuses) and one fetus with multiple head anomalies from male
No. 2749. Defects of the head (hydrocephaly, acephaly and macroglossia) also occurred in fetuses
sired by other males. In addition, other malformations observed in this study had been seen in the
previous study of teratology. These included spina bifida, fused or severely malaligned sternebrae,
hydrocephaly, short tail, heart and/or great vessel anomalies, vertebral defects, rib anomalies, midline
closure defects, kidney anomalies and diaphragmatic hernia.
Table 34. Incidence of malformations in control groups of (BUK:(CRL)NZWfBR) New Zealand
White rabbits
Type of malformation
No. of fetuses affected (No. of litters affected) a
Control group 1 Control group 2 Sham control group
Total No. examined 182 (33) 233 (39) 186 (37)
External malformations 1 (1) 6 (6) 7 (5)
Conjoined twins 0 (0) 1 (1) 0 (0)
Acephaly 0 (0) 1 (1) 0 (0)
CYROMAZINE X-X JMPR 2006