Registration Dossier

Toxicological information

Toxicity to reproduction: other studies

Currently viewing:

Administrative data

Endpoint:
toxicity to reproduction: other studies
Adequacy of study:
other information

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2013

Materials and methods

Test animals

Species:
rat
Strain:
Long-Evans
Sex:
female

Administration / exposure

Route of administration:
oral: gavage
Duration of treatment / exposure:
Continuous from weaning, through young adulthood, mating and lactation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 500, 1000 mg/kg bw/d
Basis:

No. of animals per sex per dose:
8-12 (females only)
Control animals:
yes
Details on study design:
mated with untreated males

Results and discussion

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day
Sex:
female
Basis for effect level:
other: fertility
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Sex:
female
Basis for effect level:
other: fertility

Observed effects

Liver weight was increased at 1000 mg/kg bw/d with no effect on body weight. The percentage of females delivering live pups was reduced by more than 50 % at 500 mg/kg bw/d and by 90 % at 1000 mg/kg bw/d in the absence of overt toxicity, whereas the ages at vaginal opening and first oestrous, oestrous cyclicity and mating indices were not significantly affected. The litter sizes from mated females were also significantly reduced at 500 and 1000 mg /kg bw/day. Many females in the 500 and 1000 mg/kg bw/day groups that were pregnant, but did not deliver pups, displayed a constant leucocytic, pregnancy-like vaginal lavage for 21–29 days (indicator of pregnancy or pseudo-pregnancy) and blood was detected in the vagina at or after midpregnancy, suggesting miscarriage, although no live or dead pups were recovered.

Any other information on results incl. tables

On GD 13, several of the DBP-treated females had ovaries that contained grossly visible haemorrhagic corpora lutea and reduced serum progesterone levels, but this was statistically significant only at the highest level. Serum progesterone levels in pregnant females with dead foetuses were very low, approaching those seen in nonpregnant females. Ex vivo progesterone production in ovarian cultures from females with live foetuses was significantly decreased in the two highest dose groups, while oestradiol production was increased.

Applicant's summary and conclusion

Conclusions:
The NOAEL was measured at 250 and the LOAEL at 500 mg/kg bw/d.
Executive summary:

In this study (Gray et al. 2006) the NOAEL for fertility in female rats was 250 mg/kg bw/d and the LOAEL 500 mg/kg bw/d, based on decreased fertility in the P0 generation.