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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Only pregnant females were treated. The original study was not available for review.

Data source

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Year:
1973
Report date:
1973
Reference Type:
secondary source
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
US Food and Drug Administration-sponsored study to investigate reproductive and developmental toxicity in rats, mice and hamsters. Test substance was administered to pregnant females only.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
FDA 71-28
IUPAC Name:
FDA 71-28
Constituent 2
Reference substance name:
Oil of nutmeg
IUPAC Name:
Oil of nutmeg

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Test animals were individually housed in mess-bottom cages in a temperature and humidity-controlled room.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
No details available.
Details on mating procedure:
Adult female Wistar rats were mated with untreated young adult males and observation of vaginal sperm plugs was considered day 0 of gestation.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Day 6 to Day 15 of gestation
Frequency of treatment:
Once per day
Details on study schedule:
No details available
Doses / concentrationsopen allclose all
Dose / conc.:
3 mg/kg bw/day (actual dose received)
Dose / conc.:
56 mg/kg bw/day (actual dose received)
Dose / conc.:
260 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
22-23 per dose
Control animals:
yes, concurrent vehicle
Details on study design:
No details available.
Positive control:
Yes. 250 mg/kg/day aspirin.

Examinations

Parental animals: Observations and examinations:
Maternal body weights were recorded on days 0, 6, 11, 15, and 17 of gestation. Females were observed daily for appearance and behavior. Food consumption and body weight were monitored to eliminate any abnormalities that may be associated with anorexia in pregnant females.

On Day 17 all dams were subjected to Caesarian section and the number of implantation sites, resorption sites, live fetuses, dead fetuses, and body weight of live pups were recorded.

Gestation index, mortality, number of implantation sites, number of corpora lutea, litter size and weights, sex and sex ratio of pups, and gross abnormalities to pups were reported. One-third of fetuses of each litter underwent detailed visceral examination at 10x magnification. The remaining two-thirds were stained with alizarin red S dye/KOH and examined for skeletal defects.
Oestrous cyclicity (parental animals):
Not examined
Sperm parameters (parental animals):
Not examined
Litter observations:
On Day 17 all dams were subjected to Caesarian section and the number of implantation sites, resorption sites, live fetuses, dead fetuses, and body weight of live pups were recorded.

Gestation index, mortality, number of implantation sites, number of corpora lutea, litter size and weights, sex and sex ratio of pups, and gross abnormalities to pups were reported.
Postmortem examinations (parental animals):
The urogenital tract of each dam was examined for anatomical abnormalities.
Postmortem examinations (offspring):
One-third of fetuses of each litter underwent detailed visceral examination at 10x magnification. The remaining two-thirds were stained with alizarin red S dye/KOH and examined for skeletal defects.
Statistics:
None
Reproductive indices:
No information
Offspring viability indices:
No information

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

The administration of up to and including 260 mg/kg bw/day of test article FDA 71-28 to pregnant rats on days 6 through 15 of gestation had no
effects on nidation, reproduction, or maternal survival.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 260 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: No adverse effects observed

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

The administration of up to and including 260 mg/kg bw/day of test article FDA 71-28 to pregnant rats on days 6 through 15 of gestation had no
effects on any measured foetal parameter.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 260 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effects observed

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a limited summary of a one-generation reproduction study with Wistar rats, there was no evidence of reproductive toxicity up to and including the highest dose tested, 260 mg/kg/day. The study pre-dates GLP and was not consistent with current guideline requirements for reproductive toxicity.