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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: the Food and Drug Administration (FDA) Good Laboratory Practice Regulations for Nonclinical Studies (GLP Guidelines) (FDA, 1988)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
during the study, lights were on from 0700h to 1900h. the ranges of average temperature and humidity for these two rooms within each replicate were 65-66 ℉ and 58%-64%, respectively

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on analytical verification of doses or concentrations:
Dose Selection. The dose levels selected for this study were based on
preliminary data furnished by the sponsor (NTP. 1990). The NTP preliminary
study found that doses of 1.250 or 2.500 mg/kg/day d-Camphor given by gavage
were highly toxic. Only one of the ten dams in the 2.500 mg/kg/day group
survived past gd 7. and it had to be euthanized on gd 10. Of the ten dams in the 1.250 mg/kg/day group. only one survived the 10-day treatment: the rest of
the dams either died or were sacrificed moribund on or before gd 10. Ataxia
and lethargy were common in these two groups and convulsions were occasionally
observed. Of the other doses tested (100. 500. and 800 mg/kg/day). only the
800_mg/kg/day dose produced any maternal or fetal toxicity.
Frequency of treatment:
Animals were observed daily before (gd 0-5). during (gd6-19). and after (gd 20-30) dosing for clinical signs of toxicity
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
camphor
Dose / conc.:
400 mg/kg bw/day (nominal)
Remarks:
camphor
Dose / conc.:
800 mg/kg bw/day (nominal)
Remarks:
camphor
No. of animals per sex per dose:
n-13-16 females per group per replicate

Examinations

Maternal examinations:
There were no CAM-related maternal deaths during the study, but two does were removed from the 400 mg/kg/day CAM group because of dosing errors.
Maternal weight gain relative to control does was reduced 13%. 5%. and 59% in the 50, 200. and 400 mg/kg/day CAM groups. respectively. Gravid uterine and absolute and relative maternal liver weights were similar to vehicle control values.
Statistics:
General Linear Models (GLM) procedures were applied for the analyses of variance (ANOVA) of maternal and fetal parameters (SAS Institute. 1989a.b: 1990a.b.c)
Nominal scale measures were analyzed by a x2 test for independence and by a test for linear trend on proportions. When a X2 test showed significant group differences. a onetailed Fisher's exact probability test was used for pair~ise comparisons of CAM and control groups.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food intake was significantly
decreased in the 400 (12%) and 800 (21%) mg/kg/day groups on gd 6 to 9. but
returned to control levels in both groups by gd 9 to 12. There was no
significant effect of 100 mg/kg/day CAM on maternal food consumption
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Relative water intake
in the two groups went from 115% of controls on gd 6 to 9 to 130-136% at the
end of the dosing period. Water consumption in these groups remained 18·32%
above controls through gd 18 to 20. Smaller increases in relative maternal
water intake were noted for 100 mg/kg/day CAM. but a significant effect was
observed only on gd 6 to 9
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
The incidence of hypoactivity/lethargy in the 800 mg/kg/day group fell from 27% (7/26) on gd 6. to 8% (2/26) on gd 7. and finally to 0% on
gd 8.
Details on results:
Both 400 and 800 mg/kg/day CAM produced comparable and consistent
increases in maternal water intake (Figure 4; Table 1). Relative water intake
in the two groups went from 115% of controls on gd 6 to 9 to 130-136% at the
end of the dosing period. Water consumption in these groups remained 18·32%
above controls through gd 18 to 20. Smaller increases in relative maternal
water intake were noted for 100 mg/kg/day CAM. but a significant effect was
observed only on gd 6 to 9. Dose-dependent effects of CAM on maternal food
consumption were also seen. but they were transient and opposite those seen
for water consumption (Figure 3: Table 1). Food intake was significantly
decreased in the 400 (12%) and 800 (21%) mg/kg/day groups on gd 6 to 9. but
returned to control levels in both groups by gd 9 to 12. There was no
significant effect of 100 mg/kg/day CAM on maternal food consumption.
Clinical signs of maternal toxicity were infrequent and generally
confined to the 800 mg/kg/day group. In that group. the most commonly
observed clinical sign was hypoact;vity. which was confined to the first two
days of dosing. The incidence of hypoactivity/lethargy in the 800 mg/kg/day group fell from 27% (7/26) on gd 6. to 8% (2/26) on gd 7. and finally to 0% on
gd 8. The above results indicate that the maternal lowest-observed-adverseeffect
level (LOAEL) for CAM-induced maternal toxicity was ~ 100 mg/kg.
although the magnitude of the effects at this dose was small.

Effect levels (maternal animals)

Dose descriptor:
LOAEL
Effect level:
< 100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The results from this study indicate that 400 mg/kg/day CAM administered orally to pregnant New Zealand White rabbits on gd 6-19 is not developmentally
toxic. These results are consistent with those found after the oral administration of CAM in (Sprague-Dawley) rats on gd 6-15 (NTP. 1991). In that study. doses of 400 mg/kg/day or 800 mg/kg/day CAM had no adverse effect on fetal growth. viability. or morphological development. However. CAM did cause minor maternal toxicity inJthe form of decreased maternal weight gain and altered food and water consumption in rats.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Embryo/fetal development was unaffected by CAM

administration. Results of the uterine examination revealed that the number

of corpora lutea per dam and the number of implantation sites per litter in

the CAM-treated dams were within 99-107% of control values (Table 2). The

number of live fetuses per litter and the average fetal body weight were

likewise unaffected (Table 2).

Applicant's summary and conclusion

Conclusions:
The results from this study indicate that CAM is neither developmentally toxic nor toxic to the does at doses as high as 400 mg/kg/day