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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:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guidline Test with GLP

Data source

Reference
Reference Type:
other: Provided by ECHA
Title:
Unnamed
Year:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
liquid: viscous
Details on test material:

No data but ECHA think it's identical with our substance.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Good Laboratry Practice

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
In the range finding test, the potential maternal toxicity and developmental toxicity of the test article, CN-1985, were evaluated. The test article in the vehicle, Mazola® corn oil, was administered to five groups of eight bred Crl:CD®(SD)BR rats once daily from gestation days 6 through 19. Dosage levels were 62.5, 125, 250, 500 and 1000 mg/kg/day administered at a dose volume of 5 ml/kg. A concurrent control group composed of eight bred females received the vehicle, corn oil, on a comparble regimen at 5 ml/kg.
The route of administration was oral by gastric intubation. Clinical observations, body weights and food consumption were recorded. On gestation day 20, a laparohysterectomy was performed on all animals. The uteri and ovaries were examined and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Mean gravid uterine weights and net body weight changes were calculated for each group. The fetuses were weighed, sexed and examined for external malformations and variations.
All animals survived to the scheduled necropsy on gestation day 20. Clinical signs observed in the 125, 250, 500 and 1000 mg/kg/day groups included several behavioral findings (animals rubbing their faces on the sides and bottom of the cage, pawing at the cage surface and/or air, clonic tremors of the forelimbs and/or excessive grooming) and salivation immediately following dose administration. Mean body weights, body weight gains and food consumption in the 62.5, 125, 250, 500 and 1000 mg/kg/day groups were unaffected by test article administration. At the scheduled necropsy on gestation day 20, no treatment-related internal findings were observed at any dose level.
Intrauterine parameters were unaffected by treatment in the 62.5, 125, 250, 500 and 1000 mg/kg/day groups. No external malformations or developmental variations were observed for any fetuses in this study.
Based on the test, dose levels of 125, 500 and 1000 mg/kg/day were selected for a definitive developmental toxicity study of CN-1985 in rats.

The potential maternal toxicity and developmental toxicity of CN-1985 were evaluated. The test article, CN-1985, in the vehicle, Mazola® corn oil, was administered to three groups of 25 bred Crl:CD®l(SD)BR rats once daily from gestation days 6 through 19. Dosage levels were 125, 500 and 1000 mg/kg/day administered at a dose volume of 5 ml/kg. A concurrent control group composed of 25 bred females received the vehicle, Mazola® corn oil, on a comparable regimen at 5 ml/kg. The route of administration was oral by gastric intubation.

Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
no data
Duration of treatment / exposure:
8-19 days
Frequency of treatment:
Dosing regime: 7 days/week
Duration of test:
once daily from gestation days 6 through 19
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
500 mg/kg
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
125 mg/kg
Basis:
nominal in diet
No. of animals per sex per dose:
no data
Control animals:
yes, concurrent vehicle
Details on study design:
no data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data
- Cage side observations checked in table were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no data

BODY WEIGHT: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: No data
Ovaries and uterine content:
On gestation day 20, a laparohysterectomy was performed on all animals.
The uteri and ovaries were examined and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded.
Fetal examinations:
Yes
Statistics:
no data
Indices:
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
AII maternal animals survived to the scheduled necropsy on gestation day 20. Treatment related clinical signs included salivation immediately following dosing in all 3 treatment groups between gestation days 10 and 19. Changes in general appearance was also noted following dosing during the same period in the 125 mg/kg, 500 mg/kg and 1000 mg/kg treatment groups with animal rubbing their faces on the cage surface, and excessive grooming and clonic tremors of the forelimbs. In the 500 mg/kg and 1000 mg/kg treatment groups, animals were observed to erratically paw the cage following dosing between gestation days 11and 19. AII these findings had subsided by 1 hour post dosing. Other clinical signs such as hair loss on various body surfaces occurred also in the control group and were not indicative of being treatment related. At necropsy there were no macroscopic findings thought to be treatment related.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Effects on fetus - Gross:
Gravid litter weights, litter size and fetal body weights were unaffected by the test substance administration. In the 500 mg/kg dose group one fetus had bilateral anophthalmia and one fetus had unilateral anoph!halmia. No other external malformations and no external developmental variations were observed in fetuses at any dose levels.
Effects on fetus - Soft tissue:
In the 500mg/kg dose group one fetus had hydrocephaly consisting of increased cavitation of both lateral ventricles and the third ventricle. One fetus in the 1000 mg/kg group had a retroesophageal aortic arch. No other soft tissue malformations were noted.
Effects on fetus - Skeletal:
No skeletal malformations were observed in fetuses at any dose level.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

No data

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, the NOAE (no-observed-adverse-effect level) for maternal toxicity and developmental toxicity was considered to be 1000 mg/kg/day.
Executive summary:

The potential maternal toxicity and developmental toxicity of CN-1985 were evaluated. The test article, CN-1985, in the vehicle, Mazola® corn oil, was administered to three groups of 25 bred Crl:CD®l(SD)BR rats once daily from gestation days 6 through

19. Dosage levels were 125, 500 and 1000 mg/kg/day administered at a dose volume of 5 ml/kg. A concurrent control group composed of 25 bred females received the vehicle, Mazola® corn oil, on a comparable regimen at 5 ml/kg. The route of administration was oral by gastric intubation. Clinical observations, body weights and food consumption were recorded. On gestation day 20, a laparohysterectomy was performed on all animals.

The uteri and ovaries were examined and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Mean gravid uterine weights and net body weight changes were calculated for each group. The fetuses were weighed, sexed and examined for external, soft tissue and skeletal malformations and variations.

Al maternal animals survived to the scheduled necropsy on gestation day 20. Clinical signs observed in the 125, 500, and 1000 mg/kg/day groups included several changes in general appearance and behavior (animals rubbing their faces on the sides and

bottom of the cage, erratic pawing of the cage sides and bottom, clonic tremors of the forelimbs and/or excessive grooming) and salivation immediately following dose administration. However, al of these findings had subsided by one-hour post-dosing and

no dose relationship was apparent. Therefore, they were not considered to be signs of systemic toxicity, but perhaps an aversion to the taste of the test article or a local irritative effect. Body weight gains and food consumption were unaffected by test article

administration at all dose levels.

Intrauterine growth and survival were unaffected by test article administration at dose levels of 125, 500 and 1000 mg/kg/day. The fetal malformations observed in the treated groups were considered to be spontaneous in origin. The fetal developmental variations

noted in this study were observed infrequently or at a similar frequency in the control group.

 

Based on the results of this study, the NOAE (no-observed-adverse-effect level) for maternal toxicity and developmental toxicity was considered to be 1000 mg/kg/day.