Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study equivalent to OECD guidelines
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report Date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Physical state: Colourless liquid
- Storage condition of test material: Stored at room temperature
- Others:
- Label identification: C-661 Inhibited
- Stability: 12 months at room temperature
- Prolonged exposure to light and exposure to free radical initiators and oxidizing agents must be avoided

Test animals

Species:
rat
Strain:
other: Sprague Dawley COBS CD rats
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding laboratories, Inc., Portage, Michigan
- Age at study initiation: 13 wk
- Weight at study initiation: 225-297 g
- Housing: Individually housed in wire mesh cages suspended above cage board
- Diet: Purina certified rodent chow; ad libitum
- Water: Tap water; ad libitum
- Acclimation period: 14 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 0.16 °C
- Humidity (%): 40 %
- Photoperiod (h dark / h light): 12 h dark / 12 h light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solution was prepared with corn oil using magnetic stir plate and bars


VEHICLE: CORN OIL
- Lot/batch no. (if required): May 14 85
- Purity: 100 %
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Presence of vaginal plug referred to as Day 0 of pregnancy
Duration of treatment / exposure:
10 d, from Day 6 to 15 of gestation, inclusive
Frequency of treatment:
Once daily
Duration of test:
25 d
Doses / concentrations
Remarks:
Doses / Concentrations:
0 and 1,000 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
30 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a range-finding study, the test dosage (1,000 mg/kg/d) was selected since it was anticipated to induce some degree of maternal toxicity but one which would not likely affect maternal survival.
- Rationale for animal assignment: Random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: From Day 0 through 20 of gestation


BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 9, 12, 16 and 20
- Mean body weight changes were calculated for each corresponding interval of gestation additionally for Day 6-16, 16-20
and 0-20


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20



Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter
Statistics:
1. The fetal sex ratios were compared by the Chi-square test with Yates' correction factor.
2. The number of litters with malformations and developmental variations were compared by Fisher's Exact Test
3. The numbers of early and late resorptions, dead fetuses and postimplantation losses were compared by the Mann-Whitney U-test
4. Mean numbers of corpora lutea, total implantations, viable fetuses, mean fetal and maternal body weights, and maternal body weight gain at each interval were analyzed by a one-way ANOVA and Dunnett's test
Indices:
- Fetal sex ratios, number of litters with malformations and developmental variations, numbers of early and late resorptions, dead fetuses and postimplantation losses
- Numbers of corpora lutea, total implantations and viable fetuses
Historical control data:
Yes, WlL historical control data appended in the report

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
- Two rats died due to an intubation error
- Slight decrease in mean body weight gain was observed during gestation Day 12-16
- Significant decrease in mean body weight gain was noticed during gestation Day 6-16
- Clinical signs of toxicity such as salivation prior to and following dosing; urogenital matting and hair loss from various body surfaces were observed

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No substance related effects observed

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The test substance produced substantial maternal toxicity at a dose level of 1,000 mg/kg bw/day but did not induce a teratogenic or embryotoxic effect in rats.
Executive summary:

The study was conducted equivalent or similar to OECD Guideline No. 414 in compliance with Good Laboratory Practices. The test substance was administered orally, admixed in corn oil, to one group of 30 bred rats at a dosage level of 1,000 mg/kg bw/day, from gestation Day 6 through 15. A control group consisting of 30 rats received the corn oil vehicle on a comparable regimen. Throughout gestation, all rats were observed twice daily for signs of toxicity. Body weights were recorded at appropriate intervals. All surviving animals were sacrificed on gestation Day 20 for the scheduled Cesarean section. Fetuses were sexed, weighed and examined for external, skeletal and soft tissue anomalies and developmental variations.

Clinical signs of toxicity such as salivation prior to and following dosing, urogenital matting and hair loss from various body surfaces were observed. Mean body weight gains were significantly reduced over the entire treatment period. No embryotoxic effects were apparent. Developmental variations were not remarkably different between the control and test material group. No statistically significant or biologically meaningful differences occurred between the control and treatment regarding the occurrence of malformations.