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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
Study period:
February 7-24, 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Not a guideline study per se. GLP compliance. Full documentation
Justification for type of information:
Read across from structurally similar substance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Females were mated with males of the same strain and source. A block design was used to assign 30 mated females to controls and each of three dosing levels. Doses were selected based on a range finding study where the highest dose was 3000 mg/kg/day and no maternal or developmental toxicity was observed. The test material was prepared weekly. Analysis of dosing preparations stored for 10 days at room temperature verified the stability of the dosing preparation for at least a week. Dosing was done by intragastric intubation through needles at a volume of 10 m?/kg. Dosing was done on gestation days 6 through 15. A vehicle control was included in the study design. The concentration of the dosing preparation was confirmed analytically. Animals were observed twice daily for mortality and signs of overt toxicity. Clinical observations were made from gestation days - 20. Individual body weights were recorded on gestation days 0, 6, 9, 12, 16 and 20. Individual food consumption was recorded concurrent with the body weighing days. Food consumption was calculated. On gestation day 20 all surviving animals were euthanized and immediately examined by cesarean section. The uterus and overies were exposed and examined. The uterus was weighed. The location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The abdominal and thoracic cavities and organs were examined for grossly evident morphological changes. Uteri from nongravid females were placed in 10% ammonium sulfide solution for detection of implantations. Individual fetuses were weighed, sexed, and examined for external malformations and variations. Approximately one-half of the fetuses were placed in Bouin's solution for subsequent soft-tissue examination using hte Wilson razor-blade sectioning technique. The remainder of the fetuses were prepared for skeletal examination. All gross, visceral and skeletal alterations observed were classified as malformations or developmental variations. Treatment and control groups were subjected to appropriate statistical comparison.
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): SAR 33-55
- Molecular formula (if other than submission substance): no data
- Molecular weight (if other than submission substance): no data
- Substance type: organic
- Physical state: clear liquid
- Analytical purity: 31.2% active ingredient
- Impurities (identity and concentrations): 64.8% water
- Purity test date: February 16, 1994
- Lot/batch No.: 9401
- Expiration date of the lot/batch: February 1995
- Stability under test conditions: stable
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: Charles River Crl:CD VAF/Plus
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Michigan
- Age at study initiation: 12.5 weeks
- Weight at study initiation: 243-312g
- Fasting period before study: no data
- Housing: individually in suspended stainless steel wire mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 71-71 degrees F
- Humidity (%): 48-59%
- Air changes (per hr): controlled
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: February 7 To: February 24

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Purina Certified Rodent Chow #5002
- Storage temperature of food: room temperature


VEHICLE
- Justification for use and choice of vehicle (if other than water): vehicle used but no data
Analytical verification of doses or concentrations:
yes
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
- Length of cohabitation: until evidence of copulatory plug (7 days maximum)
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug
- Any other deviations from standard protocol: no data
Duration of treatment / exposure:
On gestation days 6-15
Frequency of treatment:
Daily
Duration of test:
Until gestation day 20
Doses / concentrations
Remarks:
Doses / Concentrations:
150, 1500 and 3000 mg/kg/day
Basis:
analytical conc.
No. of animals per sex per dose:
30 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: prior range finding study (study 715-001)
- Rationale for animal assignment (if not random): random block
- Other:

Examinations

Maternal examinations:
Animals were observed twice daily for mortality and signs of overt toxicity. Clinical observations were made from gestation days - 20. Individual body weights were recorded on gestation days 0, 6, 9, 12, 16 and 20. Individual food consumption was recorded concurrent with the body weighing days. Food consumption was calculated. On gestation day 20 all surviving animals were euthanized and immediately examined by cesarean section.
Ovaries and uterine content:
The uterus and overies were exposed and examined. The uterus was weighed. The location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The abdominal and thoracic cavities and organs were examined for grossly evident morphological changes. Uteri from nongravid females were placed in 10% ammonium sulfide solution for detection of implantations.
Fetal examinations:
Individual fetuses were weighed, sexed, and examined for external malformations and variations. Approximately one-half of the fetuses were placed in Bouin's solution for subsequent soft-tissue examination using hte Wilson razor-blade sectioning technique. The remainder of the fetuses were prepared for skeletal examination. All gross, visceral and skeletal alterations observed were classified as malformations or developmental variations.
Statistics:
Treatment and control groups were subjected to appropriate statistical comparison. Dunnett t-test for body wight, food consumption, numbers of corpora lutea, total implantations, live fetuses and mean fetal body weights. Chi-square or Fishers test for male to female sex ratios and proportion of litters with malformations and developmental variations. Kruskal-Wallis test for the proportion of resorbed and dead fetuses and postimplantation losses
Indices:
see "Statistics" above

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
One death occurred at the 1500 mg/kg/day dose but it was considered a gavage injury. No clinical observations or necropsy findings. No effects on body weight or body weight gain. There was a significant increase in food consumption for the 3000 mg/kg/day during gestation interval 12-16 but this was considered normal biological variation and not a direct effect of the test substance.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day
Basis for effect level:
other: No observable adverse effects at highest dose

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No indications of developmental toxicity including teratogenesis. All indices were comaparable to the corresponding controls.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day
Basis for effect level:
other: No observable adverse effects at highest dose

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The test substance did not induce developmental or teratogenic effects at doses up to 3000 mg/kg/day.