Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1 June 1980 - 20 March 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted under GLP conditions and according to methods equivalent to those outlined in OECD guideline 414. The treatment period of the study was GD6-15, which is not in accordance with the current guideline (prescribes exposure during the entire gestation period). Due to this limitation and the limited reporting of foetal abnormalities, the study report was assigned a Klimisch 2 rating.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Santicizer 141
- Physical state: Liquid

Test animals

Species:
rat
Strain:
other: COBS CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at study initiation: 16 weeks (at time of mating)
- Weight at study initiation: 273-276 g (mean weights per group on gestation day 0)
- Housing: Individually, under standard laboratory conditions
- Diet (e.g. ad libitum): Ad libitum, rodent chow
- Water (e.g. ad libitum): Ad libitum, tap water
- Acclimation period: 42 days

ENVIRONMENTAL CONDITIONS
Animals were maintained in a temperature-, humidity-, and light-controlled environment, with a photoperiod (hrs dark / hrs light) of 12/12.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test article was dispensed daily and administered orally undiluted at total dosage volumes of 0.275, 0.917 and 2.750 ml/kg. The control group received 2.750 ml/kg distilled water.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 days (GD6-15)
Frequency of treatment:
Daily
Duration of test:
Approximately one month
No. of animals per sex per dose:
25 (female)
Control animals:
yes
Details on study design:
- Dose selection rationale: No data
- Rationale for animal assignment: Block design

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations: Mortality and overt changes in appearance and behavior

BODY WEIGHT: Yes
- Time schedule: On GD 0, 6, 9, 12, 16 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Examinations: Abdominal and thoracic cavities and organs for gross evident morphological changes. Tissues were preserved for microscopic esamination when deemed necessary by gross findings.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of viable fetuses: Yes
- 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
Statistics:
- Chi-square test with Yates' correction for 2x2 contingency tables and/or Fisher's exact probability test
- Mann-Whitney U-test
- Bartlett's test for homogeneity of variances and the appropriate t-test using Dunnett's multiple comparison tables
Indices:
Not relevant
Historical control data:
Available at the testing facility

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No mortality was observd. Body weight (gain) was decreased for the mid (primarily caused by 3 animals) and high dose (caused by all animals) group during the treatment period, but this finding was not significant.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
3 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
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:
No biologically meaningful or statistically significant teratogenic or developmental effects were noted in any of the treatment groups.

Effect levels (fetuses)

Remarks on result:
other: information not available
Remarks:
information not available

Fetal abnormalities

Abnormalities:
not specified
Description (incidence and severity):
information not available

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

RESULTS OF TEST DOSING GROUPS
Control Low (300 mg/kg bw/day) Medium (1000 mg/kg bw/day) High (3000 mg/kg bw/day)
MATERNAL TOXIC EFFECTS BY DOSE LEVEL 
Number of animals 25 25 25 25
Mortality x x x x
Clinical signs x Increase in hair loss Increase in hair loss, yellow staining and/or matting on the ventral, anogenital and/or inguinal areas Increase in hair loss, yellow staining and/or matting on the ventral, anogenital and/or inguinal areas, fissuring on primarily the inguinal area and dry red matter on the forelimbs and/or head
Body weight x x x Mean weight loss during first 6 days of treatment
Body weight gain x x Slightly reduced over the entire treatment period (GD6-15), primarily caused by 3 of the dams Severe reduction over entire treatment period
Number pregnant per dose level 19 22 21 21
Number that delivered 0 0 0 1
Number of corpora lutea (mean per dam) 16.1 16.5 15.7 16.1
Number of implantations (mean per dam) 13.4 14.6 13.6 14.0
Post-implantation loss (mean per dam) 0.8 0.6 0.8 0.8
Number of resorptions (early, mean per dam) 0.8 0.6 0.6 0.8
Number of resorptions (late, mean per dam) 0 0 0 0
Duration of pregnancy Caesarian section on GD20 Caesarian section on GD20 Caesarian section on GD20 Caesarian section on GD20 (one female with delivery on GD20)
Number of litters 19 22 21 21
FETAL DATA (preferably per litter)
Litter size (mean per dam) 12.6 14.0 12.8 13.2
Number viable (mean per dam) 12.6 14.0 12.8 13.2
Sex ratio (M/F) 1:1.14 1:0.96 1:1.04 1:0.85
Litter weights (mean per dam) 3.6 3.7 3.8 3.7
Grossly external abnormalities x x Increase in number of fetuses with malformations (not dose-related) Increase in number of fetuses with malformations (not dose-related)
Visceral abnormalities x x x x
Skeletal abnormalities x Increase in number fetuses with 14th rudimentary ribs and sternebrae #5 and/or #6 unossified (in range of historical control) Increase in number fetuses with 14th rudimentary ribs and sternebrae #5 and/or #6 unossified (in range of historical control) Increase in number fetuses with 14th rudimentary ribs and sternebrae #5 and/or #6 unossified (in range of historical control)
x = no treatment related effects (as compared to control group)

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, no developmental effects were observed as a result of treatment with Santicizer 141 from GD6-15. A severe (but not significant) reduction in body weight gain was noted in dams during treatment. Based on these results, a NOAEL of 3000 and 1000 mg/kg bw/day was established for developmental and maternal toxicity, respectively.
Executive summary:

This study was performed according to methods equivalent to those outlined in OECD guideline 414 (prenatal developmental toxicity study). Dams were exposure to Santicizer 141 during GD6-15, which is not in line with the current guideline that prescribes exposure throughout the entire gestation period. Mortality, clinical signs and body weight of the dams were recorded and several teratogenic parameters and malformations were evaluated.

No mortality was observed. Body weight (gain) was decreased for the mid and high dose group during the treatment period, but this change was not significant. No biologically meaningful or statistically significant teratogenic effects or malformations were noted in any of the treatment groups.

Under the conditions of this study, no teratogenic or developmental effects were observed as a result of treatment with Santicizer 141. A severe (but not significant) reduction in body weight gain was noted in dams during treatment. Based on these results, a NOAEL of 3000 and 1000 mg/kg bw/day was established for developmental and maternal toxicity, respectively.