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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:
7 January 1980 - 30 January 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to methods resembling those described in OECD guideline 414 and was performed under GLP conditions. Due to the shorter treatment period (only GD 6-19) the study was assigned a Kliimsch 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 154
- Physical state: Liquid
- Stability: Stable for one year
- Storage condition of test material: At ambient temperature in the dark

Test animals

Species:
rat
Strain:
other: Charles River COBS CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The Charles River Breeding Laboratories, Inc., Portage, Michigan, USA
- Age at study initiation: approx. 13 weeks
- Weight at day 0 of gestation: 246-261 g
- Housing: Individually (except during mating)
- Diet: Ad libitum, Purina Certified Laboratory Rodent Chow
- Water: Ad libitum, tap water
- Acclimation period: min. of 10 days

ENVIRONMENTAL CONDITIONS
Animals maintained in a temperature-, humidity, and light-controlled environment. Photoperiod: 12 hrs light/12 hrs dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test article dispensed daily and administered undiluted at dosage levels of 300, 1000 and 3000 mg/kg bw/day, corresponding with 0.254, 0.847 and 2.542 ml/kg, respectively.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not relevant
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:
GD6-19
Frequency of treatment:
Once daily
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
300, 1000, 3000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
25 (only females)
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Based on pilot study
- Rationale for animal assignment: Block design

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: GD0, 6, 9, 12, 16 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Gross necropsy: abdominal and thoracic cavities and organs of the dams, and uterus of non-gravid females
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
- Location and viability of fetuses: Yes
Fetal examinations:
- General examinations: Weight and sex, all per litter
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
- Significance level: 0.05
- Chi-square test with Yates' correction for 2x2 contigency tables and/or Fisher's exact probability test (sex distribution and number of litters with malformations)
- Mann-Whitney U-test (early and late resorptions and postimplantation loss)
- One-way ANOVA, Bartlett's test for homogeneity of variances and the appropriate t-test using Dunnett's multiple comparison tables (viable fetuses, total implantations, corpora lutea and mean fetal body weights)
Indices:
Not relevant
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:
Clinical signs were reported troughout all groups, including the control group.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
3 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
3 000 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:
Statistically significant decrease noted in the mean number of early resorptions and mean postimplantation loss in the mid-dose group, but this was attributed to random occurrence. Slight increase in number of litters (but not pups) with malformations in the 3000 mg/kg bw/day group, but this was not considered biologically relevant as the malformations occurred as single incidences.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
3 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Highest dose level tested

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 No mortality No mortality No mortality No mortality
Body weight x x x x
Body weight gain x x x x
Clinical signs 3 animals: dried red matter in nasal region and on forepaws 2 animals: dried red matter in nasal region and on forepaws Slight increase in yellow staining and matting, 4 animals: dried red matter in nasal region and on forepaws All animals: yellow staining and matting in anogenital area, with or without yellow staining and matting on abdominal and thoracic area, 12 animals: dried red matter in nasal region and on forepaws
Number pregnant per dose level 19 (1 animal delivered before caesarian section and is not included) 20 22 25
Number of litters 19 19 21 24
Corpora lutea (mean/dam) 15.8 15.3 15.5 15.5
Implantations (mean/dam) 13.7 13.7 13.8 12.2
Post-implantation loss (mean/dam) 1.4 0.7 0.7* 0.6
Early resorptions (mean/dam) 1.4 0.7 0.7* 0.6
Late resorptions (mean/dam) 0 0 0 0
Gross necropsy 4 animals: hydrometra 2 animals: hydrometra, 2 animals: pitted kidney, 1 animal: hydronephrosis 2 animals: clear fluid in abdominal cavity and hemorrhagic thymus 1 animal: slightly congested lungs
FETAL DATA 
Litter size (mean/dam) 12.3 13 13 11.5
Viability x x x x
Sex ratio (M/F) 1:0.96 1:1.10 1:0.82 1:1.04
Litter weights 3.5 3.7 3.8 3.6
Grossly external abnormalities x x x x
Visceral abnormalities x x x x
Skeletal abnormalities x x x x
Developmental and genetic variation x x x x
x = no effects (as compared to control group)
* = significantly different (as compared to control group)

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, no biologically significant effects were observed in rats exposed to Santicizer 154 during day 6-19 of gestation or their litter. Therefore, a NOAEL of 3000 mg/kg bw/day was established for both developmental and maternal toxicity.
Executive summary:

This study was performed to determine the developmental toxicity potential of Santicizer 154 in rats. Gravid rats were exposed during GD6-19 to 0, 300, 1000 or 3000 mg/kg bw/day. Clinical signs, mortality and body weights were recorded. Gross necropsy and uterine examination in the dams was performed, as well as external, visceral and skeletal malformations in the fetuses.

Clinical signs were reported troughout all groups, including the control group. Statistically significant decrease noted in the mean number of early resorptions and mean postimplantation loss in the mid-dose group, but this was attributed to random occurrence. Slight increase in number of litters with malformations in the 3000 mg/kg bw/day group, but this was not considered biologically relevant as the malformations occurred as single incidences.

Under the conditions of this study, no biologically significant effects were observed in rats exposed to Santicizer 154 during day 6-19 of gestation or their litter. Therefore, a NOAEL of 3000 mg/kg bw/day was established for both developmental and maternal toxicity.