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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:
not indicated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study design appears to follow OECD Guideline 414 (2001). Study pre-dates GLP requirements. No analytical verification of dose concentrations (considered acceptable, as substance was found stable in other studies).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
treatment only from day 6 - day 15
GLP compliance:
no
Remarks:
Study pre-dates GLP.
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10047 (Tinuvin P)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: closed SPF breeding colony (facility name not reported).
- Weight at study initiation: about 240 g (females).
- Housing: successfully mated females kept in groups of 5 in Macrolon cages.
- Diet (e.g. ad libitum): ad libitum.
- Water (e.g. ad libitum): ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 to 22.5 degrees Celcius.
- Humidity (%): 51 to 61%.
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): the amount of fluid administered was 1 mL/100 g of body weight.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused.
- If cohoused:
- M/F ratio per cage: 1:3
- Length of cohabitation: overnight.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy.
Duration of treatment / exposure:
From Day 6 until Day 15 of pregnancy, inclusive.
Frequency of treatment:
Once/day.
Duration of test:
Females were dosed from Day 6 until Day 15 of pregnancy (inclusive) and dams were autopsied and foetuses removed by Caesarean section on Day 21.
Doses / concentrationsopen allclose all
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 females/dose group and 30 females in the control group.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: None reported.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily.

BODY WEIGHT: Yes
- Time schedule for examinations: daily.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: As per study report, "The examinations were carried out in accordance with W.H.O. recommendations (Wld. Hlth. Org. Techn. Rep. Ser. 364, 1967)." Organs examined included the ovaries and uterus (mucosa and contents, including amniotic fluid and placentae).
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: 1/3 of the foetuses were fixed in a mixture of alcohol and formol to which acetic acid was added.
- Skeletal examinations: Yes: 2/3 of the foetuses following clearing in potassium hydroxide and staining with Alizarine Red S.
Statistics:
Not reported.
Indices:
Not reported.
Historical control data:
yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
Slight increase in feed consumption was noted towards the end of treatment.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No adverse effects on embryonic and foetal development were noted, when data on the rates of implantations and embryolethality (resorptions) as well as foetal average weight were compared with the corresponding data of the CMC-control. By applying the slicing technique few minor anomalies were detected. The incidence of anasarca (slight oedema-like changes of siabcutis) was 5% at the highest dose group compared to 1% in the cumulative control and is still within the 99 % confidence limits of the CMC-control.
Skeletal assessment did not reveal any clear-cut deviation from the CMC-control except for a slight decrease in the number of not yet ossified phalangeal nuclei of the hind-limb as well as in the number of still incompletely ossified sternebrae at the mid dose only.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The substance causes no teratogenicity, embryotoxicity, developmental toxicity and maternal toxicity in rats.