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:
1982-01-05 to 1982-02-03
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Good quality study to GLP; considered adequate for assessment.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983
Reference Type:
secondary source
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
does not include the pre-implantation phase or use dose levels with some maternal/developmental toxicity
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): Cereclor S52
- Substance type: technical product
- Physical state: clear, slightly viscous liquid
- Analytical purity: no data
- Composition of test material, percentage of components: C14-17 chlorinated paraffin; 51.8% chlorinated.
- Impurities (identity and concentrations): No stabiliser
- Lot/batch no: 306

Test animals

Species:
rabbit
Strain:
Dutch
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Langshaw Farms, Augusta, Michigan, USA- Age at study initiation: approx. 7 months- Weight at study initiation: between 1.9 and 3.0 kg- Fasting period before study: no- Housing: Individually in suspended wire cages- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 50 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 22-23- Humidity (%): 43-51- Air changes (per hr): no data- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Weighed amounts of chlorinated paraffin were mixed with corn oil vehicle by shaking. Dosing solutions were prepared daily.VEHICLE- Justification for use and choice of vehicle (if other than water): test material soluble in corn oil- Concentration in vehicle: 20, 60 and 200 mg/ml (nominal)- Amount of vehicle (if gavage): 0.5 ml/kg bw- Purity: "100% pure"
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
not done
Details on mating procedure:
Rabbits artificially inseminated using semen from male rabbits of same strain and source. Day of insemination designated day 0 of gestation.
Duration of treatment / exposure:
days 6 to 27 of gestation
Frequency of treatment:
daily
Duration of test:
Dams sacrificed on day 28 of gestation
No. of animals per sex per dose:
16 females/dose level
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on data from two range-finding studies

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: Twice dailyDETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: once daily for signs of toxicityBODY WEIGHT: Yes - Time schedule for examinations: days 0, 6, 12, 18, 24 and 28 of gestationPOST-MORTEM EXAMINATIONS: Yes - Sacrifice on gestation day # 28- Organs examined: uterus and organs visible in the abdominal and thoracic cavityOTHER: abdominal adipose tissue recovered for analysis of test material concentration
Ovaries and uterine content:
At sacrifice the numbers and location of viable and non-viable fetuses, early and late resorptions and the number of total implantations and ovarian corpora lutea were determined
Fetal examinations:
All fetuses were weighed and examined for external malformations. Each fetus was dissected, internally sexed and examined for visceral malformations and following maceration in potassium hydroxide and staining, examined for skeletal malformations (although the draft RAR (EU, 2008) reports that only half of the fetuses were examined for visceral and half for skeletal abnormalities).
Statistics:
Fetal sex distribution and numbers of litters with malformations compared using Chi-squared test or Fisher's exact test. Numbers of non-viable fetuses, early and late resorptions and post-implantation losses compared by the Mann-Whitney U-test. Mean fetal body weight, number of viable fetuses, total implantations and corpora lutea were compared by analysis of variance, Bartlett's test and the appropriate t-test.
Indices:
No data
Historical control data:
yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effectsDetails on maternal toxic effects:Three dams died during the study (one in the control group, one in the 10 and one in the 30 mg/kg bw/day groups). Abortions occurred in the control group (1 dam) and in the 30 (2 dams) and 100 (2 dams) mg/kg bw/day groups. The mortalities and pattern of abortions seen was not indicative of a treatment-related effect.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:No adverse effects seen. The number of viable foetuses was significantly increased in the 30 mg/kg bw/day dose group, but within the historical control range for this parameter.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
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:
No treatment-related adverse effects were seen in pregnant rabbits given a C14-17 chlorinated paraffin (52% chlorinated) by oral gavage in corn oil at dose levels up to 100 mg/kg bw/day on gestational days 6 to 27, or on their foetuses examined on gestational day 28. Therefore, the test material was not toxic to development in rabbits under the conditions of this study.
Executive summary:

Groups of 16 pregnant female rabbits were given unstabilised Cereclor S52 (a C14 -17 chlorinated paraffin; 52% chlorinated) by oral gavage in corn oil at dose levels of 0, 10, 30 and 100 mg/kg bw/day on gestational days 6 to 27 and sacrificed on gestational day 28. At this time the dams were examined for the numbers and positions of viable and non-viable foetuses, resorption sites, and total number of implantations and ovarian corpora lutea. All foetuses were examined for external malformations, and for visceral and skeletal malformations (although the draft RAR (EU, 2008) reports that only half of the fetuses were examined for visceral and half for skeletal abnormalities).

No significant treatment-related mortalities or clinical signs of toxicity were seen in the dams and no treatment-realated malformations were seen in the foetuses. The level of abortions (1, 2 and 2 in the 0, 30 and 100 mg/kg bw/day dose groups respectively) and the increased number of viable foetuses in the 30 mg/kg bw/day dose group were not considered to be of toxicological significance.

The results of this study suggest that Cereclor S52 did not adversely effect the development of rabbits at up to 100 mg/kg bw/day (the highest tested dose), a dose level which failed to induce signs of maternal toxicity.