Fatty acids, C16 and C18-unsaturated, methyl esters, chlorinated

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-07-11 to 1983-08-04

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Good quality study to GLP; considered adequate for assessment.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

2008

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Does not include period from implantation to start of organogenesis (days 1-5)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Alkanes, C14-17, chloro

EC Number:

287-477-0

EC Name:

Alkanes, C14-17, chloro

Cas Number:

85535-85-9

Molecular formula:

Substance is a range of chlorinated isomers of C14 to C17 paraffin

IUPAC Name:

alkanes, C14-17, chloro

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
- Impurities (identity and concentrations): no stabiliser
- Composition of test material, percentage of components: C14-17 chlorinated paraffin (51.8% chlorinated)
- Lot/Batch no: 306

Test animals

Species:

rat

Strain:

other: Charles River CD

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Breeding Labs. Portage, Michigan USA- Age at study initiation: 70 days on receipt (91 days at mating)- Weight at study initiation: 219-294 g at time of mating- Fasting period before study: none- Housing: Individually in suspended wire cages- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 21 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 21 to 24- Humidity (%): 52-64- Air changes (per hr): no data- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: 1983-07-11 To: 1983-08-04

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: "Appropriate amount of test material was dissolved in vehicle by shaking". VEHICLE- Justification for use and choice of vehicle (if other than water): test material soluble in corn oil- Concentration in vehicle: 100, 400 and 1000 mg/ml (nominal)- Amount of vehicle (if gavage): 5 ml/kg bw- Purity: no data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Weekly samples of dosing solutions taken prior to dosing and the concentration of chlorinated paraffin measured by viscometry.

Details on mating procedure:

- Impregnation procedure: co-housed- If cohoused: - M/F ratio per cage: 1/1 - Length of cohabitation: no data - Verification of same strain and source of both sexes: no; suitable stock males, strain not reported, used - Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

from gestational days 6 to 19

Frequency of treatment:

daily

Duration of test:

Animals sacrificed on gestational day 20.

No. of animals per sex per dose:

25 mated females per dose level

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on the results of two preliminary sighting studies- Rationale for animal assignment (if not random): sequential addition of mated females to the 4 study groups

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes- Time schedule: twice daily for mortality and overt changes in appearance/behaviourDETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: daily for clinical signs of toxicityBODY WEIGHT: Yes - Time schedule for examinations: on gestation days 0, 6, 9, 12, 16 and 20.POST-MORTEM EXAMINATIONS: Yes - Sacrifice on gestation day # 20- Organs examined: uterus and organs visible in the abdominal and thoracic cavities

Ovaries and uterine content:

At sacrifice the numbers and location of viable and non-viable fetuses, early and late resorption sites and number of total implantations and ovarian corpora lutea were determined

Fetal examinations:

All fetuses were weighed, sexed and examined for external malformations. One half of the fetuses from each litter were then examined for visceral malformations and the other half for skeletal malformations.

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:yesDetails on maternal toxic effects:Wet and/or matted fur in the anogenital region (with red or yellow staining) and an increased incidence of soft stool prior to sacrifice was seen in animals given Cereclor S52 at dose levels of 2000 and 5000 mg/kg bw/day. One mid-dose group female died on gestational day 16 (the cause of death was not established, but was probably not treatment-related).

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

5 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:Single instances of anophthalemia, microphthalemia, spine and rib anomalies and tail/anal opening anomalies were seen which were not considered treatment-related.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

5 000 mg/kg bw/day

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 develpmental effects were seen in the offspring of pregnant rats following exposure to Cereclor S52 (a C14-17 chlorinated paraffin; 52% chlorinated) at dose levels up to 5000 mg/kg bw/day, administered daily by gavage in corn oil on gestational days 6 to 19. Signs of maternal toxicity were seen at the two highest dose levels.

Executive summary:

Groups of 25 mated female Charles River CD rats received 0, 500, 2000 or 5000 mg/kg bw/day of Cereclor S52 (a C14 -17 chlorinated paraffin; 52% chlorination), in corn oil by oral gavage on gestational days 6-19, with sacrifice on day 20. The numbers and location of viable and non-viable foetuses, resorption sites and total number of implantations and ovarian corpora lutea were determined. All foetuses were examined for external malformations, and one half of the foetuses from each litter were then examined for visceral malformations and the other half for skeletal malformations.

Clinical signs of maternal toxicity were seen at 2000 and 5000 mg/kg bw/day, comprising wet and/or matted fur in the anogenital region (with red or yellow staining) and an increased incidence of soft stool. Treatment did not affect the uterine parameters examined, pup weights or the incidence of foetal malformations. In this study, no developmental effects were observed at dose levels up to 5000 mg/kg bw/day (the highest tested dose), and this can therefore be considered as the study NOAEL for these effects.