Alcohols, C9-11-branched and linear

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

group sizes are smaller than recommended, 10 pregnant females rather than 20; some omissions in reporting

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(only 10 animals per group instead of the 20 indicated in guideline; some omissions in reporting)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Alcohols, C7-11-branched and linear

EC Number:

287-623-3

EC Name:

Alcohols, C7-11-branched and linear

IUPAC Name:

Alcohols, C7-11-branched and linear

Test material form:

liquid

Test animals

Species:

rat

Strain:

other: Wistar Chbb/THOM

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr K Thomae GmbH, Biberach, Germany
- Age at study initiation: 68-85 days (females)
- Weight at study initiation: 214-233 g (females)
- Fasting period before study: no data
- Housing: singly in stainless steel wire-mesh cages
- Diet (e.g. ad libitum): ground Kliba feed 343 rat/mouse/hamster, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): no data (air-conditioned)
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: double-distilled water with Cremophor EL as emulsifier

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: emulsified in double-distilled water containing 0.005% Cremophor EL. Prepared daily using a high-speed sonicator; a magnetic stirrer was used to keep the emulsion homogenous during dosing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): to ensure even distribution of the test material
- Concentration in vehicle: 28.8, 144 or 288 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bw/day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentrations analysed by gas chromatography after homogenization by the addition of dioxane.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 male to 1-4 females
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no

Duration of treatment / exposure:

days 6-15 post coitum

Frequency of treatment:

daily

Duration of test:

20 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

144 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

720 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

1 400 mg/kg bw/day

No. of animals per sex per dose:

8-10 females

Control animals:

yes, concurrent vehicle

other: double-distilled water

Details on study design:

- Dose selection rationale: based on equimolar dose levels as this was a study to compare toxicity of various C7-11 alcohols
- Rationale for animal assignment (if not random): random

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: yes

WATER CONSUMPTION: no

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live foetuses, dead foetuses, numbers of implantations were shown as: live foetuses, dead implantations, early resorptions (stained), early & late resorptions (unnstained), dead foetuses; conception rates and pre & post implantation losses were calculated.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: yes: half per litter

Statistics:

Dunnetts test for most reproductive parameters and Fishers exact test for evaluaton of conception rate and all foetal findings.

Indices:

no data

Historical control data:

none

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
No maternal toxicity or deaths occurred. There were no differences in body weight gain between the treated and control groups on days 0, 6, 15 or 20 and no differences in food consumption was evident. No differences were seen in the uterus, placental and foetal weights and the number of corpora lutea, implantation sites and live foetuses per dam were similar between the groups.

- Number pregnant per dose level: water control 9, aqueous emulsifier control 10, 144 mg/kg bw/day 9, 720 mg/kg bw/day 10, 1440 mg/kg bw/day 8.
- Number aborting: None
- Number of resorptions: comparable in treated and control groups. Resorptions/dam (mean) 1.2, 1.1 (control groups) 1.0, 1.2 and 1.1 for low, mid and high dose groups respectively.
- Number of implantations: comparable in treated and control groups. Implantation sites/dam (mean) 15.0, 15.7 (control groups) 14.8, 15.8 and 13.9 for low, mid and high dose groups.
- Post implantation loss: comparable in treated and control groups.
- Number of corpora lutea: comparable in treated and control groups. Corpora lutea/dam (mean) 16.1, 16.0 (control groups) 17.0, 17.0 and 15.6 for low, mid and high dose groups respectively.
- Duration of Pregnancy: comparable in treated and control groups.

No haematology, clinical chemistry, macro- or microscopic examinations were carried out and organs were not weighed (other than the uterus).

Effect levels (maternal animals)

1

Key result

Dose descriptor:

NOAEL

Effect level:

1 440 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

1 440 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No embryotoxic effects were detected that were attributed to the treatment. Similar numbers of abnormalities occurred in the treated and control groups for the following parameters: bilateral renal pelvis, hydroureter, thoracic vertebral body dumbbell shaped, skeletal variations and skeletal retardations.

- Litter size and weights: comparable in treated and control groups. Foetal weights (mean) 3.8, 3.82 (controls) 3.88, 3.79 and 3.82 for low, mid and high dose groups respectively.
- Number viable: viability was comparable to controls. Live foetuses/dam (mean) 13.8, 14.6 (controls) 13.8, 14.6 and 12.8 for low, mid and high dose groups respectively.
- Sex ratio: Not reported.
- Total malformations, variations and retardations: the incidence was unaffected by treatment. Litters (%) with malformations (no. of litters) 11.1% (1), 20.0% (2)(controls) 11.1% (1), 40.0% (4) and 12.5% (1) for low, mid and high dose groups respectively.
- Litters (%) with variations (no. of litters) 88.9% (8), 100% (10) (controls) 100% (9), 100% (10) and 100% (8) for low, mid and high dose groups respectively.
- Litters (%) with retardations (no. of litters) 88.9% (8), 100% (10) (controls) 77.8% (7), 90.0% (9) and 87.5% (7) for low, mid and high dose groups respectively.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

1 440 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

In a reliable study, conducted to a protocol similar to OECD guideline 414, a mixture of mainly linear C7-9-11 alcohols exhibited no maternal or foetal toxicity after oral administration to rats on gestation days 6-15 at up to 1440 mg/kg bw/day. The study was performed to GLP.

Executive summary:

C7-11-branched and linear alcohols was administered at daily gavage doses of 0, 140, 720 and 1440 mg/kg bw/day to pregnant rats. No maternal toxicty was observed, and no adverse effects were recorded on foetal and developmental parameters.