3,7,11-trimethyldodeca-1,6,10-trien-3-ol,mixed isomers

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study according to GLP

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes (incl. QA statement)

Remarks:

BASF SE, Experimentelle Toxikologie und Ökologie

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

3,7,11-trimethyldodeca-1,6,10-trien-3-ol,mixed isomers

EC Number:

230-597-5

EC Name:

3,7,11-trimethyldodeca-1,6,10-trien-3-ol,mixed isomers

Cas Number:

7212-44-4

Molecular formula:

C15H26O

IUPAC Name:

3,7,11-trimethyldodeca-1,6,10-trien-3-ol

Details on test material:

- Name of test material (as cited in study report): Nerolidol
- Physical state and colour: Liquid/colorless, clear
- Analytical purity: sum of isomers: 99.1 %
- Lot/batch No.: 01940329U0
- Stability under test conditions: Expiry date Oct 2011
- Storage condition of test material: Room temperature; avoid temperatures >50 °C

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Wistar rats Crl:WI(Han) were supplied Charles River Laboratories, Research Models and Services, Germany GmbH.
- Age at study initiation: 11-12 weeks.
- Weight at study initiation: The body weight of the males was in the range of 111.0-141.1 g (group mean: 130.4 g) and the body weight of the females was in the range of 102.4 - 123.7 g (group mean: 114.6 g).

- HOUSING: The rats were single housed in Makrolon cages type M III on type Lignocel PS 14 fibres, dustfree bedding and wooden gnawing blocks (Typ NGM E-022) as enrichment. Motor activity measurements were conducted in clean polycarbonate cages. The animals were housed in a fully air-conditioned room.
- DIET: Ground Kliba maintenance diet mouse/rat “GLP”; ad libitum.
- WATER: Drinking water from bottles ad libitum
- Acclimation period: 7 days (including randomization).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70% relative humidity
- Photoperiod (hrs dark / hrs light): 12 /12

IN-LIFE DATES: From: 2009-10-19 (first administration, males and females) To: 2009-11-24 (sacrifice of parental males after withdrawal of food for about 16 - 20 hours) and 2009-12-15 (sacrifice of parental females after withdrawal of food for about 16 - 20 hours).

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION:
The test substance was weighed and thoroughly mixed with a small amount of food. Corresponding amounts of food, depending on the dose group, were added to this premix in order to obtain the desired concentration. Mixing was carried out for 10 minutes in a Ruberg (EM 100) laboratory mixer.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analysis confirmed the correctness of the concentrations. The recovery rates were within a range of 91.0 - 97.2% of the target concentrations.

Details on mating procedure:

- Males/Females ratio per cage: 1:1
- Length of cohabitation: max. 2 weeks
- Proof of pregnancy: A vaginal smear was prepared after each mating and examined for sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm were detected was denoted "day 0" and the following day "day 1" p.c. (post coitum).
- After successful mating each pregnant female was caged in Makrolon cages type M III on type Lignocel PS 14 fibres, dustfree bedding and wooden gnawing blocks (Typ NGM E-022) as enrichment. Pregnant females were provided with nesting material (cellulose wadding) toward the end of gestation

Duration of treatment / exposure:

Males 37 days, females 58 days

Frequency of treatment:

The test substance was administered daily via the diet.

Duration of test:

Males 37 days, females 58 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0; 1500; 4000; 12000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

10 rats per sex per dose

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: Doses are approximatelx equivalent to a test substance intake of 100, 300 and 1000 mg/kg body weight (bw).

- Rationale for animal assignment: Before the start of the administration period, male and female rats were allocated to the test groups according to weight. The list of randomization instructions was compiled by a computer.

Examinations

Maternal examinations:

See Chapter "Toxicity to reproduction"

Ovaries and uterine content:

See Chapter "Toxicity to reproduction"

Fetal examinations:

See Chapter "Toxicity to reproduction"

Indices:

See Chapter "Toxicity to reproduction"

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY
F0 animals:
12000/4000/1500 ppm:
- No mortality, no test substance related findings.

BODY WEIGHT AND FOOD CONSUMPTION
12000 ppm:
- Statistically significantly reduced food consumption in females, week 0 – 1, 25% below controls.
- Statistically significantly reduced food consumption in females, entire gestation, average 20% below controls.
- Statistically significantly reduced food consumption in females, postnatal days 1 - 4, 32% below controls.

- Statistically significantly reduced mean body weight in females, gestation, final weight 12% below controls.
- Statistically significantly reduced mean body weight in females, lactation, final weight 13% below controls.
- Statistically significantly reduced mean body weight gain in females, week 0 – 1, 73% below controls.
- Statistically significantly reduced mean body weight gain in females, gestation, average 37% below controls.
- Reduced mean body weight gain in females, lactation, 40% below controls.

TEST SUBSTANCE INTAKE
Corresponds to about 105, 279, 705 mg/kg bw/d in non-pregnant females; 120, 340 and 824 mg/kg bw/d in pregnant females; 193, 468, 1194 mg/kg bw/d in lactating females

DCO, FOB AND MOTOR ACTIVITY
12000/4000/1500 ppm:
- No test substance related findings.

REPRODUCTIVE PERFORMANCE

12000/4000/1500 ppm:
- No test substance related effects on mating, gestation and parturition
- 1 low dose and 1 high dose female did not become pregnant resulting in fertility indices of 100%, 90%, 100% and 90% in 0, 1500 ppm, 4000 ppm and 12000 ppm respectively. No histomorphological correlate was found in females to explain the apparent infertilities. These values reflect the normal range of biological variation inherent in the strain of rats used for this study.


12000 ppm:
- Slightly, non-significantly lower number of implants and, subsequently litter size

CLINICAL PATHOLOGY
12000 ppm:
- Increased GGT values in rats of both sexes
- Reduced prothrombin time in females
- Increased calcium levels in females

4000/1500 ppm:
No treatment-related, adverse effects

ORGAN WEIGHTS

12000 ppm:
- statistically significantly decreased terminal body weight in females (95% of control)
- statistically significant absolute and relative increased liver weights in females (149% of control)

4000 ppm:
- statistically significant absolute and relative increased liver weights in females (120% of control)

GROSS PATHOLOGY
12000/4000/1500 ppm:
- no significant gross lesions

HISTOPATHOLOGY
12000 ppm:
- minimal or slight central hepatocellular hypertrophy and central fatty change in females

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

1 500 ppm

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

4 000 ppm

Basis for effect level:

other: Developmental toxicity based on growth and development of offspring, secondary to maternal toxicity. Dose corresponds to about 270 mg/kg bw/d in males and 279, 340 or 468 mg/kg bw/d in non-pregnant, pregnant or lactating females, respectively.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Effects on offspring

VIABILITY

12000/4000/1500 ppm:

- No mortality

CLINICAL SIGNS

12000/4000/1500 ppm:

- No test substance-related findings

BODY WEIGHT

12000 ppm:

- Statistically significantly reduced mean pup body weight, postnatal day 4, 13% below controls.

- Statistically significantly reduced mean pup body weight gain, postnatal days 1 - 4, 38% below controls.

PUP NECROPSY

12000/4000/1500 ppm:

- No test substance-related findings