Fusel oil

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Publication of guideline study with basic raw data information.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1995

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-methylbutan-1-ol

Cas Number:

123-51-3

Molecular formula:

C5H12O

IUPAC Name:

3-methylbutan-1-ol

Constituent 2

Reference substance name:

3-Methyl-1-butanol

IUPAC Name:

3-Methyl-1-butanol

Details on test material:

- Name of test material (as cited in study report): MEB
- Physical state: liquid
- Analytical purity: 98.6%
- Stability under test conditions: at least 6 months

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach/Riss, Germany
- Age at study initiation: 10 to 11 weeks
- Weight (mean) at study initiation: 216 g
- Housing: housed individually in wire cages (rats, type DK III; rabbits, type K300/8; EBECO, Becker and Co., Castrop-Rauxel, Germany)
- Diet: KLIBA rat/mouse laboratory diet 24-343-4, 10-mm pellets (Klingentalmuehle AG, Kaiseraugst, Switzerland), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24
- Humidity (%): 49-64
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass/steel construction with volumes of approximately 1.1 m³; manufactured by BASF AG, Ludwigshafen, Germany
- Source and rate of air: clean air with 15 air changes per hour
- Method of conditioning air: Concentrations were achieved by supplying the test substances via continuously operating pumps to evaporators maintained at 50-70 °C by a water circulation thermostat. The vapours were diluted with clean air.
- Temperature, humidity, pressure in air chamber: 21-24 °C, 49-64% humidity, minimal negative pressure
- Air flow rate: 16.5 m³/h
- Air change rate: 15

TEST ATMOSPHERE
- Brief description of analytical method used: Samples of the inhalation atmospheres were analyzed hourly by gas chromatography (Hewlett-Packard gas chromatograph Model 5840 A with an automatic sampler Model 7671 A, FID; column, 2 mx2 mm with 15% Ucon LB 550 x on Chromosorb W/HP; 80/100 mesh; oven temperature, 90 °C).
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis by gas chromatography.

Details on mating procedure:

- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

Day 6-15 of gestation

Frequency of treatment:

6 h/day

Duration of test:

Day 6-20 of gestation

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.5, 2.5, 10 mg/L
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.51, 2.5, 9.8 mg/L
Basis:
analytical conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
510, 2500, 9800 mg/m³
Basis:
analytical conc.

No. of animals per sex per dose:

25 (females)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on range-finding inhalation studies the highest possible vapour concentration was used.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily (behaviour and state of health)

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 3, and 6; afterwards at 3-day intervals until day 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 (by cervical dislocation)
- Organs examined: at least uterus and ovaries

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

Fetal examinations:

- External examinations: Yes
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Statistics:

The Dunnett test was used to statistically compare body weight, body weight changes, corrected body weight gain, intact uterine weight, fetal and placental weights, the number of corpora lutea, implants, resorptions, live fetuses, and pre- or postimplantation losses. The Fisher's exact test was used for evaluating the conception rate, maternal mortality, and all fetal findings.

Historical control data:

Historical control data were provided in the discussion part sporadically. No source of the data was provided.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects. Remark: 9800 mg/m³: slight change of body weight gain, non adverse

Details on maternal toxic effects:
MEB inhalation (0.5 and 2.5 mg/liter) did not significantly influence the body weights and the body weight changes. A slight retardation in body weight increase was observed between days 6 and 9, whereas an increase was observed between days 12 and 15. No biologically relevant or clearly concentration-related differences were apparent between the groups regarding corrected body weight gain.
No substance-induced clinical findings were observed. One female rat was found dead on day 12 in the 0.5 mg/L exposure group.
Examination of the rats for gross pathological findings revealed no effects that could be attributed to exposure to MEB. Findings such as hydrometra, edema, or marginal emphysema of lungs which occurred in a few rats without any relation to treatment were considered to be spontaneous events.
The uterine weights of the rats exposed to MEB were not significantly different from the controls. Analyses of the reproduction data showed for all groups of rats that no compound-related effects occurred for conception rate.

Effect levels (maternal animals)

1

Key result

Dose descriptor:

NOAEC

Effect level:

>= 9 800 mg/m³ air (analytical)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Key result

Dose descriptor:

NOAEC

Effect level:

>= 9 800 mg/m³ air (analytical)

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 effects were observed on the mean number of corpora lutea and implantation sites. No test substance-related effect was observed in the values calculated for the pre- and postimplantation loss and the number of resorptions as well as viable fetuses.
The sex distribution did not differ between treated groups and controls. The mean placental and fetal weights were not affected by the treatment of the dams.
The examination of the fetuses for external changes revealed three types of malformations. These were polydactyly found in 1 fetus of 326 fetuses at the highest MEB concentration. No external variations were found in any group. In the MEB groups so-called unclassified observations were recorded for 4 control fetuses (blood coagulum around placenta), 9 fetuses (from one litter) after exposure to 2.5 mg/L (placentae necrobiotic), and 1 fetus after exposure to 10 mg/L (placenta fused).
When examining the fetuses for soft tissue changes, two malformations, globular shaped heart and dextrocardia, were observed in two fetuses after exposure to 2.5 mg/L MEB. Variations were seen in all groups including the controls. Specifically, dilated renal pelvis (frequently observed in fetuses of this rat strain) and hydroureter occurred independent of exposure or concentration. No unclassified observations were recorded for any test group.
The skeletal examination of the fetuses revealed various malformations of the sternebrae and/or the vertebral column. After MEB exposure they occurred in four to eight fetuses (from four to seven litters) from all test groups. The differences were not statistically significant. The variations observed in the ribs and the sternum were found in all groups and did not occur in a concentration-related manner. Retardations such as incomplete or missing ossification of hyoid, skull bones, metacarpal or metatarsal bones, vertebral bodies, and/or sternebra(e) were seen in all groups.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEC

Effect level:

>= 9 800 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: the NOAEC developmental toxicity was determined to be ≥ 9800 mg/m³, as no substance-related effects were observed up to the highest concentration tested.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified