Reaction mass of lithium 3-hydroxy-2,2,4-trimethylpentanoate and lithium isobutyrate and sodium 3-hydroxy-2,2,4-trimethylpentanoate and sodium isobutyrate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Studies on the Prenatal Toxicity of 3-Methyl-1-butanol and 2-Methyl-1-propanol in Rats and Rabbits Following Inhalation Exposure

Author:

Klimisch H.J. and Hellwig, J.

Year:

1995

Bibliographic source:

Fundamental and Applied Toxicology 27, 77-89 (1995)

Report date:

1995

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Fifteen female rabbits per group were exposed to 2-Methyl-1-propanol vapours at concentrations of 10, 2.5, or 0.5 mg/L, 6 hr/day. The rabbits were exposed on Days 7 -19 postinsemination . Control groups were exposed to clean air. The body weights of the animals were determined several times throughout the studies. All rabbits were killed on Day 29 postinsemination. The foetuses were removed from the uterus and examined for compound-related effects.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-Methyl-1-propanol

IUPAC Name:

2-Methyl-1-propanol

Constituent 2

Reference substance name:

2-methylpropan-1-ol

EC Number:

201-148-0

EC Name:

2-methylpropan-1-ol

Cas Number:

78-83-1

IUPAC Name:

2-methylpropan-1-ol

Constituent 3

Reference substance name:

Isobutanol

IUPAC Name:

Isobutanol

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): 2-Methyl-1-propanol
- Molecular formula (if other than submission substance): Not reported
- Molecular weight (if other than submission substance): Not reported
- Smiles notation (if other than submission substance): Not reported
- InChl (if other than submission substance): Not reported
- Structural formula attached as image file (if other than submission substance): see Fig. Not reported
- Substance type: Not reported
- Physical state: Not reported
- Analytical purity: 2-Methyl-1-propanol 99.8%
- Impurities (identity and concentrations): Not reported
- Composition of test material, percentage of components: Not reported
- Isomers composition: Not reported
- Purity test date: Not reported
- Lot/batch No.: Not reported
- Expiration date of the lot/batch: Not reported
- Stability under test conditions: Stable for at least 6 months
- Storage condition of test material: Not reported

Test animals

Species:

rabbit

Strain:

Himalayan

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach/Riss, Germany
- Age at study initiation: 24 - 29 weeks
- Weight at study initiation: 2.5 - 2.7 kg
- Fasting period before study: None
- Housing: Individually in wire cages
- Diet (e.g. ad libitum): KLIBA rabbit laboratory diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

IN-LIFE DATES: From: Not reported To: Not reported

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

clean air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Horizontal-flow whole-body exposure chamber
- Method of holding animals in test chamber: Not reported
- Source and rate of air: Not reported
- Method of conditioning air: Not reported
- System of generating particulates/aerosols: Concentrations were achieved by supplying the test substances via continuously operating pumps to evaporators maintained at 50-70°C by a water circulation thermostat.
- Temperature, humidity, pressure in air chamber: Supply and exhaust air flows were adjusted by flow meters, in order to achieve a minimal negative pressure in the inhalation chamgers. Temperature was 21-24°C amd relative humidity was 49-60%
- Air flow rate: 15 air exchanges per hour
- Air change rate: 15 air exchanges per hour
- Method of particle size determination: Not reported
- Treatment of exhaust air: Not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Samples of inhalation atmospheres were analysed houly by gas chromatography.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of inhalation atmospheres were analysed houly by gas chromatography.

Details on mating procedure:

The rabbits were fertilized by artificial insemination; the day of insemination was defined as Day 0 and the following day was defined as Day 1 postinsemination

Duration of treatment / exposure:

Daily for 6 hours/day from days 7 - 19 postinsemination.

Frequency of treatment:

Daily for 6 hours/day

Duration of test:

After termination of the exposure period, the rabbits were observed up to Day 29 postinsemination.

Doses / concentrations

Remarks:

Doses / Concentrations:
0.5, 2.5, 10 mg/L, 6 hr/day
Basis:
nominal conc.

No. of animals per sex per dose:

15 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

No further data on dosing rationale.
The animals were randomly allocated to the test groups.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: state of health

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 3 and 7 and from then on at 3-day intervals until Day 29 postinsemination

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Day 29 postinsemination
- Organs examined: Uterus and ovaries were removed for the following delerminations: intact uterine weight, number of corpom lutea, and number of
implants, the latter being differentiated into live fetuses and dead implants (early and late resorptions, dead fetuses). The pre- and postimplantation losses were calculated.

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: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all 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 postimplantat ion losses. The Fisher's exact test was used for evaluating the conception rate, maternal mortality, and all fetal findings.

Indices:

No further data

Historical control data:

No further data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: slight maternal toxic effects at the highest dose (10 mg/L) of 2-Methyl-1-propanol

Details on maternal toxic effects:
Only slight maternal toxic effects were induced in Himalayan rabbits after exposure to 10 mg/L of 2-Methyl-1-propanol

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

ca. 2.5 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

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 treatment related effects. All effects were concidered incidental and were within the normal variations for the species.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: teratogenicity

2

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: embryotoxicity

3

Dose descriptor:

NOAEL

Effect level:

> 10 mg/L air

Based on:

other: 2-Methyl-1-propanol

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

No further data

Applicant's summary and conclusion

Conclusions:

The highest concentration of 10 mg/L appeared to be a borderline concentration for causing maternal toxicity. 2.5 mg/L was therefore the NOAEL after exposure to 2-Methyl-1-propanol.
The highest concentration level of 10 mg/L was found to be a clear NOAEL for the fetal organisms.

Executive summary:

Fifteen female rabbits per group were exposed to 2-Methyl-1-propanol (isobutanol) vapours at concentrations of 10, 2.5, or 0.5 mg/L, 6 hr/day. The rabbits were exposed on Days 7 -19 postinsemination. Control groups were exposed to clean air. The body weights of the animals were determined several times throughout the studies. All rabbits were killed on Day 29 postinsemination. The foetuses were removed from the uterus and examined for compound-related effects. The high concentration of 10 mg/L caused a slight retardation of body weight gain in the dams exposed to 2-Methyl-1-propanol during the first days of the exposure period.. The foetuses exhibited no signs of embryotoxicity, fetotoxicity or teratogenicity effects caused by 2-Methyl-1-propanol. Under the experimental conditions, 2.5 mg/L was found to be a no-observable-adverse-effect level (NOAEL) for the dams exposed to 2-Methyl-1-propanol. For both substances 10 mg/L was defined as the NOAEL for the conceptuses.