Isovaleric acid

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:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP guideline study Readacross is justified due to the toxicokinetic arguments described within the Endpoint Summary.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Reference 2

Reference Type:

other: Toxicological assessment

Title:

Unnamed

Year:

1997

Report date:

1997

Reference 3

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-methylbutan-1-ol

EC Number:

204-633-5

EC Name:

3-methylbutan-1-ol

Cas Number:

123-51-3

IUPAC Name:

3-methylbutan-1-ol

Details on test material:

Name of test material (as cited in study report): 3-methyl-l-butanol
- Test substance No. 88/56
- Physical state: liquid/colourless
- Analytical purity: 98.6%
- Date of purity test: 1988-02-02
- Stability under test conditions: The stability was ensured for the study period under the specified storage conditions by reanalysis ( see report of Nov 25, 1988)
- Storage condition of test material: at room temperature

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

- Source: Dr. K. Thomae GmbH, D-7950 Biberach/Riss, FRG). The animals were free from any clinically evident signs prior to the beginning of the study.
- Age at study initiation: approx. 11 weeks
- Weight at study initiation: approx. 216 g
- Housing: singly in wire cages
- Diet: KLIBA rat/mouse laboratory diet 24-343-4 10 mm pellets, Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland; during the exposure-free observation period ad libitum
- Water: tap water ad libitum; during the exposure-free observation period
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- 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: the animals were exposed singly in wire cages in the whole-body inhalation chambers (volumes ca. 1100 L (test group 1, 2 and 3), and ca. 1600 L (test group 0 and parts of the test groups during the pre-flow period).
- Method of holding animals in test chamber: animals were expose din the wire cages
- Source and rate of air: the test substance was supplied by means of two continuously driven metering pumps to a vaporizer heated with a circulating thermostat. The evaporation temperature was 50-70°C. A measured stream of fresh air took up the vapours and was mixed with another stream of fresh air. After passing through a mixing device, this mixture of vapours and air was supplied to the exposure chamber.
- Temperature, humidity, pressure in air chamber: temperature and pressure in the inhalation chamber was measured continuously (generally 3 times/exposure). The relative humidity was measured at least daily.
- Air flow rate: all air flows, supply air and exhaust air were adjusted by means of flowmeters for all test groups and recorded, as a rule, 6 times/exposure.

TEST ATMOSPHERE
- Brief description of analytical method used: The concentrations of the test groups were analyzed by gas chromatography after absorption of 3-methylbutanol in 2-propanol. The gas chromatograph was calibrated with the test substance.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromatography

Details on mating procedure:

- Impregnation procedure:cohoused
- If cohoused:
- M/F ratio per cage: 1:4
- Length of cohabitation: over night
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

Gestation days 6 - 15; 6 hours/day

Frequency of treatment:

daily

Duration of test:

20 days

Doses / concentrations

Doses / concentrations 1

Remarks:

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

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.51±0.02, 2.50±0.17,and 9.8±0.66 mg/L
Basis:
analytical conc.
GC

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on the results of a pilot study. Doses up to 5 mg/L caused no toxicity in females.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation days 0, 3, 6, 9, 12, 15, 18, and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20.
- Organs examined: uterus, ovaries, placenta

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:

Statistics:

DUNNETT's test, Fisher's exact test

Indices:

The folowing indices were calculated:
- conception rate ( %;): (number of pregnant animals/ number of fertilized animals)*100
- preimplantation loss (%): (number of corpora lutea - number of implantations/number of corpora lutea)*100
- postimplantation loss (%): (number of implantations - number of live fetuses/number of implantations)*100

Historical control data:

yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: marginal body weight retardation at 10 mg/L

Details on maternal toxic effects:
Transient marginal body weight reduction at 10 mg/L at beginning of the study

Effect levels (maternal animals)

1

Dose descriptor:

NOAEC

Effect level:

2.5 mg/L air (analytical)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEC

Effect level:

10 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. Remark: at any dose level

Effect levels (fetuses)

Dose descriptor:

NOAEC

Effect level:

10 mg/L air (analytical)

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:

In an OECD 414 study (inhalation, rats) , 3-methylbutanol caused marginal maternal toxicity but no toxicity to reproduction (development, teratogneicity).

Executive summary:

The toxicity of 3-methylbutanol to reproduction was examined in Wistar rats (25 females per dose; whole body inhalation exposure at 0, 0.5, 2.5, and 10 mg/L; gestation days 6-15, 6 hours per day) according to OECD 414 and under GLP conditions. No maternal or developmental toxicity was noted in a pre-test at 5 mg/L.

In the main study, maternal toxicity was limited to a transient marginal body weight retardation at the start of the exposure period. Reproduction parameters were not affected at any dose. There was no effect regarding viability, development and malformations noted in the fetuses. The NOAEC for maternal toxicity was 2.5 mg/L, the NOAEC for developmental toxicity and teratogenicity was 10 mg/L, the highest tested dose (Klimisch, 1990).

Since 3-methylbutanol is rapidly oxidised to isovaleric acid, this result can be transferred to isovaleric acid. In this context it could be further noted that the same result (NOAEC 2.5 mg/L for the maternal organism and 10 mg/L for the foetal organism) was obtained in a GLP OECD 414 inhalation study with white Himalayan rabbits (15 dams/group; 0.5, 2.5, and 10 mg/L; gestation days 6-19, 6 hours/day; Klimisch and Hellwig, 1990). These results are suitable for the assessment of isovaleric acid.