2-methylvaleric acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Screening test method. Restrictions: compared to OECD 414 low number of dams and reduced scope of examination of malformations (number of fetuses and number of tissues reduced). Acceptable for assessment because a total of 15 structurally related acids were tested.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1994

Report date:

1994

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Principles of method if other than guideline:

Method: other: Screening acc. to Chernoff, N. and Kavlock, J. Toxicol. Environ. Health, 10, 541-550, 1982

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methylvaleric acid

EC Number:

202-594-9

EC Name:

2-methylvaleric acid

Cas Number:

97-61-0

Molecular formula:

C6H12O2

IUPAC Name:

2-methylpentanoic acid

Details on test material:

- Source: Chem. Dynamics Corp., not further specified

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC, USA
- Time mated

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 +/- 1°C
- Humidity (%): 50 +/- 10%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): low water solubility
- Concentration in vehicle: 375 and 500 mg/mL
- Amount of vehicle (if gavage): 1 mL/kg bw

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Time-mated animals

Duration of treatment / exposure:

Gestation days 6 - 15

Frequency of treatment:

once per day

Duration of test:

Duration of test: up to post-natal day 6

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 187.5 and 250 mg/kg bw and day
Basis:
actual ingested

No. of animals per sex per dose:

Controls: 20
Treated: 15

Control animals:

yes, concurrent vehicle

Details on study design:

Sex: female

- Dose selection rationale: based on the results on maternal toxicity of pilot studies using non-gravid rats. The high dose was expected to produce moderate maternal toxicity and the low dose was 75% of the high dose.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily
- Results: report, table 1


DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: GD 6, 8, 10, 13, 16, and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 6
- Organs examined: uterine implantation sites

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: 2 per litter; one per sex if possible
- Head examinations: No

Statistics:

Dams that died or had only one implant were excluded from statistics. General linear model was used. Visceral alterations in fetuses were only examined in dead pups and were therefore excluded from statistics. When a significant treatment effect was detected by analysis of variance, Student’s t-test was used to identify significantly different groups.

Indices:

not calculated

Historical control data:

Indenpendent controls (n=20) were run for each of the 15 test substances, i.e. a total of 300 control animals was analysed

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
% animals affected:
Controls: rales (5). Body weight change (g) GD 6-20: 58.4; n=18
375 mg/kg bw /d: rales (100); dyspnea (40), motor depression (13), death (213. Body weight change (g) GD 6-20: 29.3 (reduced; p<0.001); n=11
500 mg/kg bw /d: rales (87), dyspnea (60), motor depression (73), death (53). Body weight change (g) GD 6-20: 30.5 (reduced; p<0.001), n=9

Effect levels (maternal animals)

Dose descriptor:

LOAEL

Effect level:

187.5 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effect on perinatal loss, pup weight, but trend at the high dose level without gaining a level of statistical significance. No malformations.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

2-MP; development

Dose (mg/kg bw)	No dams	No. implants (means)	No. live pups (means)		Perinatal loss (%) (means)	Pup weight (g) (means)
			PD1	PD6		PD1	PD6
0	18	12.8	12.1	11.4	10.7	7.1	14.2
187.5	11	12.4	11.3	11.2	10.7	7.0	14.0
250	9	13.4	12.0	11.8	19.9	7.0	13.7

PD1, PD 6 = postnatal day 1 and 6, respectively

 

 

Skeletal findings 2-MP (T02102)

Skeletal findings (2 pubs/litter examined)	Dose level (mg(kg bw and day)
	0	187.5	250
No pups (litters) examined	36 (18)	22 (11)	16 (8)
Rudimentary lumbar rib	10 (7)	10 (8)	3 (2)
Bilobed centrum	3 (3)	2 (2)	1 (1)
Extra sternebra	2 (2)	1 (1)	0

Applicant's summary and conclusion

Conclusions:

In a Chernoff/Kavlock screening assay, 2-methylpentanoic acid was not reprotoxic in female Sprague Dawley rats at maternally toxic doses

Executive summary:

2-methylpentanoic acid was tested in a Chernoff/Kavlock screening assay using pregnant Sprague Dawley rats (20 controls, treated rats 15 per dose level). The test substance was administered in corm oil (1 mL/kg bw) at 187.5 and 250 mg/kg bw. The doses were selected based on the maternal toxicity observed in non-gravid females in preceding studies. Clinical signs, body weight, and pre-implantation loss in dams was recorded. Foetal weight at birth and at day 6 was recorded. Histopathology on the pups was performed on a screening level as follows:

Dead pups: soft tissue alterations
Externally malformed pups: skeletal and/or soft tissue alterations as indicated by the gross findings
Surviving pups: skeletal alterations in 2 pups per litter (one per sex).

The results indicate maternal toxicity at both dose levels, with mortalities of 13% and 27%, respectively, and with clinical signs and significantly reduced body weight gain during pregnancy in the surviving dams. Peri-natal loss and pup weight at birth or postnatal day 6 was not affected; there was a trend for effects at the high dose level without gaining statistical significance. Treatment-related malformations were not reported (Narotsky, Francis, and Kavlock, 1994).

The study protocol used was a screening protocol for developmental toxicity. The study is not comparable with current screening methods (OECD 412 or 422) or the specific developmental toxicity protocol (OECD 414). It can, however, be used in a weight of evidence approach because the publication reports the results for a total of 15 acids (13 of these branched) what allows to read across the results to isovaleric acid. Other than isovaleric acid, 2-methylpentanoic acid bears the methyl group at the 2-position. The authors found developmental toxicity only with those acids bearing a side chain at the 2-position, with a side chain lengths of 2 or more carbons.

The study is considered to be valid with restrictions.