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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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: Acceptable, well-documented publication which meets basic scientific principles. Screening test method, accepted scientific standards, sufficiently documented, acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Method: other: see Method
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
Sodium isovalerate
EC Number:
208-723-5
EC Name:
Sodium isovalerate
Cas Number:
539-66-2
IUPAC Name:
sodium 3-methylbutanoate
Details on test material:
The anhydrous acid was treated with NaOH to give sodium isovalerate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation: 4 weeks
- Weight at study initiation: 90 g
- Housing: in groups of 5 or 6
- Diet: ad libitum (30% dextrose, 20% cormmeal; 20% soybeanmeal, 10% casein, 9% corn starch, 5% corn oil, 4% salt mixture, 2% mixture of vitamins in dextrose)

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Details on oral exposure:
DIET PREPARATION
no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
14 d (pilot study) and 90 d (main study)
Frequency of treatment:
continuous
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
5 % [= 50000 ppm)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
approx. 5000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 to 6 males
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
weight gain 6.2g/day; identical to controls
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
14g/day
Haematological findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
no findings; 35 organs examined
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
no findings; 35 organs examined

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 50 000 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: 5% in feed = 50,000 ppm in feed
Dose descriptor:
NOAEL
Effect level:
5 other: %
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Calculated, assuming a food uptake of 100g/kg bw and day

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Range-finding study:

At 10-% TS, food consumption was markedly reduced, associated with substantial weight loss. 

Definitive study:
At 5 % [approx. 5000 mg/(kg bw and day)], no adverse effects were noted with respect to body weight development and organ weights, histology, and blood parameters. No local effects (irritation) were observed at that dose level.

The mean urinary pH value was 8.4 in animals ingesting isovaleric acid salt, compared with 7.2 for the control animals (Amoore et al, 1978). 

 

Applicant's summary and conclusion

Conclusions:
Despite the low number of animals it can be concluded that in light of the high dose applied the prolonged uptake of the TS is not associated with toxic effects in rats.
Executive summary:

In a rat feeding study, neutralised isovaleric acid was fed to a group of 5 to 6 male SD rats for 90 days at 5% (50,000 ppm) in the diet. In a pilot study with 10%, the food intake was significantly reduced, rats lost significantly weight, and one rat dies. No effects were seen in the main study In the main study, the parameters examined (food consumption, bodyweight development, organ weights, haematology, blood chemistry, urinalysis, and histopathology of 35 organs) did not significantly differ from controls with the exception of a more basic urine in treated rats compared to controls (pH 8.4 versus 7.2). Based on the above the authors concluded that the NOAEL was 5% in diet or 5000 mg/kg bw/day in this study (Amoore et al, 1978). 

 

The protocol of this pre-guideline, pre-GLP study is not fully comparable to current guideline studies since the animal number was low, only male rats were used, and because the documentation is brief. On the other hand side the study clearly showed that ingestion of even large amounts of isovaleric acid with the feed over a 3-months period did not cause local or systemic adverse effects. The study is therefore considered to be valid and suitable for assessment.

 

NOAEL of 5000 mg/kg for sodium isovalerate corresponds to an NOAEL of 4100 mg/kg for the free isovaleric acid.