Trimethyl orthoacetate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP, non-guideline, animal experimental study. Minor restrictions in design and/or reporting but otherwise adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Effect of Vitamin B12 on the Metabolism in the Rat of volatile Fatty Acids

Author:

Dryden LP and Hartman AM

Year:

1971

Bibliographic source:

Journal of Nutrition, Vol. 101, pp 589-592

Materials and methods

Principles of method if other than guideline:

Feeding study designed to determine whether vitamin B12 is required for the metabolism of odd-carbon fatty acids higher than propionate and of certain branched-chain fatty acids that lead to propionate.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium acetate

EC Number:

204-823-8

EC Name:

Sodium acetate

Cas Number:

127-09-3

Molecular formula:

C2H4O2.Na

IUPAC Name:

sodium acetate

Details on test material:

- Name of test material (as cited in study report): Sodium acetate

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- From mothers who were transferred from a stock ration to a vitamin B12 deficient ration at parturition and continued on the deficient ration during lactation.
- Age at study initiation: Approximately 28 days
- Housing: Individually in cages with raised screen floors
- Diet: 25% protein, vitamin B12 deficient diet ad libitum, with or without the addition of fatty acids
- Fatty acids, when fed, replaced an equal quantity of dextrin in the diet. 1.58% acetate moiety (fed as sodium acetate, 3.58% of ration)
- Vitamin B12, when given, was included in the ration at a level of 5 µg/10 g diet
- Water: ad libitum
- Acclimation period: At least 3 days

ENVIRONMENTAL CONDITIONS: no data
IN-LIFE DATES: no data

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

Continuous

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
3.58% sodium acetate
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
equivalent to 1.58% as the acetate moiety
Basis:
nominal in diet

No. of animals per sex per dose:

6 males (without vitamin B12), 7 males (with vitamin B12)

Control animals:

yes, plain diet

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Effect levels

Dose descriptor:

NOAEL

Effect level:

1.58 other: % based on the acetate moiety

Sex:

male

Basis for effect level:

other: The effect on growth of rats fed diet containing 3.58% sodium acetate, with or without vitamin B12, was not significantly changed when compared to rats fed basal diet only.

Remarks on result:

other: see "Overall remarks, attachments"

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Acetate and higher even-carbon fatty acids had no effect on such growth. While the 5-, 7- and 9-carbon straight-chain fatty acids depressed growth on the control ration, as did propionate itself, the extent of depression decreased as the carbon chain lengthened, reflecting perhaps a tendency for the higher acids to be partially metabolized by an alternate pathway. The branched-chain acids (isobutyric, 2-methyl butyric and 4-methyl valeric), depressed growth on the control ration but isovaleric acid did not.

Effect of vitamin B12 on growth of rats fed acetic acid

			Average weight gain g (weeks 2-4)
Amount in diet %	# rats per group	Vitamin B12	Basal diet	Basal diet + fatty acid	% change
1.58	6	No	39	45	+15
1.58	7	Yes	125	124	-1

 

Applicant's summary and conclusion

Conclusions:

The effect on growth of rats fed diet containing 3.58% sodium acetate (1.58% acetate moiety) in basal diet, with or without vitamin B12, was not significantly changed when compared to rats fed basal diet only. Accordingly, the NOAEL was determined to be 3.58% sodium acetate or 1.58% based on the acetate moiety. These doses correspond to concentrations of 5370 mg/kg bw/day for sodium acetate and 2370 mg/kg bw/day for the acetate moiety (see "Overall remarks, attachments").