ETHYL FORMATE
Explanation
The biological data on ethyl formate were reviewed at the
eleventh meeting of the Joint FAO/WHO Expert Committee on Food
Additives, specifications were prepared, and a conditional acceptable
daily intake (ADI) of 0-5 mg/kg bw (as total formic acid from all food
additive sources) was established (FAO/WHO, 1967; FAO/WHO, 1968).
Since this previous review, new data have become available and
are included in this summary.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Ethyl formate is absorbed through the lungs, from the
gastrointestinal tract, and to a small extent through the skin
(Browning, 1967). This ester is hydrolysed into ethyl alcohol and
formic acid with subsequent metabolism via well-known pathways,
primarily to CO2 in the case of ethanol, while formic acid is reduced
to biologically active methyl, or excreted as the free acid. (FEMA,
1974; Williams, 1959).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
In a 24-week screening test, groups of 15 male and 15 female A/He
mice received in the first eight weeks of the test period, a total
dose of 2.4 or 12.0 g/kg bw of ethyl formate in 24 thrice-weekly i.p.
injections. The higher dose had previously been calculated to be the
maximum tolerated dose. There was no increase in the incidence of
tumours of the lung, liver, kidney, spleen, thymus, intestine, or
salivary or endocrine glands. Survival was not affected (Stoner et
al., 1973).
Special studies on pharmacological effects
In rabbits the single oral Narcotic Dose (ND50) of 28 mmol/kg bw
(approximately equivalent to 2070 mg/kg bw, the oral LD50 dose)
produced stupor and loss of voluntary movements; higher doses caused a
disappearance of corneal reflexes, nystagmus, dyspnoea and bradycardia
(Munch, 1972).
Acute toxicity
Animal Route LD50 Reference
mg/kg bw
Rat Oral 1 850 Jenner et al., 1964
Rat Oral 4 290 Smyth et al., 1954
Guinea-pig Oral 1 110 Jenner et al., 1964
Rabbit Oral 2 070* Munch, 1972
Rabbit Dermal 5 000 Opdyke, 1978
Rabbit Dermal 20 (ml/kg) Smyth et al., 1954
* Approximately equivalent to 28 mmol/kg.
Short-term studies
Mouse
The maximum tolerated dose (MTD) of ethyl formate, defined as the
maximum single dose that all five mice tolerated after receiving six
i.p. injections over a two-week period, was found to be 500 mg/kg bw
(Stoner et al., 1973).
Rat
Groups of 10 male and 10 female rats were maintained for 17 weeks
on diets containing ethyl formate at levels of 0, 1000, 2500, and
10 000 ppm (approximately equivalent to 0, 50, 150, and 500 mg/kg bw).
No adverse effects were observed on body weight gain, organ weights,
or histology of major organs (Hagan, 1967).
Groups of 15 male and 15 female rats were fed for 12 weeks a diet
containing a mixture of ethyl esters, including ethyl formate at a
level equivalent to 79.4 mg/kg bw/day. No adverse effects were noted
as judged from body weights, haematology, organ weights, gross
examination and histopathology (Oser, 1967).
Rabbit
Rabbits, receiving daily oral doses of 6.8 mg/kg bw over a period
of three months, showed a fall in body weight, some disturbance in
carbohydrate metabolism, as evidenced by high fasting blood sugar
level and longer hyperglycaemic period, and proteinuria with
histological evidence of chronic nephritis (Shillinger, 1950).
Long-term studies
In a study of 100-150 days' duration, six male (castrated) and
six female pigs per dosage group were fed diets containing 0 (control)
and 0.9% formic acid plus 0.4% propionic acid. Neither growth rate nor
EFU of the experimental group were significantly different from the
controls in either ad lib or restricted feeding (Perez-Aleman et
al., 1971).
Calcium formate fed at 0.2% of the diet produced no adverse
effects when fed to rats over five generations over a three-year
period. In a related study, 0.4% calcium formate was similarly
negative (Malorny, 1969).
Comments
Ethyl formate was evaluated on the basis of the short-term
studies, its known metabolic fate, and toxicological data from formic
acid and other formic acid esters. The Committee concluded that ethyl
formate could be included in a group ADI for formic acid.
EVALUATION
Estimate of acceptable daily intake for man
Group ADI for formic acid 0-3 mg/kg bw expressed as formic acid.
REFERENCES
Browning, E. (1965) Toxicity and metabolism of industrial solvents,
Elsevier, London and New York
FAO/WHO (1967) Toxicological evaluation of some flavouring
substances and non-nutritive sweetening agents, FAO Nutrition
Meetings Report, Series No. 44a; WHO/Food Add./68.33
FAO/WHO (1968) Specifications for the identity and purity of food
additives and their toxicological evaluation: some flavouring
substances and non-nutritive sweetening agents. Eleventh Report
of the Joint FAO/WHO Expert Committee on Food Additives. FAO
Nutrition Meetings Report Series No. 44; Wld Hlth Org. techn.
Rep. Ser. No. 383
FEMA (1974) Scientific literature review of aliphatic primary
alcohols, aldehydes, esters, and acids in flavor usage. Published
by the National Information Services under Contract with the
Food and Drug Administration
Hagan, E. C. et al. (1967) Food flavourings and compounds of related
structure. II. Subacute and chronic toxicity, Food Cosmet.
Toxicol., 5, 141-157
Jenner, P. M. et al. (1964) Food flavourings and compounds of related
structure. I. Acute oral toxicity, Food Cosmet. Toxicol., 2,
327-343
Malorny, G. (1969) Acute and chronic toxicity of formic acid and
formates, Z. Ernaehrungswiss., 9 (4), 443-449
Munch, J. C. (1972) Aliphatic alcohols and alky esters: narcotic and
lethal potencies to tadpoles and to rabbits, Industrial
Medicine, 41 (4), 31-33
Opdyke, D. L. J. (1978) Fragrance raw materials monographs, Food
Cosmet. Toxicol., 16, Suppl. 1
Oser, B. L. (1967) Unpublished report
Perez-Aleman, S. et al. (1971) Moist barley preserved with acid in
the diet of the growing pig, Anim. Prod., 13 (2), 271-277
Shillinger, Yu. I. (1950) Action of some synthetic substances on
animal organisms, Gig. i. San., 3, 37-41 (In Russian)
Smyth, H. F. et al. (1954) Range finding toxicity data. List V. Arch.
Ind. Hyg. Occup. Med., 10, 61-68
Stoner, G. D. et al. (1973) Test for carcinogenicity of food additives
and chemotherapeutic agents by the pulmonary tumor response in
strain A mice, Cancer Res., 33, 3069-3085
Williams, R. T. (1959) Detoxication mechanisms, p. 50: the metabolism
and detoxication of drugs, toxic substances and other organic
compounds
See Also:
Toxicological Abbreviations
Ethyl formate (ICSC)
Ethyl formate (FAO Nutrition Meetings Report Series 44a)
ETHYL FORMATE (JECFA Evaluation)