Toxicological evaluation of some food
additives including anticaking agents,
antimicrobials, antioxidants, emulsifiers
and thickening agents
WHO FOOD ADDITIVES SERIES NO. 5
The evaluations contained in this publication
were prepared by the Joint FAO/WHO Expert
Committee on Food Additives which met in Geneva,
25 June - 4 July 19731
World Health Organization
Geneva
1974
1 Seventeenth Report of the Joint FAO/WHO Expert Committee on
Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
FAO Nutrition Meetings Report Series, 1974, No. 53.
p-HYDROXYBENZOATE, BUTYL
Explanation
This substance has been evaluated for acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
Ref. No. 13) in 1965.
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and is reproduced
in its entirety below.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Dogs given 1000 mg/kg bw of the butyl ester excreted only 48.2%
of the dose in the urine within 48 hours. Metabolic pathways other
than hydrolysis and subsequent conjugation may account for the poor
recovery of butyl ester metabolites in balance experiments (Jones et
al., 1956). Dogs fed 1000 mg/kg bw of butyl ester or given 50 mg/kg bw
i.v. excreted 40-48% of the ester in the urine as metabolites and 0.5%
as unchanged ester (Sokol, 1952).
The metabolism of various alkyl p-hydroxybenzoates (butyl, ethyl,
methyl and propyl) was investigated in rabbits using oral dose levels
of 0.4 and 0.8 g/kg and compared with that of p-hydroxybenzoic acid,
which is a major metabolite of their esters. Metabolism of the esters
was very rapid and excretion of the free p-hydroxybenzoic acid in the
urine after administration was much less than that of p-hydroxybenzoic
acid but output of the acid conjugated with glycine and glucoronic
acid was much larger. When various alkyl esters were administered,
those were converted into the free acid (25-39%), glycine conjugate
(15-29%), ester-type glucuronide (5-8%), ether-type glucuronide
(10-18%) and the sulfate (7-12%) during 24 hours (Tsukamoto & Terada,
1964).
TOXICOLOGICAL STUDIES
Special studies on teratogenicity
An attempt has been made to correlate the potential teratogenic
activity of three salicylate derivatives, with their ability to
inhibit acid mucopolysaccharide synthesis. The sodium salt of
p-hydroxybenzoic acid, a metabolite of the esters did not exhibit
teratogenic potential (Larsson & Boström, 1965).
Acute toxicity
LD50 References
Animal Route (mg/kg bw)
Mouse Oral (free acid) 5 000 Sokol, 1952
Oral (Na salt) 950 Matthews et al., 1956
i.p. (free acid) 230 appox. Sokol, 1952
i.p. (Na salt) 230 ± 24 Matthews et al., 1956
Short-term studies
Rat
Groups of 12 male and 12 female weanling rats were fed dietary
levels of 0, 2 and 8% of butyl ester for 12 weeks. At the 8% level,
no males survived the experimental period, the mortality rate in the
females was higher than that of the controls, and the rate of weight
gain was markedly affected; the animals at this level also showed
depressed and decreased motor activity. However, autopsies with
histological examination of animals dying during the test showed only
pneumonia and pulmonary consolidation, without difference between
treated and control animals. Food consumption was unaffected in all
groups and necropsy of all survivors showed no difference other than
the body weight depression at 8% (Matthews et al., 1956 and Report on
Preservatives 1959).
Long-term studies
Data are not available.
OBSERVATIONS IN MAN
Cases of sensitivity have been reported (Schamberg, 1967 - one
case; Schorr & Mohajerin, 1966 - one case; Epstein, 1968 - three
cases; Wuepper, 1967 - four cases). It has been found that 0.5% or
less of p-hydroxybenzoate esters in a skin cream is capable of
producing a relentless progression and extension of a dermatitis.
Cross sensitivity to all the significant esters (butyl, ethyl,
methyl, propyl) is seen in most patients who develop sensitivity to
one of them. In a two-year survey of 273 patients with chronic
dermatitis, the incidence of positive patch-tests with 5%
p-hydroxybenzoate was 0.8% (Schorr, 1968).
Comments:
The available data do not include any long-term studies and only
one species has been investigated in short-term experiments. There is
no information on human metabolism.
EVALUATION
Not possible with the data provided.
REFERENCES
Epstein, S. (1968) Ann. Allergy, 26, 185
Jones, P.S. et al. (1956) J. Amer. pharm. Ass. sci. Ed., 45, 270
Larsson, K. S. & Boström (1965) Acta Paediat. Scand., 54, 43
Matthews, C. et al. (1956) J. Amer. pharm. Ass. sci. Ed., 45, 260
Report on Preservatives (1959) Food Standards Committee S.O. Code No.
24-280
Schamberg, I. L. (1967) Arch. Derm., 95, 626
Schorr, W. F. (1968) J. Amer. med. Ass., 204, 859
Schorr, W. F. & Mohajerin, A. H. (1966) Arch. Derm., 93, 721
Sokol, H. (1952) Drug Stand., 20, 89
Tsukamoto, H. & Terada, S. (1964) Chem. Pharm. Bull., 12, 765
Wuepper, K. D. (1967) J. Amer. med. Ass., 202, 579