FAO Nutrition Meetings
Report Series No. 40A,B,C
WHO/Food Add./67.29
TOXICOLOGICAL EVALUATION OF SOME
ANTIMICROBIALS, ANTIOXIDANTS, EMULSIFIERS,
STABILIZERS, FLOUR-TREATMENT AGENTS, ACIDS AND BASES
The content of this document is the result of the deliberations of the
Joint FAO/WHO Expert Committee on Food Additives which met at Rome,
13-20 December, 19651 Geneva, 11-18 October, 19662
1 Ninth Report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series, 1966 No. 40;
Wld Hlth Org. techn. Rep. Ser., 1966, 339
2 Tenth Report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series, 1967, in press;
Food and Agriculture Organization of the United Nations
World Health Organization
1967
ADIPIC ACID
Chemical name Hexanedioic acid; 1,4-butanedicarboxylic
acid
Empirical formula C6H10O4
Structural formula COOH
'
(CH2)4
'
CCOH
Molecular weight 146.14
Definition Adipic acid contains not less than 99.6
per cent. and not more than the
equivalent of 101 per cent. of
C6H10OT4.
Description Adipic acid occurs as white, odourless
crystals or crystalline powder, with an
acid taste.
Use As an acidulant.
Biological Data
Biochemical aspects
Adipic acid is oxidized in vitro by isolated rat liver
mitochondria (Lang & Bässler, 1953). The capacity of man and animals
to utilize adipic acid is limited to a relatively small amount. In
balance studies, groups of 10 and 4 rats, previously fed for 20-25
weeks on a normal diet or on an adipic acid diet, were given 400 mg or
800 mg adipic acid daily for 14 days. Both groups excreted 2.4-6 per
cent. of the dose independent of the previous feeding regime. No
metabolite of adipic acid could be detected in the urine (Lang &
Bartsch, 1953).
Four rabbits given 4-6 g adipic acid excreted 57 per cent. of the
dose in the urine in 4 days (Enders, 1941). A dog given a total of
23.1 g of disodium adipate during 3 days excreted 58 per cent in the
urine (Verkade et al., 1937). Man could metabolize not more than 2-5 g
adipic acid per day. The utilization increased with decreasing dose
(Weitzel, 1941; Weitzel 1947). Small amounts of adipic acid have been
frequently found in the normal human urine (Hanson, 1943). Feeding of
adipic acid to man did not influence the excretion of oxalic acid
(Kabelitz, 1343).
Rats given 250 mg/kg body-weight 14C-labelled adipic acid
oxidized up to 70 per cent. of the dose to 14CO2. The tissues from
the sacrificed rats showed very little radioactivity, the highest
activity appearing in the kidneys. Some adipic acid was excreted in
the urine; in addition other radioactive substances (urea, glutamic
acid, citric acid and ß-keto adipic acid) were found in the urine
(Rusoff et al., 1960).
Acute toxicity
Animal Route LD50 References
(mg/kg
body-weight)
Mouse oral (free acid) 1 900 Horn et al., 1957
i.p. (disodium 4 000 Rhone-Poulenc, 1965
salt)
Rat i.p. (free acid) 275 Horn et al., 1957
Short-term studies
Rat. Repeated large doses of 638-1332 mg/kg body-weight, when
given to immature rats depressed the rats of weight gain (Foulger,
1943). Five young rats given 2430 mg/kg. body-weight daily for 4 weeks
gained the same weight as controls. Three adult rats fed the same dose
for a similar period of time maintained steady body-weight, appeared
healthy and had a normal blood urea level at the end of the
experiment. Analysis of the body lipids showed no retention of adipic
acid in the body (Enders, 1941).
Groups of 18 young male rats were fed 0, 200, 400 and 800 mg
adipic acid per rat per day for 5 weeks. The highest level produced
significant growth depression with severe diarrhoea in the first 2-3
weeks. In another experiment groups of 15 male and female young rats
were fed 0, 400 and 800 mg per rat per day of adipic acid for 33
weeks. Toxic effects i.e. apathy, change in the fur, severe diarrhoea,
growth depression and high mortality rate occurred especially in the
first weeks of the experiment at the highest level only.
Histopathological examination of the animals showed no abnormalities
at levels of 0 and 400 mg/day. At the highest level enlarged hepatic
nuclei and polynucleated cells, with increased number and size of
Kupffer cells, were observed. The gut showed chronic inflammation with
much regenerative activity and mucosal damage. In a third experiment,
a protein-deficient diet was given together with 0, 50, 100, 200 and
400 mg per day for 19 weeks. At the highest level mortality rate was
increased and growth significantly depressed (Lang & Bartsch, 1953).
Rabbit. Slight nephropathic action was demonstrated in fasting
rabbits given 2 or 4 disodium adipate by s.c. injection. Phthalein dye
excretion was slightly reduced and urinary non-protein nitrogen and
creatinine were raised for 48 hours after injection (Rose et al.,
1925).
Long-term studies
Groups of 20-39 male and female rats received 0, 0.1, 1, 3 and 5
per cent. adipic acid for 2 years. Body-weight was initially depressed
significantly in males at the 3 per cent. and 5 per cent. levels and
the 5 per cent. group had the lowest weights and slightly reduced food
consumption. There was no significant difference in survival among the
various test groups from controls. Autopsy findings and tumour
incidence were not significantly different from controls and on
histopathological examination the major organs were found normal (Horn
et al., 1957). Data concerning the reproduction of the animals are not
given in the paper.
Comments
The long-term studies are satisfactory but were carried out in
one species only. Reproduction was not investigated in these
experiments, though a short-term experiment showed no apparent
deleterious effect. Parenterally administered disodium adipate appears
to be nephrotoxic to the rabbit.
Evaluation
Level causing no toxicological effect
Rat. 10 000 ppm in the diet, equivalent to 500 mg/kg
body-weight/day.
Estimate of acceptable daily intake for man
mg/kg body-weight
Conditional acceptance 0-5
Further work required
Studies of kidney function in man.
REFERENCES
Enders, A. (1941)Arch. exp. Pathol. Pharmacol., 197, 597
Foulger, J. H. (1943) Haskell Laboratory of Industrial Toxicology
(Unpublished Report)
Hanson, H. (1943) Z. ges. inn, Med.., 113, 226
Horn, H. J., Holland, E. G. & Hazleton, L. W. (1957) Agr. Food
Chem., 5, 759
Kabelitz, G. (1943) Klin. Wschr., 22, 439
Lang, K. & Bartsch, A. R. (1953) Biochem. Z., 323, 462
Lang, K. & Bässler, K. H. (1953) Biochem., Z., 323, 456
Rhône-Poulenc (1965) Unpublished report
Rose, W.C. et al., (1925) J. Pharmacol. exp. Ther., 25, 59
Russoff, I. I. et al. (1960) Toxicol. appl. Pharmacol., 2, 316
Verkade, P. E., Lee, J van der & Alphen, A. J. S. van (1937)
Hoppe-seylers Z. physiol. Chem., 250, 47
Weitzel, G. (1941) Berl. Verhdl. Sächs. Akad. Wiss. Math. -Phys.
Kl., 93, 9
Weitzel, G. (1947) Hoppe-Seylers Z. physiol. Chem., 282, 185
See Also:
Toxicological Abbreviations
Adipic acid (ICSC)
Adipic acid (WHO Food Additives Series 12)
ADIPIC ACID (JECFA Evaluation)