Toxicological Evaluation and Limit Values for Nonylphenol, Nonylphenol Ethoxylates, Tricresyl, Phosphates and Benzoic Acid

6. Summary

Description

Benzoic acid appears at room temperature as colourless crystals or a white powder with no or a faint, pleasant odour. It is only slightly soluble in water, but soluble in alcohol and chloroform.

The major use of benzoic acid is as preservative in food and industrial products.

Environment

Benzoic acid may be released into the environment as emissions and largely appears as aerosols. It is formed in combustion processes and found in automobile exhaust, refuse combustion and has been measured in tobacco smoke. Only very sparse data are available concerning atmospheric concentrations of benzoic acid. Concentrations at 1-26 ppt (in city air) and 0-0.30 ppm (industrial environment) have been measured. Benzoic acid is released into wastewater during its production and use in manufacturing of other compounds.

In addition, benzoic acid occurs naturally in foodstuffs up to 30 mg/kg.

Benzoic acid seems readily biodegradable in water and soil and does not accumulate.

Human exposure

The general population is mainly exposed to benzoic acid through the ingestion of foods which contains benzoic acid naturally or as a preservative. In addition to the oral route, exposure may result from inhalation via auto exhaust, tobacco smoke and other combustion sources.

Toxicokinetics

Benzoic acid is rapidly and almost completely absorbed after oral administration in man and animals. After dermal application to humans the absorption is about 40%. Within 24 hours benzoic acid is nearly completely excreted in the urine, mainly as hippuric acid. Endogenous formation of benzoic acid in the organism is taken place. No accumulation in the body.

Human toxicity

Sublimated benzoic acid as well as benzoic acid dust in the air has been connected with occurrence of rhinitis, shortness of breath and eye irritation. No data on duration and exposure was given.

Benzoic acid has been reported to cause gastro-intestinal disorders after single oral or short term administration of 1-5 g, corresponding to approx. 14-70 mg /kg bw. However, doses below 14 mg /kg bw/day for 88-92 days were without visible effect. The effects seen in humans after ingestion of benzoic acid and sodium benzoate may be related to a disturbance in acid-base equilibrium (systemic effect) or to irritation of the surface epithelium (local effect).

Besides the gastro-intestinal effect, benzoic acid is able to induce hypersensitivity reactions. Some persons who suffer from asthma, rhinitis, or urticaria undergo exacerbation of symptoms following ingestion of benzoic acid. Oral doses corresponding to less than 4 mg benzoic acid/kg bw has been shown able to cause skin reactions in sensitive persons. Anaphylaxis has been induced in sensitive persons after ingestion of a meal containing sodium benzoate as preservative and a following provocation test with oral administration of 160 mg sodium benzoate (corresponding to 2.5 mg benzoic acid/kg bw) induced localised urticaria.

Dermal exposure to benzoic acid may induce transient non-immunological contact reactions (erythema, local urticaria).

Animal toxicity

A lot of animal exposure data exists on benzoic acid/sodium benzoate, however the majority of the studies mentioned below are of an earlier date and do not meet the requirement of today’s quality standards.

An acute one hour inhalation toxicity study in rats using benzoic acid, stated to be in the vapour phase, has shown that the LC₅₀value is > 26 mg/m³.

In a four-week study rats were exposed by inhalation to benzoic acid dust aerosol. Doses of 25, 250 or 1200 mg/m³ for 6 hours/day, 5 days/week caused upper respiratory tract irritation in all mid- and high-dose animals. Deaths were seen at 1200 mg/m³. Statistically significant decrease in body weight gain and some organ weights were found in high-dose animals. The histopathological examination revealed compound-related lesions in the lungs: an increase in the intensity and extent of interstitial inflammatory cell infiltrate and an increase in the incidence and intensity of interstitial fibrosis. The lung lesions were seen in all dosed groups, and with respect to the cell infiltration the effect seems dose related. The author stated that the results of the study indicate that levels as low as 25 mg/m³ benzoic acid for four weeks produce toxic effects in the lungs.

The acute oral toxicity of benzoic acid is rather low. LD₅₀-values have been reported within the range of 1700-2500 mg benzoic acid/kg bw.

The results of the short and long term toxicity studies in rats, mice, cats and dogs are given in table I and II. From the table it is seen that administration of benzoic acid or sodium benzoate at levels higher than about 1% in the diet for rodents (˜ 600 mg benzoic acid /kg/day), 0.5% for cats (˜ 400 mg/kg/day) and ˜ 1000 mg/kg/day for dogs resulted in adverse effects (increased mortality, changes in body and organ weight, damage to liver and kidney, neurological disorders).

The LD₅₀-value for dermal exposure is low (>10.000 mg/kg bw). Benzoic acid is found minimally irritating to the skin and slightly irritating to the eyes.

developmental effects

No human data have been found.

In a four generation feeding experiment in rats benzoic acid in doses up to 1% benzoic acid (roughly corresponding to 600 mg/kg bw/day) did not lead to any effect on fertility and litter size. Up to 2% sodium benzoate in the diet during the whole gestation period (approx. 1180 mg benzoic acid/kg bw/day) was without adverse effect. At higher levels maternal toxicity, perinatal death and foetal abnormalities of organs and the skeletal system were found. Maternal toxicity and severe adverse effects on foetal development has been reported when benzoic acid was given to rats in doses of 450 mg/kg bw/day in day 7-16 of gestation, however, details were not specified (abstract only).

Studies in mice, rabbits and hamsters did not show any signs of benzoic acid induced maternal or foetal toxicity. However, only dose levels up to 150-250 mg/kg/day were tested.

Genotoxicity

Benzoic acid/sodium benzoate was found without mutagenic effect in in vitro mutagenicity tests. However, with respect to sodium benzoate -but not benzoic acid- positive or ambiguous results were obtained in some of the in vitro chromosomal aberration tests and tests for effects on DNA. Negative results were seen in the in vivo chromosomal aberration tests.

Carcinogenicity

Two studies are available. According to the authors, no carcinogenic effect was observed. However, the studies do not meet the requirements of today’s guidelines and are inadequate for evaluation.