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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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Diss Factsheets

Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This is a summary of studies reviewed by the expert group of the World Health Organization, in CICAD 26 (2000), which accepted the data as scientifically valid.

Data source

Reference
Reference Type:
review article or handbook
Title:
Benzoic Acid and Sodium Benzoate
Author:
World Health Organization
Year:
2000
Bibliographic source:
International Chemical Assessment Document 26: 1-48. http://www.inchem.org/documents/cicads/cicads/cicad26.pdf

Materials and methods

Type of sensitisation studied:
skin
Study type:
case report
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
reports of adverse skin reactions
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Benzoic acid
EC Number:
200-618-2
EC Name:
Benzoic acid
Cas Number:
65-85-0
IUPAC Name:
benzoic acid

Method

Type of population:
other: atopic patients and general population
Ethical approval:
not specified
Subjects:
see discussion below
Clinical history:
see discussion below
Route of administration:
dermal

Results and discussion

Results of examinations:
Cases of urticaria, asthma, rhinitis, or anaphylactic shock have been reported following oral, dermal, or inhalation exposure to benzoic acid and sodium benzoate. The symptoms appear shortly after exposure and disappear within a few hours, even at low doses (Maibach & Johnson, 1975; Clemmensen & Hjorth, 1982; Larmi et el., 1988; Ring, 1989; Gailhofer et al., 1990; Aberer et al., 1992; Lahti et al., 1995; Anderson, 1996; Bindslev-Jensen, 1998; Coverly et al., 1998).

In the literature, several studies (e.g., oral provocation tests or patch tests) are available, which have been performed with small groups of patients suffering from urticaria, dermatitis, asthma, and Melkersson-Rosenthal syndrome (Juhlin et al., 1972; Freedman, 1977; Østerballe et al., 1979; Lahti & Hannuksela, 1981; Clemmensen & Hjorth, 1982; Ibero et al., 1982; Moneret-Vautrin et al., 1982; Veien et al., 1987; Aguirre et al., 1993; McKenna et al., 1994; BUA, 1995; Munoz et al., 1996; Petrus et al., 1996; Vogt et al., 1999). In most of these studies, atopic individuals have demonstrated reactions to oral and dermal challenge with benzoic acid or sodium benzoate.

The information concerning skin reactions caused by benzoic acid or sodium benzoate in the general population is limited. In a study with 2045 patients of dermatological clinics, only 5 persons (approximately 0.2%) showed a positive reaction in patch tests (Brasch et al., 1993), while 34 of 5202 patients (approximately 0.7%) with contact urticaria reacted positively (Broeckx et al., 1987). From these data, it can be concluded that skin reactions caused by benzoic acid or sodium benzoate in the healthy general population are rare.

In US FDA (1972a) and WHO (1996), several older studies concerning oral exposure to benzoic acid or sodium benzoate are described. However, owing to the limited number of individuals (mostly single case studies), the validity of these studies is limited. No adverse effects were reported after a single oral dose of 10 000 mg benzoic acid or up to 1000 mg per day over a period of up to 92 days (Gerlach, 1909). In another study with volunteers given 1000, 1500, 2000, or 2500 mg/day for 5 days each, marked symptoms, signs of discomfort, and malaise (nausea, headache, weakness, burning and irritation of oesophagus) were reported (Wiley & Bigelow, 1908). Chittenden et al. (1909) found no abnor- malities in blood picture, urine composition, nitrogen balance, or well-being in six men given 300–400 mg per day via diet for up to 62 days. In nine patients on peni- cillin treatment given 12 000 mg benzoic acid divided into eight doses over 5 days in eight subjects and over 14 days in one subject, no adverse effects on blood urea nitrogen or creatinine clearance were reported (Waldo et al., 1949). A single dose of 2000–3000 mg sodium benzoate caused signs of intoxication similar to those described for benzoic acid by Wiley & Bigelow (1908).

Sodium benzoate is used in the treatment of patients with urea cycle enzymopathies (i.e., hyperammo- naemia due to inborn errors of urea synthesis) in order to facilitate an alternative pathway of nitrogen excretion. The therapeutic dose given over several years is in the range of 250–500 mg/kg body weight per day (Batshaw & Brusilow, 1981; Green et al., 1983; Batshaw & Monahan, 1987; O’Connor et al., 1987; Kubota & Ishizaki, 1991; Tremblay & Qureshi, 1993; Feillet & Leonard, 1998). At this dose level, clinical signs of toxicity are rare and in most cases limited to anorexia and vomiting, especially after intravenous bolus infusions.

Applicant's summary and conclusion

Conclusions:
In the general human population, adverse health reactions to benzoic acid and sodium benzoate are rare. Cases of urticaria, asthma, rhinitis, or anaphylactic shock have been reported following oral, dermal, or inhalation exposure to benzoic acid and sodium benzoate. Sodium benzoate has been used therapeutically in patients with urea cycle abnormalities, at a dose range of 250-500 mg/kg bw/d, without significant adverse effects. This study is informative for evaluation of the toxicity of members of the Alkyl Benzoates category.