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Case studies are available that indicate that the test substance may be involved in the development of vasculitis or pruritis (Vogt 1999, Asero 2006).

Epidemiological studies showed no evidence of increased level of sensitized patients after the test substance challenge (Brasch 1993 and 2010). In  a retrospective study, patients with reported urticaria, with or without angio-oedema, after ingesting meals or products containing the test substance, were challenged with 25, 50 and 100 mg the test substance. 1/37 was reported with an increased plasma IgE level (Nettis 2004).

Freedman (1977) reports effects in 4 of 10 patients (asthma) that were challenged with 20 mg, 80 mg and 300 mg of the test substance in an orange drink at 40 min intervals. The effect was a decrease in measured FEV1.

Twelve healthy volunteers receiving apple juice supplemented with the test substance at 0.1-0.3% (1-3 g) developed clinical symptoms including a stringent peppery taste, fulness of head, frontal headache, nervousness, belching, griping, passage of gas by rectum, nausea, dry mouth, excessive perspiration, itching of skin and scalp, pain in the stomach and vomiting. In addition, effects on urinary excretion (volume, albuminuria and increased specific gravity) were reported (Lucas, 1909). The study was very old, symptoms were self-reported, no analysis of the tested solutions was performed and the information on the subjects is limited (bias cannot be excluded).

The described results are confirmed by challenge tests in patients where of urticaria was reported in 2 of 75 patients (Ros, 1975), as well as in several publications that lack sufficient detail to be considered individually, but provide a weight of evidence of non-sensitization in healthy subjects.

A study by Warin in 111 patients showed effect in 12 of these subjects, but in this study subjects were self-reporting on the effects (Warin 1975), which renders the results less reliable.

Additional information

The available case studies are too limited to allow conclusions on the toxicity of the test substance and to allow derivation of a NOAEL. Epidemiological studies (Brasch, 1993, Brasch 2010) are available that clearly indicate that the test substance does not induce sensitization. Many studies use the human patch test in a single challenge. The validity of this test design is not officially confirmed and therefore the results of the individual tests need to be considered as preliminary. However, in view of the consistence of the results, it can be concluded that based on the information available, no sensitizing properties are associated with the test substance in healthy subjects. In patients with frequent urticaria or asthma, symptoms or exacerbation of the symptoms were observed after challenge with the test substance. A study in healthy volunteers (Lucas 1909) showed effects at low doses, but deficiencies in the study design and bias prohibit proper evaluation of the results.