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Description of key information

Several data on human dermal exposure with Bronopol to estimate its irritating and sensitising potential were created and published (e.g. multicenter studies).

Additional information

Relevant and reliable studies on volunteers and other persons (patch testings) were marked as key studies and listed under "Epidemiological data" and "Direct observations".Some of the publications listed under "Epidemiological data" due to their topics include also important data on the irritation and sensitisation potential of Bronopol. For the sake of completeness, under the chapter "Sensitisation data" these data are seperately presented in a basic way, too.

 

 

DATA ON SENSITISATION IN HUMANS (Human patch tests)

 

Attley, 1977

A Skin sensitization test in human volunteers using occlusive epidermal application for both induction and challenge was performed by Attley (1977). For induction, 107 male volunteers received 10 applications of 5% Bronopol in Yellow Soft Paraffin (0.5 g) at the back over a period of 3 weeks.Applications were covered by an occlusive patch. After a two week rest period, a challenge patchcontaining 0.25 % Bronopol in 0.5 g Paraffin was applied at a different site and left in place for 72 hours.

Skin reactions were assessed on a 6-point scale prior to each induction application and after the 10th application, and also 72 hr after the challenge, as follows: 0 = negative, +/- = equivocal, 1 = erythema, 2 = erythema and induration, 3 = erythema, induration and vesicles, 4 = erythema, induration and bullae.

As a result, of the 107 subjects who started the study, 93 completed the program (14 subjects withdrew during the study for reasons unrelated to toxicity). During the induction phase 5% Bronopol caused irritation reactions in many subjects, e.g. 22 subjects (21%) of those who started showed reactions graded as 3 or higher at least once during the induction phase.Challenge carried out in 93 subjects resulted in skin reaction scores of zero (0) in every case.The authors suggest that previous observations of the skin sensitizing activity of Bronopol (Antimicrobials: experimental contact sensitization in man. Marzulli, F.N. and Maibach, H.I., J. Soc. Cosmet.Chem. 24, 399, 1973) was false positive due to the use of irritant concentrations of Bronopol in the challenge phase.

Conclusively, after a three-week induction period with 5% Bronopol (an irritant concentration), followed by a two-week incubation period, elicitation with a concentration known to be sub-irritant (0.25%) showed Bronopol to be without skin sensitising activity. The study is classified as key study.

 

Geier et al., 2011

In a publication of Geier et al. (2011), Bronopol was identified as one of the most frequent contact allergens. This epidemiological surveilance of contact sensitization included as time period the years 2007 to 2009. For Bronopol, in case of women (n = 21.250), a relative response rate of 1.3% (1.2 - 1.5 %, 95% confidence interval) and in case of men (n = 12841), a relative response rate1.6% (1.4 - 1.9%, 95 % confidence interval) were found. The publication is classified as key study.

 

Latorre et al., 2011

Patients with positive patch test reactions to formaldehyde or any of seven formaldehyde-releasers, including Bronopol, were investigated by Latorre et al. (2011). A total of 7838 patients underwent patch testing with at least the baseline series. Bronopol were tested in 1192 patients. The most frequent allergens were formaldehyde (1.72 %), imidazolidinyl urea (1.05 %), quaternium-15 (0.88 %), and diazolidinyl urea (0.79 %). Patients with sensitization to only formaldehyde had a higher frequency of occupational dermatitis (25 %) than patients with sensitization to only formaldehyde-releasers (9.5 %). The test substance was positive in 2 patients (0.16 %). Furthermore, patients allergic to Bronopol showed also an allergy towards otherformaldehyde-releasers (DMDM hydantoin,1,3,5-Trihydroxyethylhexahydrotriazine, Methenamine).The publication is classified as key study.

 

Schnuch et al., 2011

In a retrospective analysis of data on patch testing of preservatives contained in the standard series and special series collected by the IVDK during 1996–2009 (Schnuch et al, 2011) the sensitisation potential of different preservatives were investigated. In case of Bronopol (0.5 %), 16396 men and 26486 women (total: 42882 individuals) were tested. A positive reaction was observed in 268 men and 345 women (positive total: 613 individuals). Bronopol was further characterized as an allergen with a sensitisation frequency of 1.25 %. The reaction index was 0.14 (0.09 - 0.18, 95 % confidence interval) and the positivity ration of preservative patch test preparations was 77.1 (74.8 - 79.3, 95 % confidence interval). The publication is classified as key study.

 

Zug et al., 2009

The North American Contact Dermatitis Group (NACDG) tested patients who have suspected allergic contact dermatitis with a broad series of screening allergens (including Bronopol) from January 1, 2005, to December 31, 2006.As positive allergen Bronopol was identified in patch testing of 4435 individuals (positive reaction: 3.4%).The publication is classified as key study.

 

Bryce, 1978

A Patch testing with Bronopol was performed (Bryce, 1978) in 149 patients, which attended a contact dermatitis clinic. As testing regime 0, 0.5, 1 and 2 % bronopol in pet., and 0, 0.05, 0.1 and 0.25 % in aqueous buffer at pH 5.5 was used. Bronopol (1 % in pet.) showed slight erythema in 2/10 patients, at 2 % in pet. moderate erythema in 4/10, and at 0.25% in aq. 1/10 slight erythema. No evidence of sensitization was seen. Conclusively, Bronopol showed to be a mild irritant when applied in pet. at 0.25 %, but no evidence of sensitization in this study. The publication is classified as key study.

 

Maibach, 1977

A patch testing with Bronopol was performed (Maibach, 1977) in 8 and 120 subjects.As testing regime 0.1, 0.5, 1, 2.5 and 5 % Bronopol in soft paraffin and 5 % (induction) and 0.25 % challenge Bronopol in soft paraffin was named. The irritancy threshold was approximately 0.5-1 %. No evidence of sensitization was observed at 0.25 %.False positive results may be obtained in patch tests by the use of Bronopol concentrations above 0.5 %. The publication is classified as key study.

 

Schnuch, 1998

Patch testing with Bronopol was performed by Schnuch (1998) in 11 443 patients (preservative series) and 1 781 patients (industrial biocides) seen in several dermatology clinics from 1990 –1994. In 134 cases (1.2 %) the patch test reaction to Bronopol (0.5 % in pet.) in preservative series and 32 cases (1.8 %) in industrial series showed positive reactions. Conclusively, sensitization rates seem to be quite low in this population. The publication is classified as key study.

 

Frosch, 1990

A patch testing with Bronopol in 6 patients with dermatitis was reported (Frosch, 1990). Positive patch test reaction to Bronopol (0.25 % in pet.) in all 6 patients (5 of them with clinical relevance was noticed. Incidence was 0.23 % (6 of 2623 patients). Conclusively, very low incidence of positive patch test reactions to Bronopol in these cases. For patch testing 0.25 % bronopol in pet. is recommended. The publication is classified as key study.

 

Ford, 1986

A patch testing with Bronopol was performed in 2298 patients (Ford, 1986). 20 of 2298 patients (0.8 %) react to Bronopol (1 % in pet.). Conclusively, only a small number of subjects react to Bronopol in this group. False positive results may be seen by approaching the irritancy threshold of Bronopol (0.5 – 1 %).The publication is classified as key study.

 

Peters, 1983

In a human assay 129 patients received patch tests to a standard screening battery containing more than 30 commonly encountered allergens - including Bronopol - from January to July, 1980.The tests were administered according to the guidelines of the North American Contact Dermatitis Group, and the AI test method was used. 129 patients were used.Of the 129 patients, 57 were tested with 1% aqueous Bronopol only.

A testing series with 3 concentrations was added in February 1980, and 72 of the 129 patients had application of patches containing 1%, 0.5% and 0.25% Bronopol.

23 patients showed irritant reactions to 1% Bronopol, 3 and 1 patients showed irritant reaction to 0.5% and 0.25% Bronopol, respectively.

Of the 72 patients tested with only 0.5 % and 0.25% Bronopol 12 patients (16.6%) tested with 0.5 and 0.25% Bronopol showed positive non-irritant reactions. 9 of these 12 (12.5% of the overall tested patients) were considered clinically relevant in terms of use history of a Bronopol-containing product in relationship to the type and course of their dermatitis of a Bronopol containing products. 5 out of 9 patients reacted only to 0.25% Bronopol, and 4 out of 9 patients showed a response to both concentrations. In most cases it was found that exposure to Bronopol occurred through use of EUCERIN cream, which contains 50% water-in-oil emulsion with petrolatum, mineral oil, mineral wax and wool wax alcohol and 0.05% Bronopol as preservative.

The stopping of routine use of EUCERIN cream resulted in a marked decrease in the number of positive patch tests to Bronopol. In fact, compared with the period from January to June 1980, where a 12.5% incidence of positive patch tests to 0.5% Bronopol and/or 0.25% Bronopol was reported, from January to June 1981, the incidence decreased to 10.7% positive patch tests to 0.5% Bronopol (7.8% to 0.25% Bronopol), and further dropped to 2.3% positive reactions to 0.5% Bronopol from January to June 1982 (2.0% to 0.25% Bronopol).

Because of the frequency of patch test reactivity in combination with a history Bronopol exposure, caution should be exercised in the prolonged and widespread use of preparations containing Bronopol by patients with dermatitis. The publication is classified as key study.

 

Peters, 1983

Peters and coworkers conducted an analysis of patch tests with Bronopol (Peters, 1983). 72 patients were tested with 0.5% and 0.25% Bronopol.Twelve (16.6%) of the tested patients showed non-irritant positive reactions.9 out of these 12 (representing 12.5% of the tested patients) were considered clinically relevant in terms of use history of a Bronopol-containing product in relationship to the type and course of their dermatitis. 5 out of 9 reacted only to 0.25% Bronopol, and 4 out of 9 showed a response to both concentrations.In most cases it was found that exposure to Bronopol occurred through use of Eucerin cream, which contains 50% water-in-oil emulsion with petrolatum, mineral oil, mineral wax and wool wax alcohol and 0.05 % Bronopol as preservative.This product was widely prescribed in as a general lubricant for patients with a variety of dermatologic problems, in particular, allergic or irritant contact dermatitis.

The author referred to three cases in detail: A 76-year-old woman had dermatitis over the extensor aspects of both forearms in the areas where she had applied Eucerin® cream.Patch tests showed positive reactions to 0.5% and 0.25% concentrations of Bronopol. A 40-year-old man who had been applying EUCERIN cream to neurodermatitis of the lower extremities had patch test reactions to 0.5 % and 0.25 % Bronopol, to EUCERIN cream, and to wool wax alcohols. The third patient that suffered from ichthyosis vulgaris and chronic hand dermatitis, had patch test reactions to both concentrations of

Bronopol.

Conclusively, caution should be exercised in the prolonged and widespread use of preparations containing Bronopol, such as e.g. EUCERIN cream, by patients with dermatitis. The publication is classified as key study.

 

Shaw, 1997

Patch testing with Bronopol was analyzed by Shaw (1997) in 2152 patients of deramtology clinics. 2 of 93 patients tested with Bronopol (1 % in pet.) showed allergic reactions, 4 irritant reactions.At 0.25 % 1 of 63 showed positivie allergic reaction and 1 irritant reaction.At 0.5% 8 out of 1996 found to show an allergic and 11 an irritant reaction. Positive patch test reaction rate to Bronopol (0.5 % in pet.) of 0.4 % in study is not considered to be quiet low. The publication is classified as key study.

 

Rudner, 1977

Patch testing was performed with Bronopol (1%) in 190 patients with dermatitis. 25 subjects showed a positive skin reaction to Bronopol at 1% in aqua. The concentration chosen for patch testing could have caused irritant reactions and are too close to the irritancy threshold to give a clear distinction between irritancy and sensitisation. The publication is classified as key study.

 

Storrs, 1983

A patch test was performed in 7 patients with dermatitis (Storrs, 1983). Positive patch test reaction to Bronopol in all seven patients (6 at 0.25 % and one at 1 %). Conclusively, positive patch test reaction to Bronopol in these cases. For patch testing 0.25 % bronopol in pet. is recommended. The publication is classified as key study.

 

Anonymous, 1984 (Section 7.12)

In a safety assessment (Anonymous, 1984), data on occupational exposure of 50 workers to Bronopol were reported. The skin of 20/50 Bronopol exposed workers showed signs of skin irritation and/or superficial burns following exposure to saturated aqueous solutions or powder of Bronopol on at least one occasion. In 8 cases a second occurrence, in 6 cases, a third occurrence and in 3 cases, a fourth occurrence were reported. None of the concerned workers had quit the job because of these injuries. Conclusively, the reported findings were described as irritant reaction rather than contact allergy.