Registration Dossier

Administrative data

Description of key information

Based on the available animal and human data the test substance is not considered to be a skin sensitiser.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Animal studies:

To assess the skin sensitization potential of the test substance, a Guinea Pig Maximization Test (GPMT) was performed according to OECD guideline 406 (2005). The test substance concentrations for the main test were selected based on the results of the pre-test. Intradermal induction was performed with a 5% test substance and the epicutaneous induction with a 25% test substance. For the challenge, a 10% test substance preparation was chosen. The study was performed using one control group (5 animals) and one test group (10 animals). The intradermal induction was performed on day 0 and the epicutaneous induction on day 7. The challenge was carried out 14 days after the epicutaneous induction. The intradermal induction caused intense erythema and swelling at the injection sites of the test substance preparation in all test group animals. After the epicutaneous induction, incrustation, partially open (caused by the intradermal induction) could be observed in addition to moderate and confluent erythema and swelling in all test group animals. The challenge did not cause any skin reactions in all test group animals. The test substance preparations caused a yellow discoloration (after the intrademal and epicutaneous induction) or a slight yellow discoloration (after the challenge) of the application areas. However this did not impair evaluation of erythema formation. Based on these results, under the conditions chosen, the test substance was considered to be not sensitizing.

 

Human data:

Eight studies were identified concerning the occurrence of contact dermatitis after dermal exposure to the test substance. Only two were considered to be performed or reported adequate for the risk assessment of skin sensitising properties. These two studies are studies by Erdmann et al (1999) and Lachapelle (2005).

 

Lachapelle (2005) reported on 500 consecutive patients who were patch tested with a 10% povidone-iodine (PVP-I) solution. Patch tests were applied for 2 days; 2 readings were made at 2 and 4 days. Two weeks later, patients with a positive patch test (+ to +++) to PVP-I were put through a repeated open application test (ROAT) using the PVP-I solution, as is (i.e. 10% PVP-I). Fourteen of the 500 patients showed a positive patch test to PVP-I (2.8%). The scoring of positive patch tests was as follows: 6 +, 7 ++ and 1 +++, at 2 days. The tests were still positive at 4 days, but there was an overall reduction in the scores. Only 2 of the 14 patients with a positive patch test to PVP-I showed a positive ROAT: 1 after 4 applications and 1 after 6 applications. The positive reactions were diffusely erythematous, slightly oedematous with follicular elevations looking like tiny papules. The authors noted that the patch test is not an appropriate method to determine skin sensitisation of PVP-I as it can lead to false positive reactions due to the irritant properties of PVP-I under occlusion. Therefore the ROAT is much more appropriate test method for irritating substances such as PVP-I.

 

Erdmann and co-workers (1999) presented two cases of post-operative dermatitis due to Povidone-iodine. In order to determine to what constituent the two patients were allergic to, the patients were exposed to 10% Povidone-iodine (Freka-cid cream) and Betaisodona solution (Betadine solution), respectively, before surgery. Patch tests were performed to assess potential sensitisation to Freka-cid cream and Betaisodona solution and its constituents. In case 1, patch testing with Freka-cid cream and all its constituents supplied by the manufacturer revealed positive reactions to Freka-cid and Povidone-iodine. Additional patch testing with a commercial series of common antiseptics showed a positive reaction to iodine. In case 2, patch testing with Betaisodona solution and all its constituents supplied by the manufacturer revealed positive reactions to Betaisodona solution and Povidone-iodine. Additional patch testing with a commercial series of common antiseptics showed a positive reaction to iodine. The experiment performed to determine to what the subjects were allergic to has been performed with a patch test. As already mentioned by Lachapelle (2005) this method is not reliable for PVP-I. Nonetheless, at least for the second case (exposed to Betaisodona solution) it is known that the effects occurred 24 hours after exposure indicating an allergic response. The other patient on the other hand was still using PVP-I when effects were observed.

 

Klimisch 3 and klimisch 4 studies

Reyazulla and co-workers (2014) reported on two cases of potential contact dermatitis, both with no history of allergy to any drugs, who developed an allergic reaction 24 hours after the usage of 5% povidone iodine solution as a pre-operative antiseptic to prepare (scrub) the lower third of face before surgical removal of third molars. The average duration for the procedure was approximately 45 minutes. Both the patients reported 24 hrs after the procedure with complaint of rashes only over the face, in the region painted with the test substance solution prior to the surgical removal. The patients first noted a stinging or burning sensation, with the onset of erythematous plaques that spread on both sides of the face over cheek region. On further clinical examination, a diffuse erythematous patch over the face, which was slightly oedematous with follicular elevations looking like tiny papules, were observed in both the patients. The erythematous patches were confined only to the areas which were painted with 5% povidone iodine. Both the patients were referred to a dermatologist, and the diagnosis was contact allergic dermatitis due to povidone iodine. However, as no information is available on what kind of povidone iodine solution was used it is unknown whether the effects observed are a result of povidone iodine or of other constituents/impurities of the solution. In this study, allergic effects were observed, but due to lack of information on the test substance, this study is considered to be Klimisch 4.

 

During a poster presentation Gonzalez-Martin and co-workers (2011) presented a case of anaphylaxis due to povidone iodine exposure. A 49-year-old woman with a cut on her hand was treated with povidone-iodine and a tourniquet to stop bleeding. After 15 min of treatment she developed oedema in one finger, which subsequently spread to the entire hand followed by hoarseness and dysphonia. The signs disappeared after corticoid and antihistamines intravenous treatment in 24 h. A Routine blood test and Complement screening analyses and the levels of thyroid hormone showed no abnormalities. A skin prick test with latex was negative as well as a patch test with Povidone Iodine. Another patch test (TRUE test) was positive for Nickel Sulphate as well as a skin prick test with Povidone Iodine (0.01% (0.1 mg/mL). No information is available on what kind of povidone iodine solution was used and subsequently it is unknown whether the effects observed are a result of povidone iodine or of other constituents/impurities of the solution. In this study, allergic effects were observed, but due to lack of information on the test substance and the report being an abstract, this study is considered to be Klimisch 4.

 

De la Cuadra-Oyanguren et al. (2005) described 7 cases of postsurgical contact dermatitis due to povidone iodine. The diagnosis was based on the clinical manifestations, the history of exposure, the site of the lesions, and the results of patch tests. Patch tests with 10, 5, and 1% povidone iodine were performed with petrolatum or water as vehicle under open and occlusive conditions. Patch tests with 10% povidone iodine in petrolatum were positive in all patients. Repeated open application tests with a commercially available solution of povidone iodine were negative. Authors conclude that the presence of the solution under occlusion during surgery is necessary both for the symptoms to develop and for the diagnosis to be made. Based on these results it was considered likely that the observed effects in the patch tests were caused by an irritating effect instead of an allergic reaction to the substance. Furthermore, apparently the authors used a non-commercially available solution of povidone iodine, which makes it impossible to conclude whether effects observed to the 7 cases postsurgical are a result of povidone iodine or of other constituents/impurities of the solution. Therefore this study is considered to be Klimisch 4.

 

Nishioka and co-workers (2000) examined 10 cases of contact dermatitis which began during the application of povidone-iodine preparations. In addition tests were performed with 10 controls. Patch tests were performed using 2 kinds of povidone-iodine preparations and their ingredients, i.e., povidone-iodine, polyoxyethylene nonylphenyl ether and glycerin, and also the components of povidone-iodine, i.e., iodine and polyvinylpyrrolidone. According to the authors it was difficult to distinguish between allergic responses from irritation. Furthermore, effects were observed in the control group. Therefore, the authors considered subjects to be positive when a stronger than + reactions to 2% povidone-iodine at days 3 to 5 was observed. Based on these criteria, 4 out of the 10 cases were considered as sensitization to povidone-iodine. Overall, as indicated by the authors, differences between irritating and sensitising effects are difficult to observe. As already indicated above patch test are not a reliable test method. Furthermore, as in the control group also sensitising effects were observed, one could argue that effects observed are rather irritating effects. The choice of the authors to conclude that a positive sensitising response only applies when an effect is observed at 2%, is rather guesswork and working towards a for them acceptable outcome than that it is scientifically justified. Based on this information the study was considered to be not reliable (Klimisch 3)

 

In a more dated study, Kunze and co-workers (1983) presented the results of patch tests performed with Iodine/potassium-iodide (3%) and commercialized povidone (PVP)-iodine preparations (Betaisodona-ointment and solution, Polyvidon-Jod-ointment "Braun", Braunol-solution "Braun", Traumasept-ointment, and Traumasept solution (not marketed), carried out in 104 patients of the Department of Dermatology of the Municipal Hospital Kassel. In addition, the according ointment and solution-bases were tested. Twenty two tests were patients with ulcera crurum, 41 patients had infectious skin diseases and there were 41 other patients. Thirty five out of the 104 patients showed positive reactions to iodine/potassium-iodide. Hyperreactivity to one or more PVP-iodine-ointments was found in 12 patients, and one or more PVP-iodine solutions in 29 patients. The results show that allergic skin reactions must be expected in 2-9% of all patients using PVP-iodine ointments, and in 12-20% of all patients using PVP-iodine-solutions. However, due to the widespread use of PVP-iodine it is hard to imagine that these high number of sensitized individuals are present in the population. Questions could therefore be raised regarding the scoring of skin sensitising effects or the method of application. It is well possible that irritating effects are regarded as skin sensitising effects by the authors. Furthermore, no control group of healthy individuals has been exposed to determine the effect of present skin conditions on the outcome of the test. Based on this information the study was considered to be not reliable (klimisch 3)

 

Finally, Sato and co-workers (2004) investigated the factors relating to occupational allergy in doctors using self-administered questionnaires. Because the subjects were physicians, they were considered by the authors to be able exactly to indicate their allergic past or present history and their etiologic factors. 89 out of 307 doctors reported the presence of occupational allergy. The number of doctors reporting contact dermatitis was the largest, i.e. 77. The most prevalent inducer was the surgical rubber glove (54 doctors); the other potential inducers were chlorhexidine gluconate (23 doctors), povidone iodine (17 doctors) and ethanol (15 doctors). The assumption however that all doctors are capable of identifying the correct disease is a bold assumption as not all doctors are dermatologists. For instance, 15 doctors identified ethanol as a skin sensitizer while repeated use of ethanol results in dryness of the skin and subsequently irritating effects rather than allergic effects. Furthermore, it is questionable whether the doctors are capable of identifying specific allergens since most of the potential allergens are used in combination which each other. In other words, this study is not reliable (Klimisch 3) and as such does not provide evidence that PVP-iodine is a skin sensitizer.

 

Conclusion:

According to the guinea pig maximisation test, the substance is not a skin sensitizer. However, several cases have been reported indicating that PVP-Iodine may cause skin sensitising effects in susceptible individuals. In some of these experiments, the authors tried to confirm the skin sensitising effect by performing patch tests. However, due to the skin irritating properties of PVP-Iodine the patch test is not a reliable test method. Furthermore, in several case reports limited information is available on the type/purity of PVP-Iodine tested or whether the effects observed were sensitising effects rather than irritating effects. Based on all available data PVP-Iodine might be at most a very rare skin sensitizer especially when taking the widespread use of PVP-iodine among the general population.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available animal study, the substance does not have to be classified as skin sensitizer in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008. However, additional human data is available, which has to be taken into account. According to the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008, a skin sensitizer can be allocated to three categories: 1, 1A, and 1B. For a substance to be classified as category 1 or 1A sensitizer, a substance has to cause skin sensitisation in a substantial number of persons or a high frequency of occurrence in humans can be presumed, respectively. For a substance to be allocated in category 1B, the substance has to show a low to moderate frequency of occurrence in humans. Based on the available data at most it can be concluded that the substance is a very rare skin sensitizer while it is even possible that the substance is not skin sensitizer at all. Especially when taking the widespread use of the test substance among the general population into account. Therefore, according to the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008, the test substance does not have to be classified as skin sensitizer.