Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Additional information:

Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):

Studies in Animals

3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was found to be sensitizing in numerous studies. Positive results were obtained in the Buehler test performed according or equivalent to the corresponding EU Directive (Zissu, Binet and Limasset, 1998;American Cyanamid Company, 1987), in the guinea pig maximization test comparable or according to OECD TG 406 (IBR/Huels AG 1983, Schmidt/Bayer AG, 1984; Vohr, 1993), in the mouse ear swelling test (Dearman, Spence and Kimber, 1992), and in the open epicutaneous test (Biosphere Research Center Inc., 1981).

"For example, in the Buehler test performed by Zissu, Binet and Limasset (1998), after occlusive epicutaneous induction with 0.5 ml of a solution of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate in petrolatum at 5% (w/v), 16/20 guinea pigs showed positive response upon occlusive epicutaneous challenge with 1% test substance. This characterizes the test substance as a strong sensitizer. Similarly, in the Guinea pig maximization test performed by Vohr (1993) using 0.1 ml of a 5% solution in olive oil for intracutaneous induction, 15/20 guinea pigs from the test group displayed a positive response upon semiocclusive rechallenge at 0.1%. However, in this study skin reactions were also observed in control animals, though at a lower incidence as compared to the test group, which is why a second challenge was performed."

Studies in Humans

"A glue, mainly based on dicyclohexylmethane-4,4'-diisocyanate (70%), was suspected of being the cause of an outbreak of severe eczema at a factory manufacturing medical equipment from August 1999 to April 2001 (Frick et al., 2003). 16 out of approximately 100 persons working in the relevant department were referred to medical consultation. When patch tested with a standard series, an isocyanate series, and work material, 4 of these 16 persons reacted to 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate.

Two Italian women who worked with polyurethane materials made of diisocyanates other than 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (diphenylmethane-4,4'-diisocyanate in one case,dicyclohexylmethane-4,4'-diisocyanatein the other) developed distinct contact dermatitis. When patch testedwith the North American Contact Dermatitis Group (NACDG) standard series and with a second series including in one case 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (1% in petrolatum), a weakly positive response towards 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was observed beside positive responses to other isocyanate materials (Militello et al., 2004).

Twenty poorly documented cases of occupational dermatoses observed between the end of 1970 and mid 1974 were reported in East Germany (Rothe, 1976). Appropriate concentrations for patch epicutaneous challenge testing were determined by self-application of medical staff. 1% solutions of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate in acetone as well as test solutions of other isocyanates were then applied to workers who were suspected to be sensitized by polyurethane chemicals. Readings were done at 24, 48, and 72 hours (some also at 96 hours). Four persons turned out to be sensitized towards 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. The main symptoms in these cases were follicular nodules. Symptoms had appeared after an accidental spill with 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate even in two of the above mentioned persons that had previously no contact with this substance, but with toluene diisocyanate and diphenylmethane diisocyanate. The skin of the sensitized workers returned to a stable healthy state after avoiding contact with 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate.

In the same poorly documented study, single-dose self-application of medical staff with undiluted 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate caused follicular papules after 10 days in 2 out of 3 persons. Sensitization was confirmed by challenge with 1% 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate in acetone. Control tests in 6 non-exposed persons with eczema were negative (Rothe, 1976).

Cross-sensitivity between 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate and the corresponding diamine 3-aminomethyl-3,5,5-trimethylcyclohexylamine was studied by Lachapelle and Lachapelle-Ketelaer (1979). Two workers who were allergic to the diamine and two volunteers who had been sensitized also to the diamine were patch tested 1 month later with 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (1% in ethanol); the patches were removed after 48 hours, and read at 48 and 96 hours. Five adult volunteers were patch tested with 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate as controls. The tests were strongly positive in the 4 patients. None of the control subjects was positive." Since 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is hydrolyzed (see chapter 2.2.3 of SIAR), which initially leads to the diamine (see chapter 3.1.1 of SIAR), traces of 3-aminomethyl-3,5,5-trimethylcyclohexylamine are expected to occur in patch tests with 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate and may trigger symptoms of sensitization in persons who are allergic towards 3‑aminomethyl-3,5,5-trimethylcyclohexylamine.

"Non-occupational skin sensitization towards 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was identified by Belsito (2003). Three out of 70 patients with allergic-appearing foot dermatitis, of which 23 were found to have allergic contact dermatitits from shoes, showed positive response when challenged with 1% 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate in petrolatum. The source of exposure appeared to be the foam rubber padding in athletic shoes, though migration from glues into the padding could not be excluded."

Liippo and Lammintausta (2008) describe patch testing with isophorone diisocyanate in 433 dermatology patients. 8 patients from 433 tested patients showed positive reactions (1.8% of the tested patients). Cross reactivity between isophorone diamine (IPDA) and isophorone diisocyanate was apparent for two of the patients. In general according to the investigated patients the association with current dermatitis was not apparent in all cases.


Migrated from Short description of key information:
Cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):
"3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was found to be skin sensitizing in the Buehler test according to or equivalent to the EU Directive, in the guinea pig maximization test comparable or according to OECD TG 406, in the mouse ear swelling test, and in the open epicutaneous test. Skin sensitization was also observed in humans."

Respiratory sensitisation

Endpoint conclusion
Additional information:

Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):

Studies in Animals

"Respiratory tract sensitization of guinea pigs following intradermal induction (1%, 100 µl) was studied by Bayer AG (1996) in accordance with the exposure criteria defined in OECD TG 403. High titer IgG1 antibody observed proved that successful sensitization had occurred. However, when challenged by nose only inhalation of aerosol at varying concentrations, the incidence of immediate-onset respiratory reactions was roughly the same in all groups. No delayed-onset reactions, deaths or anaphylactic reactions were observed. Challenge with acetylcholine did not show specific respiratory responses indicating that the animals were hyperrespondive to cholinergic acetylcholine stimuli. Severe reactions were observed with trimellitic anhydride (CAS No. 552-30-7) when investigated with the current animal model, using the equivalent induction and challenge."

The study of Plitnick et al. (2005) is based on the hypothesis on the idea that respiratory sensitizers can be identified based on relativly high expression of cytokines characteristic of Th2 cells. Thus, cytokine profiling may be an effective way to detect respiratory sensitizers. After exposure with the stest item Isophorone Diisocyanate auricular lymph nodes were removed from the animals, the total RNA was extracted and Cytokine mRNA was analysed. Response after exposure with the test item Isophorone Diisocyanate was variable but was comparatively weaker as for strong respiratory sensitizers used in this study. Biological relevance of this results are still under discussion but in general as the result of this study the authors conclude that the test item Isophorone Diisocyanate has at least respiratory sensitizing potential under the conditions of the study.

De Jong et al. (2009) and Arts et al. (2008) reported an induction of cytokine IL-4 after inhalation exposure of IPDI in an inhalative LLNA study, which is discussed to be an indicator of respiratory sensitizers.

Further studies examined cytokine profiles, serum antibodies and respirative responses after dermal exposure with IPDI followed by intranasal challenge with IPDI (Farraj et al. 2007) or followed by inhalation of metacholine (Selgrade et al. 2006)

in order to predict and screen for a respiratory sensitizing potential by using the dermal route of exposure. Although the results were ambigous and further experimental work is needed the authors conclude that IPDI appears to have some potential to induce respiratory hypersensitivity.

Studies in Humans

"A 50-year old spray painter developed severe asthma soon after introduction of a new paint containing 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. His asthma was associated with an abnormal chest X-ray, blood eosinophilia, normal IgE level, negative skin prick tests and no precipitins to Aspergillus fumigatus. After successful initial therapy, the person was left in an enclosed room for 30 minutes each on three days, followed by spirometry at hourly intervals for nine hours. Exposure conditions in the enclosed room were as follows:

Day 1: Sitting

Day 2: Painting a chair without 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate in the spraying enamel

Day 3: Painting a chair with 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate in the spraying enamel

Exposure was not quantified. On day 3, the patient required treatment 3 hours 35 minutes after cessation of challenge. A very large reduction in forced expiratory volume was observed on that day (Clarke and Aldons, 1981).

Germanaud et al. (2003) published a case of occupational hypersensitivity pneumoapathy, which according to the investigators is rarely caused by isocyanates. A 50 year old man had worked in the production of polyurethane foams and polyurethane coatings for 32 years with a generally low exposure. He then was engaged more closely in a polyurethane synthesis from 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. Few hours after the beginning of this new occupational exposure, which was not defined any more specifically, he showed dyspnea, fever (39°C), and crepitant rales. Further investigations revealed ground glass appearance on the thoracic CT scan and lymphocytosis in the broncho-alveolar lavage. Effects were confirmed by transbronchial biopsy. Only the functional assessment (airflow obstruction and absence of marked reduction in CO transfer) was atypical for hypersensitivity pneumapathies.

A poorly documented case is also reported by Tyrer (1979): In 1974, a sprayer in a firm of motor body repairers used for some months intermittently a two-pack paint containing 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate (not quantified), toluene and xylene, with no ill-effects. The spraying was done in a large, completely enclosed booth with effective downdraught through the floor. He then developed tightness of the chest and dyspnea, which disappeared when he took a few days off, but recurred, shortly after his return to work. The sprayer who took his place had similar symptoms in a milder form, which lasted only a few hours. A causal relationship between the asthmatic symptoms and a specific substance was not established in this mixed exposure case."


Migrated from Short description of key information:
Cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):
"No validated animal model is available to assess the potential for respiratory sensitization or asthma in humans, and one animal study did not show respiratory tract sensitization when exposed by inhalation (challenge) following intradermal induction. However, due to the well known reactivity of diisocyanates, respiratory sensitization is likely to occur."

Justification for classification or non-classification

The substance 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is classified according to the criteria of EC Directive 67/548/EEC (Annex I) as follows: "May cause sensitization by inhalation and skin contact (R 42/43).

Subcategorisation of IPDI concerning skin sensitization

Data:

Animal data

CLP Sub-category

LLNA, EC3 > 0.1 and < 0.25 %

1A

GPMT, intradermal induction: 10 %, sensitization rate: 80 %

1B

BT (Buehler test), induction conc.: 5 %, sensitization rate: 80 %

1A

 

 

Human data

CLP Sub-category

Schlede et al. (2003): proven contact allergenic effect less frequently, cross-reactivity

1B

 

Discussion:

ICCVAM concluded in its report of 2011 (NIH Publication No. 10-7512

http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-app/TMER.htm) that the>>LLNA cannot be considered a stand-alone assay to determine skin sensitization potency categories. … Among the 21 substances that produced a LLNA EC3 ≤ 2 %, 67 % (14/21) were correctly identified as strong sensitizers, but 33 % (7/21) were incorrectly overclassified as strong skin sensitizers based on available human test data.<<

The results of GPMT and BT are contradictory. Both assays have not been developed for potency determination. Therefore, among the animal data available for IPDI the LLNA is the one which should be considered for sub-categorisation here. This would be then sub-category 1A.

Schlede et al. (2003) evaluated IPDI mainly based on the available human data to be a proven human sensitizer not with high but moderate frequency in humans. This would correlate to sub-category 1B.

Conclusion:

Sub-categorisation for IPDI leads to 1A based only on LLNA and to 1B based only on human data.

Based on the current data it cannot be decided on a scientifically valid basis to which sub-category IPDI has to be allocated.

According to the 2ndATP of CLP regulation paragraph 3.4.2.2.1.1>> skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.<<.

Therefore, a classification of IPDI in Category 1 of hazard class “skin sensitization” is appropriate here.