Registration Dossier

Administrative data

Description of key information

Animal data on skin sensitization do not result in conclusive evidence on the skin sensitization potential of MDA. However, based on the data on humans there is convincing evidence that MDA is a skin sensitizer. MDA also demonstrates cross-reactions to para-groups. Based on human data MDA is already classified as "sensitising". (From the EU Risk assessment on MDA published 2001)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
no guideline available
Principles of method if other than guideline:
Lintine discs having a diameter of 1 1/4 inches were saturated with methylene dianiline dissolved in Dowanol 50B. The patches were applied every other day for 15 applications to the skin of the fifty subjects. Results were graded and recorded upon removal of the patches. Twenty-four hours after removal of the patches, the sites were examined for delayed reactions. The material was originally patched as a 5% solution in Dowanol 50B. After the second application, the concentration was reduced to 2 1/2%. Following the fourth application, the concentration was further reduced to 1% in 50B for the remaining number of applications. Following a two week recuperation period after the removal of the fifteenth application, the methylene dianiline as a 1% solution in Dowanol 50B was re-applied for twenty-four hours. Results were graded and recorded upon removal of the patches. Twenty-four hours after removal, the sites were examined for delayed reactions.
GLP compliance:
no
Remarks:
prior to GLP
Type of study:
other: Human Repeated Insult Patch test
Justification for non-LLNA method:
This study was conducted due to non-REACH regulatory requirements. With the existing data from this study not only being acceptable but of good quality (Klimisch Score 2), this study precludes the need for an additional LLNA study. In addition, a supplementary LLNA study would violate the ECHA objectives with regards to animal welfare.
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: R. L. Titus, K1937-5 (Ref.: Bi/38; Bi/809)
Species:
human
Sex:
male/female
Route:
epicutaneous, occlusive
Vehicle:
other: Dowanol 50B
Concentration / amount:
1, 2.5, 5%
Route:
epicutaneous, occlusive
Vehicle:
other: Dowanol 50B
Concentration / amount:
1 %
Day(s)/duration:
14 / 24 hours
No. of animals per dose:
25 of each sex
Challenge controls:
vehicle (Dowanol 50B)
Positive control substance(s):
no
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
1%
No. with + reactions:
5
Total no. in group:
50
Clinical observations:
1 male showed a 2+ reaction, 3 male subjects showed a 3+ reaction, and 1 female subject showed a 3+ reaction
Group:
positive control
Remarks on result:
not measured/tested
Group:
negative control
Remarks on result:
not measured/tested

The material was found to cause a sensitization reaction in 5 of 50 human subjects patch tested by a repeated insult technique.

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

In a guinea pig maximisation test, MDA showed a weak sensitizing potential (Thorgeirsson, 1978). However, patch tests in volunteers revealed a skin sensitizing potential of MDA in man (Dow, 1954). No skin sensitising potential was observed in an available Buehler assay (Dow, 1954).

Lintine discs having a diameter of 1 1/4 inches were saturated with methylene dianiline dissolved in Dowanol 50B (Dow, 1954). The patches were applied every other day for 15 applications to the skin of fifty volunteers. Results were graded and recorded upon removal of the patches. Twenty-four hours after removal of the patches, the sites were examined for delayed reactions. The material was originally patched as a 5% solution in Dowanol 50B. After the second application, the concentration was reduced to 2 1/2%. Following the fourth application, the concentration was further reduced to 1% in 50B for the remaining number of applications. Following a two week recuperation period after the removal of the fifteenth application, the methylene dianiline as a 1% solution in Dowanol 50B was re-applied for twenty-four hours. Results were graded and recorded upon removal of the patches. Twenty-four hours after removal, the sites were examined for delayed reactions.

There were sporadic 1 +, 2 +, or 3+ reactions after induction applications. As a check against the possibility of irritation being elicited by the solvent, separate patches were run with the Dowanol 50B. These patches were all negative.

Upon removal of the challenge application, 1 male showed a 2+ reaction, 3 male subjects showed a 3+ reaction, and 1 female subject showed a 3+ reaction. These reactions were characterized by welts and edema extending well beyond the area of the patch. The reactions following the challenge application indicate that 2 male subjects were sensitized by methylene dianiline. It is believed that 2 male subjects and the female subject, who elicited a response after one or two applications during the induction phase, may have exhibited a cross-sensitization reaction to a similar material. In summary, the results of the skin tests with human subjects show that methylene dianiline is not a primary irritant or a fatiguing agent, but it is capable of causing sensitization.

Thorgeisson et al. conducted a GMPT in accordance with Magnusson and Kligman. The animals (guinea pigs) were sensitized in a two-stage procedure- intradermal injections with Freunds Complete Adjuvant (FCA) and topical application. Two weeks after the second stage of sensitization, a 24-hour occluded patch test (AI-test, Imece, Astra Agency) was performed on the flank without chemical depilation. The challenge site was evaluated 24 hours after removal of the patch. Three hours before reading, the test site was shaved with an electric razor. Only obvious redness and swelling was regarded as an allergic response. The reactions were judged by two persons independently. The test substance produced reactions in 20% of the animals (mild sensitizer).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance needs to be classified and labelled as skin sensitising cat. 1 (H317 may cause allergic skin reaction) under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.