Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
other: weight of evidence of supporting substance (structural analogue)
Adequacy of study:
weight of evidence
Study period:
1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no information on GLP
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Principles of method if other than guideline:
According to Magnusson Kligman Assay
GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Study conducted in 1997 by Leung et al. based on former standards. The study was conducted before the Local Lymph Node Assay was accepted as a OECD TG (first in 2002).
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Dunkin Hartley Haz:(DH)fBR albino guinea pigs
- Source: HRP Inc. (Denver, PA).
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 278-444 gr)
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
Intradermal induction 5%, Epicutaneous induction 10%, Epicutaneous challenge 5%
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
Intradermal induction 5%, Epicutaneous induction 10%, Epicutaneous challenge 5%
No. of animals per dose:
10 male and 10 female
Details on study design:
The maximization procedure involved the induction of an immunologically based sensitization process by injection of the test material into the skin (intradermal induction) followed by application of test material on the skin at the challenge site. Any of the observations greater than that seen in the irritation control animals was considered an allergic response.

Groups of 10 male and 10 female guinea pigs each received 0.1 mL intradermal induction injections into 2 sites each of the clipped shoulder skin as follows: 50% (v/v) Freund's complete adjuvant (FCA) water emulsion, the test material or vehicle, and the test material in FCA/water emulsion or FCA/water emulsion. Epicutaneous inductions were conducted 7 days later. The test material was applied to a 2 x 4 cm filter paper, which was then placed on the test site and secured with tape. The patches were left in place for 48 h, after which they were removed and the skin wiped free of any excess test material.
Epicutaneous challenge was undertaken by applying 2 x 2 cm filter paper squares soaked in the ethylenediamine solution to a previously untreated site (right flank) 14 days after epicutaneous induction (i.e., 21 days from the start of the study). Patches were left in place for 24 h, and the sites inspected for signs of irritation 24-48 h after removal of the occlusive dressings.

In general, scores of 1 or greater were considered clearly indicative of sensitization. Scores of 0.5 were considered equivocal, although a high percentage of 0.5 scores with no response in irritation control animals would be considered suggestive of sensitization. The percentage of animals reacting, rather than the intensity of reactions, was the criterion for assessing sensitization potency.

Grading scale used for evaluation of skin responses:
Score 0: No reaction
Score 0.5: Very slight (barely perceptible) erythema, usually nonconfluent
Score 1: Slight (well-defined) erythema
Score 2: Moderate erythema
Score 3: Severe erythema, with or without edema, necrosis, or eschar formation
Challenge controls:
Irritation control animals, five male and five female guinea pigs, received the same challenge procedures as in the definitive sensitization study, but did not have preceding intradermal and/or epicutaneous induction procedures
Positive control substance(s):
no
Reading:
other: 1st and 2nd reading
Hours after challenge:
2 448
Group:
test group
Dose level:
5%
No. with + reactions:
9
Total no. in group:
20
Clinical observations:
45% in the group (n = 20) showed a positive skin response with score equal or greater than 1 at readings 24-48h after removal of the occlusive dressings.
Remarks on result:
other: see Remark
Remarks:
Reading: other: 1st and 2nd reading. . Hours after challenge: 2448.0. Group: test group. Dose level: 5%. No with. + reactions: 9.0. Total no. in groups: 20.0. Clinical observations: 45% in the group (n = 20) showed a positive skin response with score equal or greater than 1 at readings 24-48h after removal of the occlusive dressings..
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Ethylenediamine was tested in the Guinea Pig Maximization Test according to the method described by Magnusson and Kligman (Leung, H.W. et al., 1997) in Dunkin-Hartley guinea pig (10 males and 10 females per dose). The maximization procedure involved the induction of an immunologically based sensitization process by injection of the test material into the skin (intradermal induction) followed by application of test material on the skin at the challenge site. Control animals (5 males and 5 females) received the same challenge procedures as in the definitive sensitization study, but did not have subsequent intradermal and/or epicutaneous induction procedures. Any of the observations greater than that seen in the control animals was considered an allergic response. Skin responses were evaluated and scored. In general, scores of 1 or greater were considered clearly indicative of sensitization. Scores of 0.5 were considered equivocal, although a high percentage of 0.5 scores with no response in irritation control animals would be considered suggestive of sensitization. The percentage of animals reacting, rather than the intensity of reactions, was the criterion for assessing sensitization potency. 45% of animals tested showed signs of sensitisation. Based on the facts that ethylenediamine was found to be a skin sensitizer and has also been reported to cross-sensitize for chemicals of similar structure (same publication, Leung, H.W. et al., 1997) and trimethylenediamine is structurally very similar to ethylenediamine (difference: chain length / one CH2-group), trimethylenediamine is assumed to be also a skin sensitizer.


Migrated from Short description of key information:
Based on the facts that ethylenediamine is reported as skin and as cross-sensitizer for chemicals of similar structure and trimethylenediamine is structurally very similar to ethylenediamine (difference: chain length / one CH2-group), trimethylenediamine is assumed to be a skin sensitizer.

Justification for selection of skin sensitisation endpoint:
A reliable read across study.

Respiratory sensitisation

Link to relevant study records
Reference
Endpoint:
respiratory sensitisation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Trimethylenediamine is structural very similar to ethylenediamine (difference: chain length / one CH2-group). Therefore, the conclusions drawn, are sufficient for read across and assessment of the toxicity of trimethylenediamine.
Qualifier:
no guideline followed
Principles of method if other than guideline:
experience in humans with ethylenediamine (CAS# 107-15-3)
GLP compliance:
no
Species:
human
Strain:
not specified
Sex:
not specified
Route of induction exposure:
inhalation
Route of challenge exposure:
inhalation
Results:
According to the evaluations reported in "OECD SIDS Ethylenediamine CASN°: 107-15 -3" (2003), there are rare reports on cases of occupational sensitization in production facilities induced by ethylenediamine. Delayed-type asthma and occasionally dual-type asthma has been observed but no cases of immediate-type asthma were reported. Also the relationship between allergy symptoms and smoking practice on respiratory sensitization to ethylenediamine has been studied in employees of a manufacturing plant in USA. A subset of 38 individuals of 337 was identified by clinical and work history as having become sensitized to ethylenediamine showing symptoms like rhinitis, coughing and expiratory wheezing which cleared after removal from ethylenediamine work environment. Based on this information ethylenediamine is found to be a respiratory sensitizer in humans. Since trimethylenediamine is structurally very similar to ethylenediamine (difference: chain length / one CH2-group), it is assumed to be a respiratory sensitizer in humans.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

According to the evaluations reported in "OECD SIDS Ethylenediamine CASN°: 107-15 -3" (2003), there are rare reports on cases of occupational sensitization in production facilities induced by ethylenediamine. Delayed-type asthma and occasionally dual-type asthma has been observed but no cases of immediate-type asthma were reported. Also the relationship between allergy symptoms and smoking practice on respiratory sensitization to ethylenediamine has been studied in employees of a manufacturing plant in USA. A subset of 38 individuals of 337 was identified by clinical and work history as having become sensitized to ethylenediamine showing symptoms like rhinitis, coughing and expiratory wheezing which cleared after removal from ethylenediamine work environment. Based on this information ethylenediamine is found to be a respiratory sensitizer in humans. Since trimethylenediamine is structurally very similar to ethylenediamine (difference: chain length / one CH2-group), it is assumed to be also a respiratory sensitizer in humans. However, no quantitative data were found regarding levels of ethylenediamine that cause respiratory sensitization in exposed workers.


Migrated from Short description of key information:
Based on the facts that ethylenediamine is reported as respiratory sensitizer and as cross-sensitizer for chemicals of similar structure and trimethylenediamine is structurally very similar to ethylenediamine (difference: chain length / one CH2-group), trimethylenediamine is assumed to be a respiratory sensitizer.

Justification for selection of respiratory sensitisation endpoint:
Most reliable read across study.

Justification for classification or non-classification

Based on read across to a Magnusson Kligman Assay performed with ethylenediamine and to observation in workers when exposed to ethylenediamine, the test substance has to be classified with respect to skin and respiratory sensitisation with

- "R 42/43 May cause sensitization by inhalation and skin contact" according to Directive 67/548/EEC (DSD) and

- "H317 May cause an allergic skin reaction" and "H334 May cause allergy or asthma symptoms or breathing difficulties if inhaled" according to Regulation (EC) No 1272/2008 (CLP, GHS).