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Administrative data

Description of key information

A GPMT (guinea pig maximisation test) according Magnusson and Kligman and a mouse ear swelling test (MEST) were conducted for the assessment of skin sensitization.

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:
other: scientifically acceptable and sufficient documented
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
The sensitization test was performed almost in accordance with the original procedure of Magnusson and Kligman with some modifications. Female albino guinea pigs of the Hartley strain were used as experimental animals. Five animals were used in each experimental group. Each group of animals was sensitized by injection of given concentration of the chemical. 21 days after the initial intradermal injection, 0.1 ml aliquots of various concentrations of test chemical in the vehicle were applied to the shaved area of the flank of each animal for challenge. All concentrations adopted are lower than the irritant concentrations. The challenge was done by the open patch test method. The chemical was left in place for 24 hours.
Dermal response of each challenge site was evaluated 48 h after the challenge application. Evaluation of skin reactions was done by scoring erythema and edema formation of each challenge concentration.
GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was published 1994. At this time an OECD guideline for a LLNA was not available.
Species:
guinea pig
Strain:
Hartley
Sex:
female
Route:
intradermal and epicutaneous
Vehicle:
other: induction: intradermal injection/topical = ethanol/propylene glycol; Challenge: topical = acetone
Concentration / amount:
Induction -intradermal injection. 0, 200, 2000 ppm
Induction - topical: 0, 2000 ppm
Challenge - topical: 0, 2, 20, 200, 2000 ppm
Route:
epicutaneous, open
Vehicle:
other: induction: intradermal injection/topical = ethanol/propylene glycol; Challenge: topical = acetone
Concentration / amount:
Induction -intradermal injection. 0, 200, 2000 ppm
Induction - topical: 0, 2000 ppm
Challenge - topical: 0, 2, 20, 200, 2000 ppm
No. of animals per dose:
Five animals per dose were used in each experimental group
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 0 ppm
Dose level:
0 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 0 ppm. Dose level: 0 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 2 ppm
Dose level:
2 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 2 ppm. Dose level: 2 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 20 ppm
Dose level:
20 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 20 ppm. Dose level: 20 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 200 ppm
Dose level:
200 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 200 ppm. Dose level: 200 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 2000 ppm
Dose level:
2000 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 0 ppm, induction topical: 0 ppm, challenge 2000 ppm. Dose level: 2000 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 0 ppm
Dose level:
0 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 0 ppm. Dose level: 0 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 2 ppm
Dose level:
2 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 2 ppm. Dose level: 2 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 20 ppm
Dose level:
20 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 20 ppm. Dose level: 20 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 200 ppm
Dose level:
200 ppm (challenge)
No. with + reactions:
3
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 200 ppm. Dose level: 200 ppm (challenge). No with. + reactions: 3.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 2000 ppm
Dose level:
2000 ppm (challenge)
No. with + reactions:
5
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 200 ppm, induction topical: 20000 ppm, challenge 2000 ppm. Dose level: 2000 ppm (challenge). No with. + reactions: 5.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 0 ppm
Dose level:
0 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 0 ppm. Dose level: 0 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 2 ppm
Dose level:
2 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 2 ppm. Dose level: 2 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 20 ppm
Dose level:
20 ppm (challenge)
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 20 ppm. Dose level: 20 ppm (challenge). No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 200 ppm
Dose level:
200 ppm (challenge)
No. with + reactions:
3
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 200 ppm. Dose level: 200 ppm (challenge). No with. + reactions: 3.0. Total no. in groups: 5.0.
Reading:
1st reading
Hours after challenge:
48
Group:
other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 2000 ppm
Dose level:
2000 ppm (challenge)
No. with + reactions:
4
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: other: induction intradermal: 2000 ppm, induction topical: 20000 ppm, challenge 2000 ppm. Dose level: 2000 ppm (challenge). No with. + reactions: 4.0. Total no. in groups: 5.0.

With an induction of 2 or 20 ppm no skin sensitization (0/5) were found, but an induction of 200 ppm (3/5) or 2000 ppm (4/5 and 5/5) animals revealed clear signs of skin sensitization. A maximal reaction was found with an intradermal induction with 200 ppm and a topical induction with 2000 ppm followed by a challenge with 2000 ppm. As a result phenyl isocyanate was positive under the conditions of this assay.

Interpretation of results:
Category 1A (indication of significant skin sensitising potential) based on GHS criteria
Conclusions:
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Skin Sens. 1A is justified.
Executive summary:

The sensitization test was performed almost in accordance with the original procedure of Magnusson and Kligman with some modifications. Female albino guinea pigs of the Hartley strain were used as experimental animals. Five animals were used in each experimental group. Each group of animals were sensitized by injection of given concentration of the chemical. 21 days after the initial intradermal injection, 0.1 ml aliquots of various concentrations of test chemical in the vehicle were applied to the shaved area of the flank of each animal for challenge. All concentrations adopted are lower than the irritant concentrations. the challenge was done by the open patch test method. the chemical was left in place for 24 hours.

Dermal response of each challenge site was evaluated 48 h after the challenge application. Evaluation of skin reactions was done by scoring erythema and edema formation of each challenge concentration.

With an induction of 2 or 20 ppm no skin sensitization (0/5) were found, but an induction of 200 ppm (3/5) or 2000 ppm (4/5 and 5/5) animals revealed clear signs of skin sensitization. A maximal reaction was found with an intradermal induction with 200 ppm and a topical induction with 2000 ppm followed by a challenge with 2000 ppm. As a result phenyl isocyanate was positive under the conditions of this assay.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

In the GPMT the evaluation of skin reactions was done by scoring erythema and edema formation of each challenge concentration.

With an induction of 2 or 20 ppm no skin sensitization (0/5) were found, but an induction of 200 ppm (3/5) or 2000 ppm (4/5 and 5/5) animals revealed clear signs of skin sensitization. A maximal reaction was found with an intradermal induction with 200 ppm and a topical induction with 2000 ppm followed by a challenge with 2000 ppm. As a result phenyl isocyanate was positive under the conditions of this assay.

Additional the potency of phenyl isocyanate (PI) as a contact sensitiser was assessed using the mouse ear swelling test. PI was found to yield an SD50 (dose predicted to sensitize 50% of the mice) of 0.04 µmol/kg. The mean hapten-specific IgG antibody titer to PI was 1.4 x 10E4. The anti-PI igG1 anaphylactic antibody titer was 1.2 x 10E4. These results indicate that phenyl isocyanate is a potent inducer of both cellular and humoral immune response.


Respiratory sensitisation

Link to relevant study records
Reference
Endpoint:
respiratory sensitisation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: scientifically acceptable and well documented.
Principles of method if other than guideline:
Groups of 10 male and 10 female Wistar rats were exposed to 1.04, 4.10, 7.18 and 10.39 mg phenyl isocyanate/m³ for 2 weeks, 6 hours per day. The animals were observed for body weight and clinical signs through day 14 followed by chemical, biochemical and histopathological examinations which indicate a lung sensitizing potential of the test compound
Species:
rat
Strain:
Wistar
Sex:
male
Route of induction exposure:
inhalation
Route of challenge exposure:
inhalation
Vehicle:
other: air
Concentration:
0.0, 0.35, 0.83, 2.79 and 10.07 mg phenyl isocyanate/m³
No. of animals per dose:
8 male rats/dose
Results:
All examined parameters of the 1.04 mg/m³ exposure group were unaffected. Little changes of the parameters ( lung function test, goblet cell hyperplasia) were found in the 4.1 mg/m³ exposure group at the end of the post-exposure period. In the groups exposed to 7.2 mg/m³ and 10.4 mg/m³ a progredient decrease of body weight, and an increase of hypothermia, mortality and clinical symptoms caused by the irritant potential of phenyl isocyanate to the respiratory tract. The following toxicological relevant changes were found. An increase of lung weight, and a decrease of spleen, thymus, liver and kidneys and an increase of blood parameters of the lung. In the bronchial lavage the biochemical and cytological correlates of a bronchioaveleolitis were determinable (increase of alkaline phosphatase, LDH, protein concentration, leucotriene). An obstructive alteration of the lung and a respiratory hyper reactivity was found. Within the post-exposure period the changes were not or only partly reversible.

On the basis of these examinations a respiratory sensitization potential of phenyl isocyanate was found.

Interpretation of results:
Category 1 (respiratory sensitising) based on GHS criteria
Conclusions:
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Resp. Sens. 1 is justified.
Executive summary:

Groups of 10 male and 10 female Wistar rats were exposed to 1.04, 4.10, 7.18 and 10.39 mg phenyl isocyanate/m³ for 2 weeks, 6 hours per day. The animals were observed for body weight and clinical signs through day 14 followed by chemical, biochemical and histopathological examinations which indicate a lung sensitizing potential of the test compound.

All examined parameters of the 1.04 mg/m³ exposure group were unaffected. Little changes of the parameters ( lung function test, goblet cell hyperplasia) were found in the 4.1 mg/m³ exposure group at the end of the post-exposure period. In the groups exposed to 7.2 mg/m³ and 10.4 mg/m³ a progredient decrease of body weight, and an increase of hypthermia, mortality and clinical symptoms caused by the irritant potential of phenyl isocyanate to the respiratory tract. The following toxicological relevant changes were found. An increase of lung weight, and a decrease of spleen, thymus, liver and kidneys and an increase of blood parameters of the lung. In the bronchial lavage the biochemical and cytological correlates of a bronchioaveleolitis were determinable (increase of alkaline phosphatase, LDH, protein concentration, leucotriene). An obstructive alteration of the lung and a respiratory hyper reactivity was found. Within the post-exposure period the changes were not or only partly reversible.

On the basis of these examinations a respiratory sensitization potential of phenyl isocyanate was found.

NOAEL = 1.04 mg phenyl isocyanate/m³ air

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

In the key-study Wistar rats were exposed to 1.04, 4.10, 7.18 and 10.39 mg/phenyl isocyanate/m³ for 2 weeks, 6 hours per day. The animals were observed for body weight and clinical signs through day 14 followed by chemical, biochemical and histopathological examinations which indicate a lung sensitizing potential of the test compound.

All examined parameters of the 1.04 mg/m³ exposure group were unaffected. Little changes of the parameters ( lung function test, goblet cell hyperplasia) were found in the 4.1 mg/m³ exposure group at the end of the post-exposure period. In the groups exposed to 7.2 mg/m³ and 10.4 mg/m³ a progredient decrease of body weight, and an increase of hypothermia, mortality and clinical symptoms caused by the irritant potential of phenyl isocyanate to the respiratory tract. The following toxicological relevant changes were found. An increase of lung weight, and a decrease of spleen, thymus, liver and kidneys and an increase of blood parameters of the lung. In the bronchial lavage the biochemical and cytological correlates of a bronchioaveleolitis were determinable (increase of alkaline phosphatase, LDH, protein concentration, leucotriene). An obstructive alteration of the lung and a respiratory hyperreactivity was found. Within the post-exposure period the changes were not or only partly reversible.

On the basis of these examinations a respiratory sensitization potential of phenyl isocyanate was found.


Justification for classification or non-classification

In the GPMT (guinea pig maximisation test) with an induction of 2 or 20 ppm no skin sensitization (0/5) were found, but an induction of 200 ppm (3/5) or 2000 ppm (4/5 and 5/5) animals revealed clear signs of skin sensitization. A maximal reaction was found with an intradermal induction with 200 ppm and a topical induction with 2000 ppm followed by a challenge with 2000 ppm. According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Skin Sens. 1A is justified.

In the key-study Wistar-rats were exposed to 1.04, 4.10, 7.18 and 10.39 mg/phenyl isocyanate/m³ for 2 weeks, 6 hours per day. The animals were observed for body weight and clinical signs through day 14 followed by chemical, biochemical and histopathological examinations which indicate a lung sensitizing potential of the test compound. According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Resp. Sens. 1 is justified.