Reaction products of cyclohexylamine and 4-alkylaniline and 1,1'-methanediylbis(4-isocyanatobenzene)

Endpoint summary

Description of key information

Skin irritation: The potential of test item to cause inflammatory or corrosive changes upon first contact with skin was assessed by semi-occluded application of 0.5 g of the test material to the closely-clipped dorsa of three New Zealand White rabbits for four hours based on OECD 404. Under the conditions of this test, the test item was classified as 'non-irritant' to the skin.

Eye irritation: The potential of test item to cause damage to the conjunctiva, iris or cornea was assessed in three New Zealand White rabbits based on OECD 405. Under the conditions of this test, the test item was classified as 'non-irritant' to the eye.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 1991-08-06 to 1991-08-09

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP study in accordance with recognised test guideline but: Lot/batch No.: not stated Expiration date of the lot/batch: not stated NOTE: study deemed acceptable because spectral data for test item are available, covering approximately before and after the test period - see section 1.4 Analytical Information.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

1981

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

- Substance type: Organic
- Physical state: Fine, off-white powder
- Analytical purity: Approximately 100%
- Storage condition of test material: ambient temperature

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ranch Rabbits, Crawley Down, Sussex, England
- Age at study initiation: approximately three months
- Weight at study initiation: 2.52-2.82 kg
- Housing: They were individually housed in suspended stainless steel cages (Type RC10/L) mounted in mobile batteries (Modular Systems and Development Company Limited, London, England). The cages measured 61 x 76 x 46 cm high and were fitted with perforated counter-sunk floor panels. A tray beneath the floor was lined with absorbent crepe paper which was changed regularly.
- Diet (e.g. ad libitum): free access to a commercially available standard pelleted rabbit diet (S.Q.C.Rabbit Diet, Special Diet Services Limited, Witham, Essex, England). The diet contained no added antibiotic or other chemotherapeutic or prophylactic treatment.
- Water (e.g. ad libitum): free access to tap water. The water was taken from the public supply; in England the supply and quality of this water is governed by Department of the Environment regulations. There was no information indicating that normal levels of common contaminants would influence the outcome of the study.
- Acclimation period: An acclimatisation period of seven days was allowed between arrival at the laboratory and administration of the test material.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°C (range 15°-23°C)
- Humidity (%): 55% R.H. (range 40%-70% R.H.)
- Air changes (per hr): 15 complete air changes per hour without re-circulation.
- Photoperiod (hrs dark / hrs light): lighting cycle of 12 hours of artificial light per day.

IN-LIFE DATES: From: 6 August 2009 To: 9 August 2009

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5g

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: the dorsum between the limb (6 x 6 cm) girdles
- Type of wrap if used: A single dose (0.5 g) was applied directly to the skin and covered by an unmedicated gauze patch (3 x 2 cm) which was held in place on the left test site by strips of Blenderm (3-M Company). The right test site, acting as a control, was covered by a similar semi-occlusive dressing but otherwise remained untreated. Pads of cotton wool and elasticated bandage were used to protect the patches and ensure good contact between the skin and the test material during the four-hour exposure period. The elasticated bandage was held in place by thin strips of waterproof plaster ('Sleek' - T &J Smith and Nephew Limited) at both edges.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treatment sites were then gently washed with warm water and dried with paper towels to remove excess test material adhering to the skin.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
DRAIZE, JH (1959). In "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" p.47. Association of Food and Drug Officials of
the United States, Austin, Texas.

Actual criteria for assessment of skin irritation responses are given in Attached Background Information.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritant / corrosive response data:

No dermal response was observed at the test site of any animal at any time during the 72 hour observation period. The control sites did not show any response to the control procedure.

TABLE 1: Mean values for erythema and oedema 24, 48 and 72 hours after treatment

Animal number	Erythema		Oedema
	Test	Control	Test	Control
91 1435M 91 1438M 91 1442M	0.0 0.0 0.0	0.0 0.0 0.0	0.0 0.0 0.0	0.0 0.0 0.0

Scoring of irritance responses

Animal Number	Type of Response	Score after removal of dressings
		1 hour		24 hour		48 hour		72 hours
		Test site	Control site	Test site	Control site	Test site	Control site		Test site	Control site
91 1435M	Erythema	0	0	0	0	0	0		0	0
	Oedema	0	0	0	0	0	0		0	0
91 1438M	Erythema	0	0	0	0	0	0		0	0
	Oedema	0	0	0	0	0	0		0	0
91 1442M	Erythema	0	0	0	0	0	0		0	0
	Oedema	0	0	0	0	0	0		0	0

Interpretation of results:

other: not irritanting

Conclusions:

Under the conditions of this test, the test item was classified as 'non-irritant' to the skin.

Executive summary:

The potential of test item to cause inflammatory or corrosive changes upon first contact with skin was assessed by semi-occluded application of 0.5 g of the test material to the closely-clipped dorsa of three New Zealand White rabbits for four hours based on OECD 404.

Dermal reactions were assessed 1, 24, 48 and 72 hours after removal of the dressings. No dermal response was observed at the test site of any animal at any time during the 72 hour observation period. Under the conditions of this test, the test item was classified as 'non-irritant' to the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 1992-07-27 to 1992-07-31

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP study in accordance with recognised test guideline but: Lot/batch No.: not stated Expiration date of the lot/batch: not stated NOTE: study deemed acceptable because spectral data for A-3622 are available, covering approximately before and after the test period - see section 1.4 Analytical Information.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Version / remarks:

Annex V (84/449/EEC) of the Sixth Amendment (79/831/EEC) to the European Communities Council Directive 67/548/EEC

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

Physic State: off-white powder
Purity: approximately 100%
Storage Conditions: at ambient temperature, in the original container

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Rosemead Rabbits, Rosemead, Waltham Abbey, Essex, England

- Age at study initiation: approximately four to four and a half months old

- Weight at study initiation: bodyweights on the day of dosing were within the range 3.17 - 3.40 kg.

- Housing: individually in suspended stainless steel cages (Type RC10/L/TR6) mounted in mobile batteries (Modular Systems and Development Company Limited, London, England). The cages measured 61 x 76 x 46 cm high and were fitted with perforated counter-sunk floor panels. A tray beneath the floor was lined with absorbent paper which was changed regularly.

- Diet (e.g. ad libitum): free access to food hoppers containing standard pelleted rabbit diet, (S.Q.C. Rabbit Diet - Special Diets Services Limited, Witham, Essex, England). The diet contains no added antibiotic or other chemotherapeutic or prophylactic treatment.

- Water (e.g. ad libitum): free access to tap water taken from the public supply

- Acclimation period: The animals were held for a period of three weeks before administration of the test material.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°C (range 15-23°C)

- Humidity (%): 55% R.H. (range 40%-70% R.H.)

- Air changes (per hr): 15 complete air changes per hour without re-circulation.

- Photoperiod (hrs dark / hrs light): lighting cycle of 12 hours artificial light per day.


IN-LIFE DATES: From: 27 July 1992 To: 31 July 1992

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg
- Concentration (if solution): not applicable

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not done
- Time after start of exposure: not done


SCORING SYSTEM:

Darize, Refer to Attached Background Information for details of the scoring system used.


TOOL USED TO ASSESS SCORE: ophthalmoscope

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

other: for all three animal tested

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

other: for all three animal tested

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

>= 0 - <= 0.7

Max. score:

2

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: for all three animal tested

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

other: for all three animal tested

Irritant / corrosive response data:

Injection of the conjunctival blood vessels was observed in two rabbits one hour following instillation of test item, and continued in one animal at the 24 hour examination. A crimson-red conjunctival appearance and very slight chemosis and discharge were observed in the remaining rabbit at the one hour examination; injection of the conjunctival blood vessels persisted in this animal to the 48 hour assessment.

Other effects:

Instillation of the test material caused practically no initial pain response.
The eyes of all rabbits were overtly normal by the 72 hour examination.

Mean values for ocular lesions 24, 48 and 72 hours after instillation. 

Animal number and sex	Corneal opacity	Iridial lesions	Redness of Conjunctiva	Chemosis
27TK 332M   27TK 338M   27TK 340M	0.0   0.0   0.0	0.0   0.0   0.0	0.7   0.3   0.0	0.0   0.0   0.0

Individual scores for ocular irritation response:

Animal No.	cornea opacity				iris				conjunctivae				chemosis
	1h	24h	48h	72h	1h	24h	48h	72h	1h	24h	48h	72h	1h	24h	48h	72h
27TK332M	0	0	0	0	0	0	0	0	2	1	1	0	1	0	0	0
27TK338M	0	0	0	0	0	0	0	0	1	1	0	0	0	0	0	0
27TK340M	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this test, the test item was classified as 'non-irritant' to the eye.

Executive summary:

The potential of test item to cause damage to the conjunctiva, iris or cornea was assessed in three New Zealand White rabbits based on OECD 405, each subject to single ocular instillation of 100 mg of the test material. Ocular reactions were examined 1, 24, 48 and 72 hours after treatment. Injection of the conjunctival blood vessels was observed in two rabbits one and/or 24 hours following instillation. The third rabbit showed a crimson-red conjunctival appearance, slight chemosis and discharge at the one hour examination and injection of the conjunctival blood vessels up to the 48 hour assessment. The eyes of all rabbits were overtly normal by the 72 hour examination. Instillation of the test material caused practically no initial pain response. Under the conditions of this test, the test item was classified as 'non-irritant' to the eye.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Skin irritation: OECD 404, erythema at 24, 48 and 72 hours: 0; oedema: 0 at 24, 48 and 72 hours

According to Regulation (EC) No 1272/2008, table 3.2.2, this substance should not be classified for this endpoint.

 

Eye irritation: OECD 405, Mean scores at 24, 48 and 72 hours:

Corneal opacity: 0.0, 0.0, 0.0; iritis: 0.0, 0.0, 0.0; conjunctivae: 0.7, 0.3, 0.0; chemosis: 0.0, 0.0, 0.0

Reversibility: The eyes of all rabbits were overtly normal by the 72 hour examination.

According to Regulation (EC) No 1272/2008, table 3.3.1 and 3.3.2, this substance should not be classified for this endpoint.