1,1'-(methylenedi-4,1-phenylene)bis(3-butylurea)

Endpoint summary

Description of key information

HAT ISO was tested for skin and eye irritation/corrosion properties in studies with rabbits. HAT ISO showed only very slight signs of irritation in eyes and on skin, which were completely reversible within the regular observation periods of the studies. It is concluded that HAT ISO can be regarded as non-irritant to skin and eyes.

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:

1993-07-09 to 1994-02-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

EC 92/69

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

1981

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4470 (Acute Dermal Irritation)

Version / remarks:

1990

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: M.A.F.F. no. 4200; 1985

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

Analytical purity: >= 99.65 %
Lot/batch No.: 93.166;

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: E.S.D. (Romans, 01400, Chatillon-sur-Chalaronne, FRANCE);
- Age at study initiation: about 3 months;
- Weight at study initiation: 2.00 to 3.00 kg
- Housing: individually in stainless steel cages;
- Diet: 150 g/animal/day; pelleted complete rabbit diet (Diet reference 112 C - Usine d'Alimentation Rationnelle, Villemoisson, 91360 Epinay-sur-Orge, FRANCE);
- Water: softened and filtered mains drinking water, ad libitum;
- Acclimation period: at least 5 days;


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 +/- 3;
- Humidity (%): > 45 R.H. (target value);
- Air changes (per hr): minimum 12 air changes,;
- Photoperiod: 12 hours artificial light/12 hours dark;

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: sterile liquid paraffine acc. to Codex

Controls:

no

Amount / concentration applied:

500 mg

Duration of treatment / exposure:

4 h

Observation period:

72 h

Number of animals:

6

Details on study design:

The test article was applied at the dose level of 0.5 g prepared as a paste with 0.32 g of sterile Codex liquid paraffin per animal, under a semi-occlusive bandage for 4 hours, to the intact skin of 6 New Zealand White male rabbits.
The cutaneous examinations were performed for erythema and oedema, according to a numerical scale, 1, 24 48 and 72 hours after removal of the bandage.
Besides, taking into account the lesions observed at 72 hours and in order to reveal a possible corrosive action of the test article, these readings were continued on Day 7.

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

63724

Time point:

24/48/72 h

Score:

0.66

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

63735

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

63737

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #4

Remarks:

63739

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #5

Remarks:

67340

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

erythema score

Basis:

animal #6

Remarks:

63745

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.39

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

63724

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

63735

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

63737

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #4

Remarks:

63739

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #5

Remarks:

63740

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #6

Remarks:

63745

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Mean values for cutaneous irritation were as follows:
- erythema: 0.39;
- edema: 0.0;
The lesions observed at 72 hours showed a total reversibility at the reading performed on Day 7.
From the results obtained under the experimental conditions employed, application of this test article to the rabbit skin provoked a slight irritation. For further information, see Sect. "Remarks on results incl. tables and figures".

Other effects:

None

EVALUATION OF IRRITATION AFTER REMOVAL OF SEMI-OCCLUSIVE PATCHES

 

RABBITS N°		63724	63735	63737	63739	63740	63745	TOTAL	MEAN
ERYTHEMA	1 HOUR	1	1	0	1	1	1	5	0.83
	24 HOURS	1	0	1	1	1	0	4	0.67
	48 HOURS	1	0	0	1	0	0	2	0.33
	72 HOURS	0	0	0	1d	0	0	1	0.17
					ERYTHEMA: MEAN 24 H + 48 H + 72 H				0.39

 

RABBITS N°		63724	63735	63737	63739	63740	63745	TOTAL	MEAN
OEDEMA	1 HOUR	0	0	0	0	0	0	0	0.00
	24 HOURS	0	0	0	0	0	0	0	0.00
	48 HOURS	0	0	0	0	0	0	0	0.00
	72 HOURS	0	0	0	0	0	0	0	0.00
					OEDEMA: MEAN 24 H + 48 H + 72 H				0.00

 

OBSERVATIONS:

 

As an excess of test article was observed after removal of the semi-occlusive patch, a wiping was performed with a gauze pad moistened with purified water. The reading was carried out 1 hour later.

 

d: Slight desquamation of the epidermis to the application area.

Interpretation of results:

GHS criteria not met

Conclusions:

HAT ISO was tested in a skin irritation test in rabbits in a 4 h semi-occlusive application of the test material. After a 72 h observation period, slight irritation was observed with mean values of 0.39 for erythema and 0.0 for edema. The lesions observed showed a total reversibility at the reading performed on Day 7. No classification and labelling for skin irritation is necessary according to Regulation 1272/2008/EC (CLP).

Executive summary:

HAT ISO was tested in a skin irritation test in rabbits in a 4 h semi-occlusive application of the test material. After a 72 h observation period, slight irritation was observed with mean values of 0.39 for erythema and 0.0 for edema.

The lesions observed showed a total reversibility at the reading performed on Day 7. No classification as skin irritant is necessary.

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:

1993-07-09 to 1994-02-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

EC 92/69

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4500 (Acute Eye Irritation)

Version / remarks:

1990

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: MAFF no. 4200; 1985

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

Analytical purity: >= 99.65 %
Lot/batch No.: 93.166

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: E.S.D. (Romans, 01400, Chatillon-sur-Chalaronne, FRANCE);
- Age at study initiation: about 3 months;
- Weight at study initiation: 2.00 to 3.00 kg
- Housing: individually in stainless steel cages;
- Diet: 150 g/animal/day; pelleted complete rabbit diet (Diet reference 112 C - Usine d'Alimentation Rationnelle, Villemoisson, 91360 Epinay-sur-Orge, FRANCE);
- Water: softened and filtered mains drinking water, ad libitum;
- Acclimation period: at least 5 days;


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 +/- 3;
- Humidity (%): > 45 R.H. (target value);
- Air changes (per hr): minimum 12 air changes,;
- Photoperiod: 12 hours artificial light/12 hours dark;

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

46 mg

Duration of treatment / exposure:

72 h

Observation period (in vivo):

72 h

Number of animals or in vitro replicates:

6

Details on study design:

The test article was reduced to a fine powder and administered without rinsing and at the dose level of 46 mg (quantity corresponding to a volume of 0.1 mL) per animal, into the inferior conjunctival sac of the right eye of 6 New Zealand White male rabbits.
The ocular examinations were performed in the conjunctiva, iris and cornea, according to a numerical scale, 1 hour after administration of the test article, then at 24, 48 and 72 hours.
Mean values were calculated from the evaluation of the ocular lesions performed in all the rabbits examined at 24, 48 and 72 hours.

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

mean

Time point:

24/48/72 h

Score:

0.11

Max. score:

3

Reversibility:

fully reversible within: 3 days

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.17

Max. score:

4

Reversibility:

fully reversible within: 3 days

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0.06

Max. score:

2

Reversibility:

fully reversible within: 3 days

Irritation parameter:

cornea opacity score

Remarks:

(opacity)

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Mean values for ocular irritation were as follows:
global average ( 24 + 48 +7 2 h):
- 0.17 for chemosis to conjunctiva,
- 0.11 for enanthema to conjunctiva;
- 0.06 for congestion to iris;
- 0.00 for opacity to cornea;
Further information: see Sect. "Remarks on results incl. tables and figures"

Other effects:

None

Test article: 

PATE HAT Application: 46 mg (quantity corresponding to a volume of 0.1 mL) per animal of the test article reduced to a fine powder, without rinsing.   

  

Readings	Rabbits N°	Conjunctiva		Iris		Cornea
		Chemosis	Enanthema	Reflex (+)	Congestion	Opacity		Ulceration
						Degree	Area
1 H	63677	0	1	N	0i	0	0	0
	63679	1	1	N	1i	0	0	0
	63685	1	1	N	1i	0	0	0
	63687	1	2	N	1i	0	0	0
	63694	1	1	N	1c	0	0	0
	63698	0	1	N	1c	0	0	0
24 H	63677	0	0	N	0i	0	0	0
	63679	1	0	N	0	0	0	0
	63685	1	1	N	0i	0	0	0
	63687	0	0	N	0	0	0	0
	63694	0	0	N	0	0	0	0
	63698	0	1	N	1i	0	0	0
	Means	0.33	0.33		0.17	0.00
48 H	63677	0	0	N	0	0	0	0
	63679	0	0	N	0	0	0	0
	63685	1	0	N	0i	0	0	0
	63687	0	0	N	0	0	0	0
	63694	0	0	N	0	0	0	0
	63698	0	0	N	0i	0	0	0
	Means	0.17	0.00		0.00	0.00
72 H	63677	0	0	N	0	0	0	0
	63679	0	0	N	0	0	0	0
	63685	0	0	N	0	0	0	0
	63687	0	0	N	0	0	0	0
	63694	0	0	N	0	0	0	0
	63698	0	0	N	0	0	0	0
	Means	0.00	0.00		0.00	0.00
MEANS 24 H + 48 H +72 H		0.17	0.11		0.06	0.00

(+) : N = Normal – R = Reduced – 0 = No reflex

 

OBSERVATIONS:

c: Circumcorneal injections + congestion of the iris. 

i: Circumcorneal injections.

Interpretation of results:

GHS criteria not met

Conclusions:

HAT ISO was tested for acute ocular irritation and reversibility in rabbits. From the results obtained under the experimental conditions employed, application of this test article to the rabbit's eye provoked a slight irritation. The observed signs were fully reversible within 3 days. No classification and labelling for eye irritation is necessary according to Regulation 1272/2008/EC (CLP).

Executive summary:

HAT ISO was tested for acute ocular irritation and reversibility in rabbits. From the results obtained under the experimental conditions employed, application of this test article to the rabbit's eye provoked a slight irritation. The observed signs were fully reversible within 3 days. No classification as an eye irritant is necessary.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

HAT ISO was tested in a skin irritation test in rabbits according to EU Method B.4 / OECD Guideline 404 in a 4 h semi-occlusive application of the test material. After a 72 h observation period, slight irritation was observed with mean values of 0.39 for erythema and 0.0 for edema.

The lesions observed showed a total reversibility at the reading performed on Day 7.

Under the conditions of the applied test, HAT ISO can be regarded as non-irritant to the skin.

HAT ISO was tested for acute ocular irritation and reversibility in rabbits according to EU Method B.5 / OECD Guideline 405. From the results obtained under the experimental conditions employed, application of this test article to the rabbit's eye provoked a slight irritation. The observed signs were fully reversible within 3 days. Thus, under the conditions of the applied test, HAT ISO was regarded as non-irritant to eyes.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on local effects, the test item does not require classification according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.