N,N''-(methyl-m-phenylene)bis[N',N'-dimethylurea]

Endpoint summary

Description of key information

There are two reliable studies available covering primary dermal and eye irritation potential in rabbits.

Among them an acute eye irritation/corrosion study according to OECD 405 and an acute dermal irritation study according to OECD 404. TDI-Urone is shown to be not irritating.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

The target substance consists of the same constituents as the source substance.
These constituents are 3-[3-(dimethylcarbamoylamino)-4-methylphenyl]-1,1-dimethylurea (CAS-No. 17526-94-2, EC-No. 241-523-6) and 3-[3-(dimethylcarbamoylamino)-2-methylphenyl]-1,1-dimethylurea (CAS-No. 17607-23-7, no EC-No. assigned). Due to the different typical concentrations of the main constituent and the 2nd constituent it became necessary to submit two registrations in order to distinguish between the mono-constituent substance (source) and the multi-constituent substance (target).
As the constituents of source and target are the same, the approach “read-across from supporting substance (structural analogue or surrogate)” is applicable because it is obvious that the physical-chemical, ecotoxicological and toxicological profiles are identical.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1 h

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

0

Other effects:

no other effects

Interpretation of results:

GHS criteria not met

Conclusions:

The test item TDI-Urone is not considered to be irritating.

Executive summary:

In a primary dermal irritation study according to OECD 404 three female New Zealand White Rabbits Crl:KBL (NZW) BR. were dermally exposed to 0.5 g of TDI-Urone for 4 hours to approximate 6 cm² of the skin on one side of the dorsal area. Animals then were observed for 3 days. The test item showed no irritant effects on the intact skin after a contact time of 4 hours. No skin reactions were recorded throughout the observation period of 72 hours as compared to untreated control sites. There were no significant body weight changes during the contact and observation period. Therefore, TDI-Urone is not irritating to the skin.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001-04-02 to 2001-04-07

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

- Name of test material (as cited in study report): N,N" (4-Methyl-m-phenylen)bis(N',N'-dimethylharnstoff)
- Substance type: organic
- Physical state: odourless solid
- Analytical purity: 100%
- Lot/batch No.: 0232 07
- Expiration date of the lot/batch: March 2003
- Stability under test conditions: stable at dry storage conditions for at least 2 years
- Storage condition of test material: store sry in closed containers

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, D-33178 Borchen.
- Age at study initiation:
- Weight at study initiation:
- Housing: semi-barrier in air conditioned rooms
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: adequate

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 +/-3°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): at least 10 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

other: the untreated other side of the dorsal area served as control

Amount / concentration applied:

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

Duration of treatment / exposure:

4 h

Observation period:

Animals were observed for 72 hours after dosing

Number of animals:

3 females

Details on study design:

TEST SITE
- Area of exposure: 6 cm²
- % coverage: no data
- Type of wrap if used: gauze patch, held in place with non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test item was removed by using water
- Time after start of exposure: 4 h

SCORING SYSTEM: see table 1 in "Any other information on materials and methods"

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1 h

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 1 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

48 h

Score:

0

Max. score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

72 h

Score:

0

Max. score:

0

Other effects:

no other effects

Interpretation of results:

GHS criteria not met

Conclusions:

The test item TDI-Urone is not considered to be irritating.

Executive summary:

In a primary dermal irritation study according to OECD 404 three female New Zealand White Rabbits Crl:KBL (NZW) BR. were dermally exposed to 0.5 g of TDI-Urone for 4 hours to approximate 6 cm² of the skin on one side of the dorsal area. Animals then were observed for 3 days. The test item showed no irritant effects on the intact skin after a contact time of 4 hours. No skin reactions were recorded throughout the observation period of 72 hours as compared to untreated control sites. There were no significant body weight changes during the contact and observation period. Therefore, TDI-Urone is not irritating 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:

2001-04-16 to 2001-04-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

- Name of test material (as cited in study report): N,N"(4-Methyl-m-phenylen)bis(N',N'­dimethylharnstoff)
- Substance type: organic
- Physical state: colourless solid
- Analytical purity:100%
- Purity test date: 01 March 2000
- Lot/batch No.: 023207
- Expiration date of the lot/batch: March 2003
- Storage condition of test material: store dry in closed containers
- Other: stable at dry storage conditions for at least 2 years

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, D-33178 Borchen
- Age at study initiation: no data
- Weight at study initiation: 4.7 kg, 4.3 kg, 3.0 kg
- Housing: Serni-barrier in air conditioned rooms
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: adequate

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18+/-3°C
- Humidity (%): 55+/-10%
- Air changes (per hr): at 10 per hour
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g

The properly grind test item was used as delivered by the sponsor.

Duration of treatment / exposure:

as long as observation period. The eyes were not washed after treatment.

Observation period (in vivo):

Animals were observed 72 h respectively and furthermore until the disappea­ rance ofthe symptoms. This was achieved at 48 h for animal No 375, at 96 h ofanimal No 358 and at 192 h for animal No 357.

Number of animals or in vitro replicates:

3 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none
SCORING SYSTEM: Draize
TOOL USED TO ASSESS SCORE: At the end of the observation period the eyes were examined with the aid of a fluorescein solution (Fluoreszein SE Thilo®, Lot H 901).

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

357

Time point:

24/48/72 h

Score:

ca. 0 - ca. 1

Max. score:

1

Reversibility:

fully reversible within: 144 h

Remarks on result:

probability of weak irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Remarks:

358

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Remarks:

375

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

357

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Remarks:

358

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Remarks:

375

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

357

Time point:

24/48/72 h

Score:

ca. 1 - ca. 2

Max. score:

2

Reversibility:

fully reversible within: 192 h

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

358

Time point:

24/48/72 h

Score:

ca. 1

Max. score:

1

Reversibility:

fully reversible within: 96 h

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

375

Time point:

24/48/72 h

Score:

ca. 1

Max. score:

1

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

357

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

358

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Other effects:

no other effects

Table 1: Individual eye irritation scores

Animal number	Hour p.a.	Cornea	Iris	Conjunctivae
				A	B	C
		T/C	T/C	T/C	T/C	T/C
357	1	0/0	0/0	1/0	0/0	0/0
	24	0/0	0/0	1/0	0/0	0/0
	48	1/0	0/0	2/0	0/0	0/0
	72	1/0	0/0	1/0	0/0	0/0
	96	1/0	0/0	1/0	0/0	0/0
	120	1/0	0/0	1/0	0/0	0/0
	144	0/0	0/0	1/0	0/0	0/0
	168	0/0	0/0	1/0	0/0	0/0
	192	0/0	0/0	0/0	0/0	0/0
358	1	0/0	0/0	1/0	0/0	0/0
	24	0/0	0/0	1/0	0/0	0/0
	48	0/0	0/0	1/0	0/0	0/0
	72	0/0	0/0	1/0	0/0	0/0
	96	0/0	0/0	0/0	0/0	0/0
375	1	0/0	0/0	1/0	0/0	0/0
	24	0/0	0/0	1/0	0/0	0/0
	48	0/0	0/0	0/0	0/0	0/0
	72	0/0	0/0	0/0	0/0	0/0

T=Test, C=Control; A=Redness; B=Chemosis; C=Discharge;

marked figures=used for calculation

Interpretation of results:

Category 2B (mildly irritating to eyes) based on GHS criteria

Conclusions:

On the basis of the results it is concluded that TDI-Urone is slightly irritating to the eyes of rabbits but not relevant for classification.

Executive summary:

In a primary eye irritation study according to OECD 405 0.1 g TDI-Urone were applied unchanged into the conjunctival sac of 3 female New Zealand White rabbits (Crl:KBL (NZW) BR). Eyes were not washed after treatment. Animals were observed 72 h respectively and furthermore until the disappearance of the symptoms. This was achieved at 48 h for animal No 375, at 96 h of animal No 358 and at 192 h for animal No 357. Irritation was scored by the method of Draize.

The test item produced redness of the conjunctivae in all three animals as well as opacity of the comea in one animal. Effects were fully reversible.

No comeal lesions were found upon fluorescein examination at the final readings.

In this study TDI-Urone was found to be slightly irritating to the eyes of rabbits but not relevant for classification.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

TDI-Urone is non-irritating to the skin. The test item showed no irritant effects on the intact skin after a contact time of 4 hours. No skin reactions were recorded throughout the observation period of 72 hours as compared to untreated control sites. There were no significant body weight changes during the contact and observation period.

In an acute eye irritation study TDI-Urone produced redness of the conjunctivae in all three animals as well as opacity of the comea in one animal. Effects were fully reversible. No comeal lesions were found upon fluorescein examination at the final readings.

In this study TDI-Urone was found to be slightly irritating to the eyes of rabbits but not relevant for classification.

Justification for classification or non-classification

TDI-Urone is neither irritating/corrosive to the skin nor irritating to the eyes based on the results of appropriate guideline studies.