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Description of key information

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

Among them an acute dermal irritation study according to Methode B.4 (Directive 92/69/EEC) and an acute eye irritation/corrosion study according to Methode B.5 (Directive 92/69/EEC). Within this studies 1,1-Dimethylurea is shown to be not irritating.

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:
May - June 2004
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)
GLP compliance:
yes
Specific details on test material used for the study:
- Analytical purity: at least 98 %
- Impurities (identity and concentrations): max. 2 % Urea, max. 0.2 % Isopropanol, max. 0.5 % diethyleneglycolmonoethylether
- Lot/batch No.: KG 03-13
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH, 97633 Sulzfeld, Germany.
- Weight at study initiation: 2.0, 2.0 and 1.7 kg
- Housing: Individual caging in metal wire cages, Ehret GmbH, Emmendingen, type KK 016R, 79 cm x 59 cm bottom area, 38 cm height, with a wooden rest shelf, 15 cm x 59 cm. Exception: rest shelves are withdrawn during the exposure
- Diet (e.g. ad libitum): Altromin 2123 maintenance diet for rabbits, rich in crude fiber, ad libitu. Hay-briquettes (supplied by SSNIFF, 59494 Soest, Germany) was offered additionally as a dietry supplement.
- Water (e.g. ad libitum): Tap water from an automatic watering system, ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Average of 19.5 °C (continuous control and recording)
- Humidity (%): Average of 67.5 % (continuous control and recording)
- Photoperiod (hrs dark / hrs light): Artificial light from 6 a.m. to 6 p.m.

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
Samples with approximately 0.5 g of the test substance (the weighed amount of the individual doses were 500, 498 and 500 mg) were moistened with 1.0 mL deionised water and were placed on cellulose patches.
Duration of treatment / exposure:
The duration of the exposure was 4 hours.
Observation period:
The skins of the animals were examined for local alterations one day before the administration of the test substance (after clipping of the hair) and immediately before the administration. The treated areas and the surrounding untreated skin (control area) of the animals were examined for erythema/eschar and oedema as well as for other local alterations approximately 1, 24, 48 and 72 hours after patch removal.
Number of animals:
3 females
Details on study design:
TEST SITE
- Area of exposure: Test sites were median on the dorsal thoracal region

REMOVAL OF TEST SUBSTANCE
At the end of the exposure period the dressings, the taps with the patches and th collars were removed, residual test substance was wiped off with wet Kleenex-tissues, if necessary.

SCORING SYSTEM:
Erythema / Eschar formation:
0 No erythema
1 Very slight erythema (barely perceptible)
2 Well-defined erythema
3 Moderate to severe erythema
4 Severe erythema (beet redness) or eschar formation (injuries in depth)

Oedema formation
0 No oedema
1 Very slight oedema (barely perceptible)
2 Slight oedema (edges of areas well defined by definite raising)
3 Moderate oedema (raised approximately 1mm)
4 Severe oedema (raised more than 1 mm and extending beyond area of exposure)
Irritation parameter:
erythema score
Remarks:
Eschar
Basis:
animal #1
Remarks:
11
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Remarks:
Eschar
Basis:
animal #2
Remarks:
12
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Remarks:
Eschar
Basis:
animal #3
Remarks:
13
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
11
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
12
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
13
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Other effects:
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured.
Interpretation of results:
GHS criteria not met
Conclusions:
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured. All exposed skin sites were normal at each examination term and 1,1 -Dimethylurea was classified as "non-irritant" to skin.
Executive summary:

Possible irritation or corrosion by the test substance 1,1 -Dimethylurea was investigated by a single application to the intact skin of rabbits. The study was performed in accordance with method B.4 of Directive 92/69/EEC.

0.5 g 1,1 -Dimethylurea, moistened with deionised water, was applied via a patch to a site of 2.5 cm x 2.5 cm of the intact skin of each 3 rabbits and covered by a semi-occlusive dressing. The duration of the exposure was 4 hours.

No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured. All exposed skin sites were normal at each examination term and 1,1 -Dimethylurea was classified as "non-irritant" to 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:
May - July 2004
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)
GLP compliance:
yes
Specific details on test material used for the study:
- Analytical purity: at least 98 %
- Impurities (identity and concentrations): max. 2 % Urea, max. 0.2 % Isopropanol, max. 0.5 % diethyleneglycolmonoethylether
- Lot/batch No.: KG 03-13
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH, 97633 Sulzfeld, Germany.
- Weight at study initiation: 2.1, 2.4 and 2.3 kg
- Housing: Individual caging in metal wire cages, Ehret GmbH, Emmendingen, type KK 016R, 79 cm x 59 cm bottom area, 38 cm height, with a wooden rest shelf, 15 cm x 59 cm.
- Diet (e.g. ad libitum): Altromin 2123 maintenance diet for rabbits, rich in crude fiber, ad libitu. Hay-briquettes (supplied by SSNIFF, 59494 Soest, Germany) was offered additionally as a dietry supplement.
- Water (e.g. ad libitum): Tap water from an automatic watering system, ad libitum.
- Acclimation period: 5 days (animal 1) and 12 days (animal 2 and animal 3)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Average of 19.6 °C (continuous control and recording)
- Humidity (%): Average of 68.2 % (continuous control and recording)
- Photoperiod (hrs dark / hrs light): Artificial light from 6 a.m. to 6 p.m.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
The weighed amounts of the individual doses were 32, 36 and 31 mg.
Duration of treatment / exposure:
72 hours
Observation period (in vivo):
Both eyes of the animals were examined within 24 hours before the installation and approximately 1, 24, 48 and 72 hours p.a. An additional examination was performed in 1/3 animals 6 days p.a.
Number of animals or in vitro replicates:
three females
Details on study design:
The test substance was administered the animals into the conjunctival sacs of the right eyes by gently pulling the lower lids away from the eyeballs for installation. The eyes were held closed for about one second to prevent a loss of test substance.
The left eye remained untreated and served as a control.

The whole eyes, especially the corneae, the irises and the conjunctivae were examined using an otoscope lamp.

In addition to the eye examiniations, the animals were observed for other than local changes.

Scoring scheme for eye lesions:
CORNEA
Opacity:Degree of density (area most dense i staken for reading)
0 No ulceration or opacity
1 scattered or diffuse areas of opacity (expect for slight dulling of normal lustre), details of iris clearly visible
2 Easily discernible translucent area, details of iris slightly obscured
3 Nacreous area, no details of iris visible, size of pupil barely discernible
4 Opaqua cornea, iris not discernible through the opacity

IRIS
0 Normal
1 Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia or injection; any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive)
2 No reaction to light, haemorrhage, gross destruction (any of all these or all together)

CONJUNCTIVAE
Redness: (refers to the most severe effect of palpebral and bulbar conjunctivae in comparison to the control eye)
0 Blood vessels normal
1 Some blood vessels definitely hyperaemic (injected).
2 Diffuse crimson colour, individual vessels not easily discernible
3 Diffuse beefy red.
Chemosis: lids and/or nictating membranes
0 No swelling
1 Any swelling above normal (includes nictating membranes)
2 Obvious swelling with partial eversion of lids
3 Swelling with lids about half closed
4 Swelling with lids more than half closed
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
51
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 #2
Remarks:
52
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:
53
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:
51
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:
52
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:
53
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
Remarks:
Redness
Basis:
animal #1
Remarks:
51
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
Remarks:
Redness
Basis:
animal #2
Remarks:
52
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
Remarks:
Redness
Basis:
animal #3
Remarks:
53
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 6 d
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
51
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:
52
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
Remarks:
53
Time point:
24/48/72 h
Score:
> 0 - < 1
Max. score:
1
Reversibility:
fully reversible within: 24 hr
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
The untreated eyes ("control eyes") were normal at each observation time.

The eyes, treated with the test substance ("test eyes") were normal before the instillation. After the instilllation of the test substance, the following findings were made:
Corneae: Not affected
Irises: Not affected
Conjunctivae, redness: A score of "1" in 1/3 animals from 24 h p.a. onwards until 72 h p.a.
Conjunctivae, chemosis: A sccore of "1" in 1/3 animals from 1 h p.a. until 24 h p.a.
Other effects:
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured.
Interpretation of results:
GHS criteria not met
Conclusions:
After the instilllation of the test substance, the following findings were made:
Corneae: Not affected
Irises: Not affected
Conjunctivae, redness: A score of "1" in 1/3 animals from 24 h p.a. onwards until 72 h p.a.
Conjunctivae, chemosis: A sccore of "1" in 1/3 animals from 1 h p.a. until 24 h p.a.
Therefore 1,1 -Dimethylurea was classified as "non-irritant" to eyes.
Executive summary:

Possible irritation or corrosion by the test substance 1,1 -Dimethylurea was investigated by a single administration to a conjunctival sac of three rabbits. The study was performed in accordance with method B.5 of Directive 92/69/EEC.

The left eyes remained untreated and served as a control. Both eyes of the animals were examined within 24 hours before instillation and approximately 1, 24, 48 and 72 hours p.a. Eye irritation were scored and recorded. In addition to the eye examinations, the animals were observed for other than local changes at all observation times.

No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured.

The untreated eyes ("control eyes") were normal at each observation time.The eyes, treated with the test substance ("test eyes") were normal before the instillation. After the instilllation of the test substance, the following findings were made:

Corneae: Not affected

Irises: Not affected

Conjunctivae, redness: A score of "1" in 1/3 animals from 24 h p.a. onwards until 72 h p.a.

Conjunctivae, chemosis: A sccore of "1" in 1/3 animals from 1 h p.a. until 24 h p.a.

Therefore 1,1 -Dimethylurea was classified as "non-irritant" to eyes.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Possible irritation or corrosion by the test substance 1,1 -Dimethylurea was investigated by a single application to the intact skin of rabbits. The study was performed in accordance with method B.4 of Directive 92/69/EEC. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured. All exposed skin sites were normal at each examination term and 1,1 -Dimethylurea was classified as"non-irritant"to skin.

In a second test possible irritation or corrosion by the test substance 1,1 -Dimethylurea was investigated by a single administration to a conjunctival sac of three rabbits. The study was performed in accordance with method B.5 of Directive 92/69/EEC.

No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured.

The untreated eyes ("control eyes") were normal at each observation time.The eyes, treated with the test substance ("test eyes") were normal before the instillation. After the instilllation of the test substance, the following findings were made:

Corneae: Not affected

Irises: Not affected

Conjunctivae, redness: A score of "1" in 1/3 animals from 24 h p.a. onwards until 72 h p.a.

Conjunctivae, chemosis: A sccore of "1" in 1/3 animals from 1 h p.a. until 24 h p.a.

Therefore 1,1 -Dimethylurea was classified as"non-irritant"to eyes.

Justification for classification or non-classification

There are two reliable studies available covering dermal and eye irritation potential in rabbits. Among them an acute dermal irritation study according to Methode B.4 (Directive 92/69/EEC) and an acute eye irritation/corrosion study according to Methode B.5 (Directive 92/69/EEC). Within this studies 1,1-Dimethylurea is shown to be not irritating and therefore does not have to be classified.

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