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Administrative data

Description of key information

There are Klimisch 1 validity studies for skin and eye irritation, both of which showed mild irritation, which in the skin was despite the use of a protocol with 24 hour occluded exposure rather than the 4 hour period typically.  There is no specific testing for respiratory irritation but there is an acute inhalation toxicity study.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study in accordance with OPPTS 870.2500 and OECD TG 404
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
1992
Deviations:
yes
Remarks:
The test duration was 24 hours instead of 4 hours
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
version 1998
Deviations:
yes
Remarks:
The test duration was 24 hours instead of 4 hours
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Myrtle's Rabbitry, Thompson Station, USA
- Age at study initiation: 11-12 weeks
- Weight at study initiation: 2.4-2.7 kg
- Housing: individually in suspended stainless steel cages
- Diet (e.g. ad libitum): PMI Certified Rabbit Chow #5322 (Purina Mills) ad libitum
- Water (e.g. ad libitum): municipal tap water treated by reverse osmosis ad libitum
- Acclimation period: acclimated to the laboratory conditions for a minimum of five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 26-56
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours darkness
Type of coverage:
occlusive
Preparation of test site:
other: clipped by avoiding abrasion and abraded
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL of pure substance and of dilution
- Concentration (if solution): 100% and 52% of test substance in aqueous dilution (57.58% and 30% of hydroxyethyl urea)
Duration of treatment / exposure:
24 hours
Observation period:
Up to 10 days after patch removal
Number of animals:
Six
Details on study design:
TEST SITE
- Area of exposure: about 6.4 square centimetres per test site, in total 4 test sites per animal (two tested with undiluted and two with diluted test material)
- % coverage: about 1% of total body surface
- Type of wrap if used: plastic wrap plus additional elastic wrap

REMOVAL OF TEST SUBSTANCE
- Washing (if done): remaining test material was removed with moistened gauze
- Time after start of exposure: 24 hours

SCORING SYSTEM:
Effects were scored according to Draize JH (Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. The Association of Food and Drug Officials of the United States, 49-51, 1959).
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 1, 24, 48 and 72 hours
Score:
0.63
Max. score:
8
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Result for the pure test substance on intact skin
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 1, 24, 48 and 72 hours
Score:
0.5
Max. score:
8
Reversibility:
fully reversible within: 10 days
Remarks on result:
other: Result for the dilution on intact skin
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 1, 24, 48 and 72 hours
Score:
1.13
Max. score:
8
Reversibility:
fully reversible within: 10 days
Remarks on result:
other: Test result with pure substance on abraded skin
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 1, 24, 48 and 72 hours
Score:
0.33
Max. score:
8
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Result for the dilution on abraded skin
Other effects:
No other effects related to treatment were noted

Table 1: Individual scoring for 100% test material (containing 57.58% hydroxyethyl urea) tested on intact skin

Animal

Scoring interval after patch removal

 

ERYTHEMA

R4467

0

0

0

0

-

-

R4472

1

1

1

0

-

-

R4471

1

1

1

0

-

-

R4430

1

1

1

0

-

-

R4426

1

1

1

1

0

-

R4461

1

0

0

0

-

-

 

Oedema

R4467

0

0

0

0

-

-

R4472

0

0

0

0

-

-

R4471

1

0

0

0

-

-

R4430

0

0

0

0

-

-

R4426

0

0

0

0

0

-

R4461

0

0

0

0

-

-

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance EXP 3982 N-2-hydroxyethylurea is an aqueous solution containing 57.58% hydroxyethyl urea. The substance is not irritating to the intact rabbit skin when tested as pure substance and does not need to be classified.
Executive summary:

The skin irritation potential of the test substance EXP 3982 N-2-hydroxyethylurea containing 57.58% of the active ingredient hydroxyethyl urea was studied under GLP in accordance with OECD TG 404. Six healthy male rabbits of the New Zealand White strain (11 to 12 weeks old, weighing 2.4 to 2.7 kg) were used in the study. The treatment area was clipped 24 hours prior to the start of the experiment. The pure test substance (57.58% hydroxyethyl urea) and a 52% aqueous solution (30% hydroxyethyl urea) were applied topically on areas of intact and abraded skin under occlusion for a duration of 24 hours, which is longer than the normal exposure duration of 4 hours given in the guideline. Each animal was treated on four sites. The skin surface area treated per site was approximately 6.5 cm2. The patches were removed after 24 hours and remaining test material was wiped off. Scoring of the skin reaction according to Draize (1959) was performed 1, 24, 48 and 72 hours and up to 10 days after removal of the patches. The scores of individual animals for erythema/eschar and oedema were up to 1 at individual ratings 24, 48 and 72 hours after patch removal. All skin reactions were fully reversible within 10 days. The test substance was non-corrosive. No other effects related to treatment were observed. Hydroxyethyl urea is not classified as a skin irritant based on GHS criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline-conform study performed under GLP
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Myrtle's Rabbitry, Thompson Station, TN
- Age at study initiation: males: 14-15 weeks, females: 15 weeks
- Weight at study initiation: males: 3.0 - 3.2 kg, females: 3.1 - 3.5 kg
- Housing: individually in suspended stainless steel cages
- Diet (e.g. ad libitum): PMI Certified Rabbit Chow #5322 (Purina Mills, Inc.) ad libitum
- Water (e.g. ad libitum): municipal tap water treated by reverse osmosis ad libitum
- Acclimation period: acclimated to the laboratory conditions for a minimum of five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 26-56
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: One eye of each rabbit remained untreated and served as a control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
single application
Observation period (in vivo):
1, 24, 48 and 72 h and up to 7 days after dosing
Number of animals or in vitro replicates:
3 males, 3 females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Following macroscopic observations at the 24-h scoring interval, any residual test article was gently rinsed from the eye using physiological saline.
- Time after start of exposure: 24 h

SCORING SYSTEM:
CORNEAL OPACITY-DEGREE OF DENSITY (AREA MOST DENSE TAKEN INTO ACCOUNT)
0: No ulceration or opacity
1: Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible
2: Easily discernible translucent area,, details of iris slightly obscured
3: Nacreous (opalescent) area, no details of iris visible, size of pupil barely discernible
4: Opaque cornea, iris not discernible through opacity

AREA OF CORNEA INVOLVED (TOTAL AREA EXHIBITING ANY OPACITY, REGARDLESS OF DEGREE)
0: No ulceration or opacity
1: One quarter (or less) but not zero
2: Greater than one quarter, but less than half
3: Greater than half, but less than three quarters
4: Greater than three quarters, up to whole area

IRITS
0: Normal
1: Markedly deepened rugae (folds above normal), congestion, swelling, modarate circumcorneal hyperemia or injection, any or all of these or combination of any thereof, iris is still reacting to light (sluggish reaction is positive)
2: No reaction to light, hemorrhage, gross destruction (any or all of these)

CONJUNCTIVAL REDNESS (REFERS TO PALPEBRAL AND BULBAR CONJUNCTIVAE EXCLUDING CORNEA AND IRIS
0: Blood vessels normal
1: Some blood vessels definitely hyperemic (injected) above normal (slight erythema)
2: Diffuse, crimson color, individual vessels not easily discernible (moderate erythema)
3: Diffuse beefy red (marked erythema)

CONJUNTIVAL SWELLING (LIDS AND/OR NICTITATING MEMBRANE)
0: No swelling
1: Any sweliing above normal (includes nictitating membrane, slightly swollen)
2: Obvious sewlling with partial eversion of lids
3: Swelling with lids about half closed
4: Swelling with lids more than half closed

CONJUNCTVAL DISCHARGE
0: No discharge
1: Any amount different from normal (does not include small amounts observed in inner canthus of normal animals)
2: Discharge with moistening of the lids and hairs just adjacent to lids
3: Discharge with moistening of the lids and hairs and considerable area around the eye


TOOL USED TO ASSESS SCORE: auxiliary light source/ fluorescein (before start of test and after 24 h)
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: mean of scores at 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
mean
Time point:
other: mean of scores at 24, 48 and 72 h
Score:
0.056
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: mean of scores at 24, 48 and 72 h
Score:
0.56
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: mean of scores at 24, 48 and 72 h
Score:
0.22
Max. score:
4
Reversibility:
fully reversible within: 48 h

Individual scores at 1 h

Cornea score: 0 for all animals

Iris score: 0 in three males, 1 in three females

Conjunctivae score: 1 in all animals

Chemosis score: 1 in all animals

Individal mean scores at 24, 48 and 72 h

Cornea score: 0 for all animals

Iris score: 0 in three males and two females, 1/3 in one female

Conjunctivae score: 1/3 in two males and one female, 2/3 in two females, 1 in one male

Chemosis score: 0 in one male and one female, 1/3 in two males and two females

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of the test, the test item is considered to be a mild irritant to the ocular tissure of the rabbit. EXP 3982 N-2-hydroxyethylurea does not have to be classified for eye irritation according to Regulation (EC) 1272/2008 (CLP).
Executive summary:

The potential irritant and/or corrosive effects of the aqueous solution EXP 3982 N-2-hydroxyethylurea containing 57.58 % of the active ingredient hydroxyethyl urea were evaluated under GLP on the eyes of New Zealand White rabbits in accordance with OECD TG 405. Each of six rabbits received a 0.1 mL dose of the aqueous solution in the conjunctival sac of the right eye. The contralateral eye of each animal remained untreated and served as a control. Test and control eyes were examined for signs of irritation for up to 7 days following dosing.

Exposure to the test article produced iritis in 3/6 test eyes at the 1-hour socring interval which resolved completely in all test eyes by the 48-hour scoring interval. Effects on the conjunctivae (redness, swelling and/or discharge) were noted in 6/6 test eyes at the 1-hour scoring interval. The conjunctival irritation resolved completely in all test eyes by study day 7.

EXP 3982 N-2-hydroxyethylurea is considered to be a mild irritant to the ocular tissue of the rabbit. It does not have to be classified for eye irritation according to Regulation (EC) 1272/2008 (CLP) /GHS.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

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

Additional information

The available information for skin and eye irritation in rabbits indicates that hydroxyethyl urea is a mild irritant to eyes and to skin with prolonged exposure.  We have no test specifically for irritation of the respiratory tract; the acute inhalation toxicity test in rats did not indicate any specific symptoms of respiratory irritation. Some red foci were observed in the lungs of some animals at all treatment levels, by when examined histologically on the third phase of the experiment they were not haemorrhages and not confirmed as related to treatment. They are therefore not necessarily an indication of irritation. The limited information from the acute inhalation toxicity study in rats does not report any specific signs of respiratory irritation, in a study which has the complication of a the presence of ca. 1.5% of ammonium lactate in the solution which is not present in the test substance used in the other toxicology studies.


Justification for selection of skin irritation / corrosion endpoint:
There is a Klimisch 1 full GLP skin irritation study in rabbits to OECD 404, this study was with a 57.58% solution of hydroxyethyl urea in water (EXP5982). Hydroxyethyl urea as a 57.58% solution in water was a mild irritant to rabbit skin with any effects reversed after 10 days after 24 hours occluded exposure, rather than the normal 4 hour exposure used when testing for classification to the EU CLP criteria.

Justification for selection of eye irritation endpoint:
There is a Klimisch 1 full GLP eye irritation study in rabbits to OECD 405, this study was with a 57.58% solution of hydroxyethyl urea in water (EXP5982). Hydroxyethyl urea as a 57.58% solution in water was a mild irritant to rabbit eyes.

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

The rabbit skin and eye irritations studies only showed mild irritation even after prolonged skin contact. The available information on respiratory irritation from the acute inhalation study does not indicate any serious irritation. Based on these studies there is no requirement to classify hydroxyethyl urea for skin or eye irritation according to the EU CLP criteria.