6-methyl-2-oxoperhydropyrimidin-4-ylurea

Endpoint summary

Description of key information

Skin irritation (RA from CAS 6104-30-9, non-guideline): not irritating (further supported by in vitro data (OECD 431) with the submission substance)
Eye irritation (RA from CAS 6104-30-9, non-guideline): not irritating (further supported by in vitro data (OECD 437) with the submission substance)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study predates the OECD test guidelines and GLP. However, the study meets basic scientific principles with acceptable restrictions when compared to current standards (limited documentation, substance tested only as 50% dilution, observation/reading only at 24 hours and 8 days, only 2 animals tested). The study is a read-across from a structural analogue substance (CAS 6104-30-9).

Principles of method if other than guideline:

The test substance was applied substance as 50% dilution for 20 hours under occlusive conditions. Observation/reading was performed only at 24 hours and 8 days and only 2 animals were tested.

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: approximately 2.8 kg
- sex: male

No further data are given in the study report.

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5 g
- Concentration (if solution): 50% aqueous preparation

Duration of treatment / exposure:

20 hours

Observation period:

8 days

Number of animals:

2

Details on study design:

TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm

Irritation parameter:

erythema score

Basis:

mean

Remarks:

over both tested animals

Time point:

other: mean over 24, 48, and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Remarks on result:

other: No signs of irritation were observed.

Irritation parameter:

edema score

Basis:

mean

Remarks:

over both animals

Time point:

other: mean over 24, 48, and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Remarks on result:

other: Nno signs of irritation were observed.

Other effects:

- Systemic toxicity: No mortality occurred. There were no signs of clinical toxicity from the dermal exposure.
- Irritation score: No skin findings were observed at any time
- Summary: Occlusive application for 20 h to rabbit skin did not lead to any signs of irritation at any time during the 8 days of observation.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

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:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study predates the OECD test guidelines and GLP. However, the study meets basic scientific principles with acceptable restrictions when compared to current standards (limited documentation, only 2 animals tested, only 50 µL applicated). The study is a read-across from a structural analogue substance (CAS 6104-30-9).

Principles of method if other than guideline:

The test substance was applied as a single instillation (50 µL) as powder, the substance was not washed out, only 2 rabbits were used

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

no data

Vehicle:

unchanged (no vehicle)

Controls:

other: treated with talcum powder

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 50 µL (50 mm³)

Duration of treatment / exposure:

single instillation of the test substance as powder, the substance was not washed out

Observation period (in vivo):

8 days

Number of animals or in vitro replicates:

2

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: none, substance not washed out

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

out of both animals

Time point:

other: mean over 24, 48, and 72 h

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Irritation parameter:

iris score

Basis:

mean

Remarks:

out of both animals

Time point:

other: mean over 24, 48, and 72 hours

Score:

0

Max. score:

2

Reversibility:

other: reversibility: not applicable

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

out of both animals

Time point:

other: mean over 24, 48, and 72 h

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

other: mean over 24, 48, and 72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: The maximal score was 1 at the 24 h reading time point.

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

other: mean over 24, 48, and 72 h

Score:

0

Max. score:

3

Reversibility:

other: reversibility: not applicable

Irritant / corrosive response data:

The treatment led to slight redness. All findings were reversible after 8 days of observation period. The control eyes which were treated with talcum powder did show the same reactions.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for read-across

No sufficient data are available for the irritating properties of 6-methyl-2-oxoperhydropyrimidin-4-ylurea (Crotodur, CAS 1129-42-6). In order to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from a structurally related substance was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Irritation/Corrosion

CAS	1129-42-6 TARGET SUBSTANCE	6104-30-9
Chemical Name	6-methyl-2-oxoperhydropyrimidin-4-ylurea (Crotodur)	N,N”-(2-methylpropane-1,1-diyl) diurea (Isodur)
MW	172.1851 g/mol	174.2010 g/mol
Skin corrosion in vitro	not corrosive	--
Skin irritation/corrosion in vivo	RA: CAS 6104-30-9	not irritating
Eye corrosion in vitro	not corrosive	--
Eye irritation in vivo	RA: CAS 6104-30-9	not irritating

 

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for 6-methyl-2-oxoperhydropyrimidin-4-ylurea (Crotodur, CAS 1129-42-6).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

Skin irritation/corrosion

In vivo data are available only for the structural analogue substance CAS 6104-30-9. The available in vitro data for the submission substance do not provide sufficient and adequate information on skin irritation for classification purposes and will therefore only serve as supporting data. Additional data obtained from an acute dermal toxicity study with CAS 6104-30-9 further support these results. 

The key study was conducted with the close structural analogue substance CAS 6104-30-9 (BASF AG, 1967). In a study predating the appropriate OECD test guidelines and GLP, 5 g of a 50% aqueous preparation of the test item was occlusively applied to 2.5 x 2.5 cm of the shaved skin of 2 male Vienna White rabbits for 20 h. The animals were then observed for 8 days post exposure. No mortality occurred. There were no signs of clinical toxicity from the dermal exposure. No skin findings were observed at any time and both the mean erythema and oedema scores over 24, 48, and 72 h was zero for both animals. Thus, the test item (CAS 6104 -30 -9) was concluded to be not irritating to the rabbits' skin under the conditions of the test.

Supporting data on skin irritation are available for the submission substance itself. An in vitro human skin model test was conducted according to OECD 431, and in compliance with GLP (BSL, 2012b). The test was performed on a total of 4 EpiDerm Skin Model tissues per test group (negative control, positive control, and test substance), 2 replicates for each treatment. Corrosivity of the test item was predicted from the relative mean tissue viabilities obtained after 3 min treatment compared to the negative control tissues concurrently treated with aqua destillata (=100%). A test item is classified as corrosive in any case, if the relative tissue viability after 3 min treatment is decreased below 50%. In addition, those test items classified as non-corrosive after 3 min (viability ≥50%) are classified as corrosive, if the relative mean issue viability after 1 h treatment compared to the concurrent negative control tissues is decreased below 15%. In this study, the test item showed no corrosive effects. The mean relative tissue viability (% negative control) was ≥50% (95%) after 3 min treatment and ≥15% (98%) after 1 h treatment. However, this study does not provide sufficient and adequate information on skin irritation for classification purposes.

Reliable data from an acute dermal toxicity study with the structural analogue substance (CAS 6104-30-9) further support that the test item is not irritating to the skin (Bioassay, 2008). The study was conducted as a limit test according to OECD 402, and in compliance with GLP. A paste of the test item with carboxymethyl cellulose at a dose of 2000 mg/kg bw was semiocclusively applied to approximately 40 cm² (corresponding to at least 10% of the body surface) of the skin of 5 Wistar rats per sex for 24 h. No local effects to the skin were observed throughout the 14-day observation period and no macroscopic findings were noted in any of the animals at necropsy. 

In summary, the submission substance was found to be not corrosive to the human skin model in vitro, and the structural analogue substance (CAS 6104-30-9) did neither exhibit any skin reactions in rabbits in a skin irritation study, nor to the rat skin in an acute dermal toxicity study. Based on the in vitro data on the submission substance itself and reliable in vivo data on the structural analogue substance, the submission substance is considered to be not irritating to the skin.

 

Eye irritation

In vivo data are available only for the structural analogue substance CAS 6104-30-9. The available in vitro data for the submission substance do not provide sufficient and adequate information on eye irritation for classification purposes and will therefore only serve as supporting data.

Key data are available from the close structural analogue substance (CAS 6104-30-9; BASF AG, 1967). In a study predating the appropriate OECD test guidelines and GLP, 50 µL of the test item as a powder were applied as a single instillation to one eye each of 2 Vienna White rabbits. The remaining eyes were treated with talcum powder and served as negative controls. The test materials were not washed out after a certain exposure duration. The animals were observed at several time points after application, including 1, 24, 48, 72 h and 8 days following instillation. The treatment led to slight redness. All findings were reversible after 8 days of observation period. The control eyes which were treated with talcum powder did show the same reactions. The mean cornea, iris, and chemosis scores over 24, 48, and 72 h were zero for both animals. The mean conjunctivae score was zero for one animal and 0.33 for the second animal. However, the effect was fully reversible within 48 h. Thus, the test item (CAS 6104-30-9) was concluded to be not irritating to the rabbits' eye under the conditions of the test.

The available supporting study on eye irritation with the submission substance itself is an in vitro bovine corneal opacity and permeability test, conducted according to OECD 437, and in compliance with GLP (BSL, 2012c). Mean irritancy scores calculated were 0.38, 0.47, and 239.56 for the negative control, the test item, and the positive control, respectively. The positive control data were within the two standard deviations of the current historical control mean and therefore this assay was considered to be valid. Thus, the test item is concluded to be not corrosive to the bovine eye in the in vitro bovine corneal opacity and permeability test. However, this study does not provide sufficient and adequate information on eye irritation for classification purposes. 

In summary, the submission substance was found to be not corrosive to the bovine eye in vitro, and the structural analogue substance (CAS 6104-30-9) is not irritating to the rabbit's eye in vivo. Based on the in vitro data on the submission substance itself and reliable in vivo data on the structural analogue substance, the submission substance is considered to be not irritating to the eye.

Justification for selection of skin irritation / corrosion endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details). The read-across study from the close-structural analogue substance (CAS 6104-30-9) was selected as key, since the in vitro test (OECD 431) available for the submission substance does not provide sufficient and adequate information on skin irritation for classification purposes.

Justification for selection of eye irritation endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details). The read-across study from the close-structural analogue substance (CAS 6104-30-9) was selected as key, since the in vitro test (OECD 437) available for the submission substance does not provide sufficient and adequate information on skin irritation for classification purposes.

Justification for classification or non-classification

Based on test substance data and read-across from the structurally similar substance, the available data on skin and eye irritation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.