6-methyl-2-oxoperhydropyrimidin-4-ylurea

Endpoint summary

Description of key information

Oral (OECD 423), rat: LD50>2000 mg/kg bw (limit test)
Inhalation: data waiving according to Column 2 of REACH Annex VIII
Dermal (OECD 402, RA from CAS 6104-30-9), rat: LD50>2000 mg/kg bw (limit test)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012-01-10 to 2012-03-16

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

(2001)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

(2008)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

(2002)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EPA Health Effects Test Guidelines, OPPTS 870.1000"Acute toxicity testing background", EPA 712-C-02-189 (2002)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

BAYERISCHES LANDESAMT FÜR GESUNDHEIT UND LEBENSMITTELSICHERHEIT, LANDESINSTITUT FÜR ARBEITSSCHUTZ UND PRODUKTSICHERHEIT, Munich, Germany

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: WISTAR rats Crl: WI(Han)
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 10-13 weeks
- Weight at study initiation: 167-178 g for step 1 (animals #1-3); 160-184 g for step 2 (animals #4-6)
- Fasting period before study: 16-19 h with free access to water
- Housing: in groups in IVC cages, type II H, polysulphone cages on Altromin saw fibre bedding (lot no. 110811) in an air conditioned room (full barrier)
- Diet: Altromin 1324 maintenance diet for rats and mice (lot no. 0815), ad libitum
- Water: tap water, sulfur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals), ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 55±10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

physiological saline

Remarks:

0.9% NaCl (AlleMan Pharma

Details on oral exposure:

VEHICLE
- Justification for choice of vehicle: due to its non-toxic characteristics
- Lot/batch no.: 111036, expiry date: 09/2014

MAXIMUM DOSE VOLUME APPLIED: 2 mL/kg bw

DOSAGE PREPARATION
The test item was weighed into a tared plastic vial on a precision balance. The test item was ground into a fine powder and then suspended in the vehicle. Homogeneity of the test item in the vehicle was maintained by vortexing the prepared suspension thoroughly before every dose administration.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females per step

Control animals:

other: not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: A careful clinical examination was made several times on the day of dosing (at least once during the first 30 min and with special attention given during the first 4 h post-dose). Thereafter, the animals were observed for clinical signs once daily until the end of the observation period.
- Frequency of weighing: on day 1 prior to administration and on days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred throughout the study period.

Clinical signs:

other: No clinical signs were observed throughout the study period.

Gross pathology:

No test material related gross pathologic findings were observed.

Interpretation of results:

not classified

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

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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: The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP. Since this is a read-across from a structural analogue substance (CAS 6104-30-9), the reliability was set from RL1 to RL2.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH
- Age at study initiation: male animals approx. 8-9 weeks, female animals approximately 12-13 weeks
- Weight at study initiation: males: 232-255 g; females: 206-224 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 20-80
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

CMC (carboxymethyl cellulose)

Details on dermal exposure:

TEST SITE
- Area of exposure: About 40 cm² (corresponds to at least 10% of the body surface)
- % coverage: at least 10 % of the body
- Type of wrap if used: semi-occlusive dressing (the bandage consists of four layers absorbent gauze, Ph. Eur. Lohmann GmbH & Co. KG and Fixomull stretch (adhesive fleece), Beiersdorf AG)


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Rinsing of the application site with warm water.
- Time after start of exposure: after 24 hours of exposure


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 g/kg (50% test substance)
- Concentration (if solution): 50 g/100 mL
- Constant volume or concentration used: yes
- For solids, paste formed: yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights shortly before administration (Day 0), weekly thereafter and on the last day of observation. Recording of signs and symptoms several times on the day of application, at least once each workday for the individual animals
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology, assessment of the skin reactions

Statistics:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred throughout the study period.

Clinical signs:

other: No systemic clinical observations were observed during clinical examination and no local effects to the skin were observed.

Gross pathology:

No macroscopic pathologic findings were noted in the animals (5 males and 5 females) examined on the last day of observation.

Interpretation of results:

not classified

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

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group, breakdown products, and similarities in PC/ECOTOX/TOX properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for read-across

No sufficient data are available for the acute toxicity 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.

Acute Toxicity

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
Acute toxicity oral	LD50 > 2000 mg/kg bw	--
Acute toxicity inhalation	waiving	--
Acute toxicity dermal	RA: CAS 6104-30-9	LD50 > 2000 mg/kg bw

 

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

Acute oral toxicity

One study is available with 6-methyl-2-oxoperhydropyrimidin-4-ylurea (Crotodur, CAS 1129-42-6), in which the acute oral toxicity was investigated (BSL, 2012a). The study was conducted according to the OECD test guideline 423 (Acute Toxic Class Method), and in compliance with GLP, the test item was administered in 2 steps to 6 female WISTAR rats at a dose of 2000 mg/kg bw as a suspension physiol. saline. No mortality and no signs of toxicity were observed after dosage and throughout the 14 days observation period. Body weight gain was as expected, except for one female rat, which showed very slight weight loss during the second week of the study, but still with an overall positive trend. At the end of the study, the animals were sacrificed and subjected to gross pathological examination. No test material related findings were noted. Based on the outcome of the study, the LD50 was set at >2000 mg/kg bw.

 

Acute inhalation toxicity

In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2 of REACH Annex VIII) does not need to be conducted as reliable data via the oral and dermal routes are available.

The submission substance is a solid at ambient conditions. The low vapour pressure indicates that inhalation of the registered substance as a vapour is not likely to occur. Similarly, the particle size distribution revealed that 98.6% of the test article particles have a diameter of ≥500 µm and are therefore not respirable. Only 1.4% of the particles are smaller than 500 µm. However, no data is given on the fraction of inhalable particles (<100 µm), especially not on those particles <15 µm, which may reach the alveolar region of the respiratory tract. Nevertheless, due to the overall distribution of the particle size, the inhalable fraction, especially the alveolar fraction, is expected to be very small and inhalation of the submission substance is therefore considered negligible.

 

Acute dermal toxicity

No data is available on the acute dermal toxicity of 6-methyl-2-oxoperhydropyrimidin-4-ylurea (Crotodur, CAS 1129-42-6), but there is one reliable study from the structurally related substance N,N”-(2-methylpropane-1,1-diyl) diurea (Isodur, CAS 6104-30-9) available, which is used for read-across based on the analogue approach (Bioassay, 2008). The test item (CAS 6104-30-9) was investigated for acute dermal toxicity in a limit test conducted according to the OECD test guideline 402, and in compliance with GLP. 2000 mg/kg bw of a paste of 50% test material formulation in CMC (carboxymethyl cellulose) were semiocclusively applied to 5 Wistar rats per sex. Following 24 h of exposure, the test material was washed off with warm water. No deaths occurred throughout the study period. No systemic clinical observations were observed during clinical examination and no local effects to the skin were observed. The mean body weights of the animals increased normally throughout the study period and no macroscopic pathologic findings were noted in the animals (5 males and 5 females) examined on the last day of observation. Based on this data, the LD50 for acute dermal toxicity for CAS 6104-30-9 was set at >2000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
The key study was selected for assessment.

Justification for selection of acute toxicity – inhalation endpoint
In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2 of REACH Annex VIII) does not need to be conducted as reliable data via the oral and dermal routes are available.

Justification for selection of acute toxicity – dermal 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).

Justification for classification or non-classification

Based on read-across from the structurally similar substances, the available data on oral and dermal toxicity 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.