6-methyl-2-oxoperhydropyrimidin-4-ylurea

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

117.11 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

2 927.82 mg/m³

Explanation for the modification of the dose descriptor starting point:

No data are available for the inhalation route. However, reliable data from a structural analogue substance (CAS 6104-30-9) are available for the oral route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

default

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default (worker)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

166.06 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

1 660.55 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data are available for the dermal route. However, reliable data from a structural analogue substance (CAS 6104-30-9) are available for the oral route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

default

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat/human)

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default (worker)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

No long term toxicity data are available for the submission substance, however, reliable data are available for the structural analogue substance (CAS 6104-30-9).

In the available Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test the structural analogue substance CAS 6104-30-9 was investigated for toxicity after repeated oral exposure (CIT, 2003a). The study was conducted according to OECD 422, and in compliance with GLP. 10 Sprague-Dawley rats per sex per dose received the test item in carboxymethyl cellulose via gavage at doses of 100, 300, and 1000 mg/kg bw/day. Males were treated throughout pre-mating (15 days), and during the mating and post-mating periods until sacrifice (34 days in total). Females received the test material throughout pre-mating (15 days) and mating period, during pregnancy and lactation, and until day 4 post partum. Treatment was conducted once daily for 7 days per week; concurrent controls received the vehicle only. Treatment with the test material did not result in any adverse effects of toxicological relevance for human health, neither for systemic toxicity, nor for toxicity to reproduction. Therefore, a NOAEL of 1000 mg/kg bw/day for both systemic toxicity and reproductive toxicity was deduced.

Further information from the structural analogue substance CAS 6104-30-9 was obtained from a study performed to investigate the toxicity to reproduction (CIT, 2003b).The one-generation study was conducted similar to the OECD test guidelines 416 and 421, and in compliance with GLP. 25 Sprague-Dawley rats per sex per dose received the test substance in carboxymethyl cellulose via gavage at doses of 600 mg/kg bw/day and 1200 mg/kg bw/day. Males were treated throughout the pre-mating period (10 weeks), mating period (2 weeks), and until sacrifice; the females received the test material throughout the pre-mating period (10 weeks), mating period (2 weeks), and pregnancy until day 14 post-coitum inclusive. Treatment was carried out daily on 7 days per week, and concurrent controls received the vehicle only. Treatment with the test material did not result in any adverse effects of toxicological relevance for human health. Therefore, a NOAEL of 1200 mg/kg bw/day for both maternal and developmental toxicity was deduced.

The available developmental toxicity/teratogenicity study (BASF AG, 1993) with the structural analogue substance CAS 6104-30-9 was conducted according to OECD 414 and in compliance with GLP. 25 naive female Wistar rats were mated in a ratio of 1/4 with respective naive males by cohousing overnight, and treated with the test substance via gavage from gestation days 6 -15. The test material was administered as a suspension in 0.5% aqueous carboxymethyl cellulose solution at doses of 100, 400, and 1000 mg/kg bw/day once daily on 7 days/week. The doses applied were selected on the basis of the outcome of a preliminary range-finding study. No test material-related effects were seen throughout the study period, neither in dams, nor in pups. Thus, the NOAEL for both the maternal and foetal organism was set at 1000 mg/kg bw/day.

In conclusion, the NOAEL of 1200 mg/kg bw/day deduced from the one-generation reproductive toxicity study (CIT, 2003b) was used for the risk assessment, since this value was obtained from the study with the longest exposure duration and is therefore considered to be the most reliable dose descriptor.

Workers - hazard via inhalation route - systemic effects - long term exposure

The long term DNEL for systemic toxicity via the inhalation route is determined by route-to route extropolation on the basis of NOAEL of 1200 mg/kg bw/day revealed from the one-generation reproductive toxicity study with the structural analogue substance CAS 6104 30-9 (CIT, 2003b).

The following correction was made to the NOAEL:

Based on the different molecular weights of 6-methyl-2-oxoperhydropyrimidin-4-yl urea (CAS 1129-42-6; 172.1851 g/mol) and the analogue substance N,N''-(isobutylidene)diurea (CAS 6104-30-9; 174.2010 g/mol), the NOAEL was corrected to 1186.11 mg/kg bw/day (MW correction target/source=172.1851 g/mol/174.2010 g/mol=0.988; 1200 mg/kg bw/day×0.988=1186.11 mg/kg bw/day).

No correction for relative absorption oral vs. inhalation: 1

Correction for number of exposures per week: 7d/5d

Correction for respiratory volume (rat/worker): 0.38 m³/kg bw (8 h)

Correction for respiratory volume (worker, light physical activity): 6.7 m³/10 m³

Therefore the corrected NOAEC for repeated-dose systemic effects via inhalation is:

1186.11 mg/kg bw/day×7/5×1/0.38 m³/kg bw ×(6.7 m³/10 m³)=2927.82 mg/m³/day

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (subchronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Intraspecies differences (worker): 5 (default)

Total AF: 2×2.5×5=25

 

The overall DNEL (repeated-dose – systemic – inhalation - worker) is therefore:

2927.82 mg/m³/day/25=117.11 mg/m³/day.

Workers- hazard via dermal route - systemic effects - long term exposure

The long term DNEL for systemic toxicity via the inhalation route is determined by route-to route extropolation on the basis of NOAEL of 1200 mg/kg bw/day revealed from the one-generation reproductive toxicity study with the structural analogue substance CAS 6104 30-9 (CIT, 2003b).

The following correction was made to the NOAEL:

Based on the different molecular weights of 6-methyl-2-oxoperhydropyrimidin-4-yl urea (CAS 1129-42-6; 172.1851 g/mol) and the analogue substance N,N''-(isobutylidene)diurea (CAS 6104-30-9; 174.2010 g/mol), the NOAEL was corrected to 1186.11 mg/kg bw/day (MW correction target/source=172.1851 g/mol/174.2010 g/mol=0.988; 1200 mg/kg bw/day×0.988=1186.11 mg/kg bw/day).

No correction for relative absorption oral vs. dermal: 1

Correction for number of exposures per week: 7d/5d

Therefore the corrected NOAEL for repeated-dose systemic effects via the dermal route is:

1186.11 mg/kg bw/day×7/5=1660.55 mg/kg bw/day

 

The following assessment factors were applied to the systemic NOAEL:

Exposure duration (subacute to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4 (default)

Intraspecies differences (worker): 5 (default)

Total AF: 2×2.5×4×5=100

 

The overall DNEL (repeated-dose – systemic – dermal - worker) is therefore:

1660.55 mg/kg bw/day/100=166.06 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20.63 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

1 031.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

No data are available for the inhalation route. However, reliable data from a structural analogue substance (CAS 6104-30-9) are available for the oral route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

defaullt

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

defaullt

AF for intraspecies differences:

10

Justification:

defaullt (general population)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.93 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

1 186.11 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data are available for the dermal route. However, reliable data from a structural analogue substance (CAS 6104-30-9) are available for the oral route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

default

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat/human)

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (worker)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.93 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

1 186.11 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

default

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat/human)

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

No long term toxicity data are available for the submission substance, however, reliable data are available for the structural analogue substance (CAS 6104-30-9).

In the available Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test the structural analogue substance CAS 6104-30-9 was investigated for toxicity after repeated oral exposure (CIT, 2003a). The study was conducted according to OECD 422, and in compliance with GLP. 10 Sprague-Dawley rats per sex per dose received the test item in carboxymethyl cellulose via gavage at doses of 100, 300, and 1000 mg/kg bw/day. Males were treated throughout pre-mating (15 days), and during the mating and post-mating periods until sacrifice (34 days in total). Females received the test material throughout pre-mating (15 days) and mating period, during pregnancy and lactation, and until day 4 post partum. Treatmentwas conducted once daily for 7 days per week; concurrent controls received the vehicle only. Treatment with the test material did not result in any adverse effects of toxicological relevance for human health, neither for systemic toxicity, nor for toxicity to reproduction. Therefore, a NOAEL of 1000 mg/kg bw/day for both systemic toxicity and reproductive toxicity was deduced.

Further information from the structural analogue substance CAS 6104-30-9 was obtained from a study performed to investigate the toxicity to reproduction (CIT, 2003b).The one-generation study was conducted similar to the OECD test guidelines 416 and 421, and in compliance with GLP. 25 Sprague-Dawley rats per sex per dose received the test substance in carboxymethyl cellulose via gavage at doses of 600 mg/kg bw/day and 1200 mg/kg bw/day.Males were treated throughout the pre-mating period (10 weeks), mating period (2 weeks), and until sacrifice; the females received the test material throughout the pre-mating period (10 weeks), mating period (2 weeks), and pregnancy until day 14 post-coitum inclusive. Treatment was carried out daily on 7 days per week, and concurrent controls received the vehicle only.Treatment with the test material did not result in any adverse effects of toxicological relevance for human health. Therefore, a NOAEL of 1200 mg/kg bw/day for both maternal and developmental toxicity was deduced.

The available developmental toxicity/teratogenicity study (BASF AG, 1993) with the structural analogue substance CAS 6104-30-9 was conducted according to OECD 414 and in compliance with GLP. 25 naive female Wistar rats were mated in a ratio of 1/4 with respective naive males by cohousing overnight, and treated with the test substance via gavage from gestation days 6 -15. The test material was administered as a suspension in 0.5%aqueous carboxymethyl cellulose solution at doses of 100, 400, and 1000 mg/kg bw/day once daily on 7 days/week. The doses applied were selected on the basis of the outcome of a preliminary range-finding study. No test material-related effects were seen throughout the study period, neither in dams, nor in pups. Thus, the NOAEL for both the maternal and foetal organism was set at 1000 mg/kg bw/day.

In conclusion, the NOAEL of 1200 mg/kg bw/day deduced from the one-generation reproductive toxicity study (CIT, 2003b) was used for the risk assessment, since this value was obtained from the study with the longest exposure duration and is therefore considered to be the most reliable dose descriptor.

General population - hazard via inhalation route - systemic effects - long term exposure

The long term DNEL for systemic toxicity via the inhalation route is determined by route-to route extropolation on the basis of NOAEL of 1200 mg/kg bw/day revealed from the one-generation reproductive toxicity study with the structural analogue substance CAS 6104 30-9 (CIT, 2003b).

The following correction was made to the NOAEL:

Based on the different molecular weights of 6-methyl-2-oxoperhydropyrimidin-4-yl urea (CAS 1129-42-6; 172.1851 g/mol) and the analogue substance N,N''-(isobutylidene)diurea (CAS 6104-30-9; 174.2010 g/mol), the NOAEL was corrected to 1186.11 mg/kg bw/day (MW correction target/source=172.1851 g/mol/174.2010 g/mol=0.988; 1200 mg/kg bw/day×0.988=1186.11 mg/kg bw/day).

No correction for relative absorption oral vs. inhalation: 1

Correction for respiratory volume (rat/general population): 1.15 m³/kg bw (24 h)

Therefore the corrected NOAEC for repeated-dose systemic effects via inhalation is:

1186.11 mg/kg bw/day×1/1.15 m³/kg bw=1031.40 mg/m³/day

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (subchronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Intraspecies differences (general population): 10 (default)

Total AF: 2×2.5×10=50

 

The overall DNEL (repeated-dose – systemic – inhalation - general population) is therefore:

1031.40 mg/m³/day/50=20.63 mg/m³/day.

General population- hazard via dermal route - systemic effects - long term exposure

The long term DNEL for systemic toxicity via the inhalation route is determined by route-to route extropolation on the basis of NOAEL of 1200 mg/kg bw/day revealed from the one-generation reproductive toxicity study with the structural analogue substance CAS 6104 30-9 (CIT, 2003b).

The following correction was made to the NOAEL:

Based on the different molecular weights of 6-methyl-2-oxoperhydropyrimidin-4-yl urea (CAS 1129-42-6; 172.1851 g/mol) and the analogue substance N,N''-(isobutylidene)diurea (CAS 6104-30-9; 174.2010 g/mol), the NOAEL was corrected to 1186.11 mg/kg bw/day (MW correction target/source=172.1851 g/mol/174.2010 g/mol=0.988; 1200 mg/kg bw/day×0.988=1186.11 mg/kg bw/day).

No correction for relative absorption oral vs. dermal: 1

Therefore the corrected NOAEL for repeated-dose systemic effects via the dermal route is:

1186.11 mg/kg bw/day×1=1186.11 mg/kg bw/day

 

The following assessment factors were applied to the systemic NOAEL:

Exposure duration (subacute to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4 (default)

Intraspecies differences (general population): 10 (default)

Total AF: 2×2.5×4×10=200

 

The overall DNEL (repeated-dose – systemic – dermal - general population) is therefore:

1186.11 mg/kg bw/day/200=5.93 mg/kg bw/day.

General population - hazard via oral route - systemic effects - long term exposure

The long term DNEL for systemic toxicity via the inhalation route is determined on the basis of NOAEL of 1200 mg/kg bw/day revealed from the one-generation reproductive toxicity study with the structural analogue substance CAS 6104 30-9 (CIT, 2003b).

The following correction was made to the NOAEL:

Based on the different molecular weights of 6-methyl-2-oxoperhydropyrimidin-4-yl urea (CAS 1129-42-6; 172.1851 g/mol) and the analogue substance N,N''-(isobutylidene)diurea (CAS 6104-30-9; 174.2010 g/mol), the NOAEL was corrected to 1186.11 mg/kg bw/day (MW correction target/source=172.1851 g/mol/174.2010 g/mol=0.988; 1200 mg/kg bw/day×0.988=1186.11 mg/kg bw/day).

Therefore the corrected NOAEL is 1186.11 mg/kg bw/day.

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subacute to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4 (default)

Intraspecies differences (general population): 10 (default)

Total AF: 2×2.5×4×10=200

The overall DNEL (repeated-dose – systemic – dermal - general population) is therefore:

1186.11 mg/kg bw/day/200=5.93 mg/kg bw/day.