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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
352.63 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
15
Modified dose descriptor starting point:
NOAEC
Value:
5 289.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
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:
200 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
15
Modified dose descriptor starting point:
NOAEL
Value:
3 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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

The chemical itself exhibits a very low toxic potential and no local or organ-specific effects were detected in toxicological studies.

Acute/short-term exposure:

As shown in toxicological studies, the chemical substance Urea, reaction products with formaldehyde and glyoxal is not toxic after short-term exposure by the oral, dermal or inhalation routes. Since no acute hazard has been identified, a DNEL for acute/short-term exposure is not quantifiable.

 

Local effects:

No hazard has been identified for local effects in toxicological studies with the registered substance. Therefore a DNEL for local effects is not quantifiable.

 

Long-term exposure - systemic effects:

Due to the low toxicity of the substance a DNEL for systemic effects after long-term exposure is considered to be sufficient to ensure the safety of human workers.

 

Dermal:

A DNEL for systemic effects after long-term dermal exposure was derived based on the NOAEL value from a subchronic (90 days) repeated dose study with oral application in rats (IRDC, 1983). The results of this study clearly confirmed the low toxicity of the substance already noted under single-dose conditions. The respective NOAEL for systemic effects was 3000 mg/kg/d (as 100% substance ). At the next dose level (6000 mg/kg), histopathological inspection revealed no specific treatment-related organ lesions, except that two males of the 6000 mg/kg dosage level group suffered from mild mineralization in the heart, and one from moderate bilateral mineralization of the testes, both phenomena considered substance-related.

The NOAEL of 3000 mg/kg/d which was taken as relevant dose descriptor for long-term toxicity had to be modified in order to get the correct starting point for DNEL derivation:

According to the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012), the oral NOAEL was converted into the dermal NOAEL by route-to-route extrapolation assuming as a worst case dermal absorption of the test substance to be equal to oral absorption. The resulting corrected dermal NOAEL for systemic effects is equal to 3000 mg/kg/d.

 

Discussion of applied assessment factors:

- Interspecies variation:

There is no evidence for differences in the general mode of action or kinetics of the substance in humans compared to rats. Thus, no allometric assessment factors were applied and the interspecies factor for remaining differences was set to be 2.5.

 

- Intraspecies variation:

Since no severe toxic effects have been observed for this substance an assessment factor of 3 for intraspecies variation is considered to be sufficient.

 

- Exposure duration:

An assessment factor of 2 was used for extrapolation of exposure duration from sub-chronic (90-day oral toxicity study) to chronic by default.

 

- Dose-response:

An assessment factor of 1 was used by default.

 

- Quality of whole database:

An assessment factor of 1 was used by default.

 

Accordingly, an overall assessment factor of 15 was calculated based on the recommendations given in the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012) and based on the above mentioned arguments. Thus, the DNEL for long-term exposure was calculated as follows:

DNEL long-term exposure systemic = NOAEL corrected / Overall AF = 3000 mg/kg bw/day / 15 = 200 mg/kg bw/day.

 

Inhalation:

The DNEL for long-term exposure following inhalation was derived considering potential spray applications of the test substance. The DNEL was quantified based on the NOAEL value from the subchronic repeated dose oral toxicty study described above (IRDC, 1983). The respective NOAEL of 3000 mg/kg which was taken as relevant dose descriptor for long-term toxicity had to be modified in order to get the correct starting point for DNEL derivation:

According to the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012), the oral rat NOAEL was converted into an inhalatory NAEC corrected for human worker exposure conditions (sRV rat for 8h exposure per day, respiratory volume adapted for a worker with light activity) by multiplying with the corresponding factors (/0.38, x 0.67, /10). The resulting corrected NOAEC for systemic effects is equal to 5289.5 mg/m³.

 

Discussion of applied assessment factors:

- Interspecies variation:

An interspecies factor for remaining differences of 2.5 was taken by default.

 

- Intraspecies variation:

Since no toxic effects have been observed for this substance an assessment factor of 3 for intraspecies variation is considered to be sufficient.

 

- Exposure duration:

An assessment factor of 2 was used for extrapolation of exposure duration from sub-chronic (90-day oral toxicity study) to chronic by default.

 

- Dose-response:

An assessment factor of 1 was used by default.

 

- Quality of whole database:

An assessment factor of 1 was used by default.

 

Accordingly, an overall assessment factor of 15 was calculated based on the recommendations given in the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012) and based on the above mentioned arguments. Thus, the DNEL for long-term exposure was calculated as follows:

DNEL long-term exposure systemic = NAEC corrected / Overall AF = 5289.5 mg/m³ / 15 = 352.63 mg/m³. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
104 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
2 609 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
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:
120 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEL
Value:
3 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
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:
120 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEL
Value:
3 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
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

The chemical itself exhibits a very low toxic potential and no local or organ-specific effects were detected in toxicological studies.

Acute/short-term exposure:

As shown in toxicological studies, the chemical substance Urea, reaction products with formaldehyde and glyoxal is not toxic after short-term exposure by the oral, dermal or inhalation routes. Since no acute hazard has been identified, a DNEL for acute/short-term exposure is not quantifiable.

 

Local effects:

No hazard has been identified for local effects in toxicological studies with the regsitered substance. Therefore a DNEL for local effects is not quantifiable.

 

Long-term exposure - systemic effects:

DNELs for systemic effects after long-term exposure are considered to be sufficient to ensure the safety of the general population.

Oral:

A DNEL for systemic effects after long-term oral exposure was derived based on the NOAEL value from a subchronic (90 days) repeated dose study with oral application in rats (IRDC, 1983). The results of this study clearly confirmed the low toxicity of the substance already noted under single-dose conditions. The respective NOAEL for systemic effects was 3000 mg/kg/d (as 100% substance). At the next dose level (6000 mg/kg), histopathological inspection revealed no specific treatment-related organ lesions, except that two males of the 6000 mg/kg dosage level group suffered from mild mineralization in the heart, and one from moderate bilateral mineralization of the testes, both phenomena considered substance-related.

No modification of the NOAEL of 3000 mg/kg/d as relevant dose descriptor for long-term toxicity was necessary in order to get the correct starting point for DNEL derivation.

 

Discussion of applied assessment factors:

- Interspecies variation:

There is no evidence for differences in the general mode of action or kinetics of the substance in humans compared to rats. Thus, no allometric assessment factors were applied and the interspecies factor for remaining differences was set to be 2.5.

 

- Intraspecies variation:

Since no severe toxic effects have been observed for this substance an assessment factor of 5 for intraspecies variation is considered to be sufficient.

 

- Exposure duration:

An assessment factor of 2 was used for extrapolation of exposure duration from sub-chronic (90-day oral toxicity study) to chronic by default.

 

- Dose-response:

An assessment factor of 1 was used by default.

 

- Quality of whole database:

An assessment factor of 1 was used by default.

 

Accordingly, an overall assessment factor of 25 was calculated based on the recommendations given in the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012) and based on the above mentioned arguments. Thus, the DNEL for long-term exposure was calculated as follows:

DNEL long-term exposure systemic = NOAEL / Overall AF = 3000 mg/kg bw/day / 25 = 120 mg/kg bw/day.

 

Dermal:

A DNEL for systemic effects after long-term dermal exposure was derived based on the NOAEL value from a subchronic (90 days) repeated dose study with oral application in rats (IRDC, 1983). The results of this study clearly confirmed the low toxicity of the substance already noted under single-dose conditions. The respective NOAEL for systemic effects was 3000 mg/kg/d (as 100% substance). At the next dose level (6000 mg/kg), histopathological inspection revealed no specific treatment-related organ lesions, except that two males of the 6000 mg/kg dosage level group suffered from mild mineralization in the heart, and one from moderate bilateral mineralization of the testes, both phenomena considered substance-related.

The NOAEL of 3000 mg/kg/d which was taken as relevant dose descriptor for long-term toxicity had to be modified in order to get the correct starting point for DNEL derivation:

According to the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012), the oral NOAEL was converted into the dermal NOAEL by route-to-route extrapolation assuming as a worst case dermal absorption of the test substance to be equal to oral absorption. The resulting corrected dermal NOAEL for systemic effects is equal to 3000 mg/kg/d.

 

Discussion of applied assessment factors:

- Interspecies variation:

There is no evidence for differences in the general mode of action or kinetics of the substance in humans compared to rats. Thus, no allometric assessment factors were applied and the interspecies factor for remaining differences was set to be 2.5.

 

- Intraspecies variation:

Since no severe toxic effects have been observed for this substance an assessment factor of 5 for intraspecies variation is considered to be sufficient.

 

- Exposure duration:

An assessment factor of 2 was used for extrapolation of exposure duration from sub-chronic (90-day oral toxicity study) to chronic by default.

 

- Dose-response:

An assessment factor of 1 was used by default.

 

- Quality of whole database:

An assessment factor of 1 was used by default.

 

Accordingly, an overall assessment factor of 25 was calculated based on the recommendations given in the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012) and based on the above mentioned arguments. Thus, the DNEL for long-term exposure was calculated as follows:

DNEL long-term exposure systemic = NOAEL corrected / Overall AF = 3000 mg/kg bw/day / 25 = 120 mg/kg bw/day.

 

Inhalation:

The DNEL for long-term exposure following inhalation was derived considering potential spray applications of the test substance. The DNEL was quantified based on the NOAEL value from the subchronic repeated dose oral toxicty study described above (IRDC, 1983). The respective NOAEL of 3000 mg/kg which was taken as relevant dose descriptor for long-term toxicity had to be modified in order to get the correct starting point for DNEL derivation:

According to the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012), the oral rat NOAEL was converted into an inhalatory NAEC corrected for human generak public exposure conditions (sRV rat for 24h exposure per day) by multiplying with the corresponding factors (/1.15). The resulting corrected NOAEC for systemic effects is equal to 2609 mg/m³.

 

Discussion of applied assessment factors:

- Interspecies variation:

An interspecies factor for remaining differences of 2.5 was taken by default.

 

- Intraspecies variation:

Since no toxic effects have been observed for this substance an assessment factor of 5 for intraspecies variation is considered to be sufficient.

 

- Exposure duration:

An assessment factor of 2 was used for extrapolation of exposure duration from sub-chronic (90-day oral toxicity study) to chronic by default.

 

- Dose-response:

An assessment factor of 1 was used by default.

 

- Quality of whole database:

An assessment factor of 1 was used by default.

 

Accordingly, an overall assessment factor of 25 was calculated based on the recommendations given in the Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, November 2012) and based on the above mentioned arguments. Thus, the DNEL for long-term exposure was calculated as follows:

DNEL long-term exposure systemic = NAEC corrected / Overall AF = 2609 mg/m³ / 25 = 104 mg/m³. 

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