Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
146.67 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC and ECHA guidance
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
DNEL value:
880 mg/m³
Explanation for the modification of the dose descriptor starting point:
ECHA guidance recommends that a factor of 2 be applied when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs. Only a dermal study NOAEL is available but as more than 50% absorption through the skin is predicted, the same approach as used for oral data is appropriate. Therefore the NOAEL from the dermal study is divided by two before the route to route extrapolation. Allometric scaling is applied by taking account for the different breathing rates between rats and humans, as described in ECHA technical guidance the oral NOAEL in the rat mg/kg/day *1/0.38 * 6.7/10 = mg/m3 inhalation NOAEC for workers
AF for dose response relationship:
1
Justification:
No adverse effects were seen at the limit dose so a factor of 1 used.
AF for differences in duration of exposure:
2
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study use an assessment factor of 2.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEC.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied.
AF for intraspecies differences:
3
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for workers is 3 and not 5 as ECHA proposed. See discussion for detailed justification
AF for the quality of the whole database:
1
Justification:
This DNEL is based on a NOAEL from a high quality modern 90 day dermal study on Hydroxyethyl urea; therefore we have used a factor of 1.
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41.67 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC and ECHA guidance
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The available data is a NOAEL from a 90 day dermal study so it is directly applicable.
AF for dose response relationship:
1
Justification:
No adverse effects were seen at the limit dose so a factor of 1 used.
AF for differences in duration of exposure:
2
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study use an assessment factor of 2.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is applied based on ECHA guidance for allometric scaling of data from rats to humans
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied.
AF for intraspecies differences:
3
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for workers is 3 and not 5 as ECHA proposed. See discussion for detailed justification
AF for the quality of the whole database:
1
Justification:
This DNEL is based on a NOAEL from a high quality modern 90 day dermal study on Hydroxyethyl urea; therefore we have used a factor of 1.
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Selection of Assessment factors for Intra – Inter species variation for workers and the general population (consumers)

  

ECHA (2010) has produced guidance on the assessment factors to use to derive a DNEL for human exposure based the application of assessment factors (safety factors) to an NOAEL or LOAEL in animal studies.

 

The ECHA guidance proposes an assessment factor of 4 for the allometric scaling from rats to humans when calculating oral and dermal DNELs. However it then proposes an additional factor of 2.5 to cover remaining differences (uncertainties). There is no clear scientific justification for this additional factor. ECETOC in itsGuidance on Assessment Factors to Derive a DNEL(2010) reviewed the scientific evidence and concluded that the factor of 4 for rats was sufficient to cover the allometric scaling from rats to humans and any remaining differences are of intra-species rather than interspecies variability. Based on this, the additional assessment factor of 2.5 for inter-species variability will not be used.

This ECETOC guidance also reviewed the intra-species assessment factors, which ECHA proposed as 5 for workers and 10 for the general population. ECETOC originally proposed in 2003, based on the scientific evidence, that assessment factors of 3 for workers and 5 for the general population are sufficient for covering any intra-species variability, which includes the remaining differences factor of 2.5. 

 

This was confirmed in the ECETOC (2010) Guidance.

 

After reviewing these proposals, we have adopted the proposal from ECETOC as our default assessment factors but consider possible additional factors on a case by case basis.

 

In this case we have decided to use an assessment factor of 3 for workers based on the ECETOC Guidance (ECETOC 2010). For Consumers we have taken the ECETOC recommended factor of 5.

 

References:

 

ECHA, 2010 Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2 December 2010

 

ECETOC, 2010Guidance on Assessment Factors to Derive a DNEL,Technical Report No.110,ISSN-0773-8072-110 (print),ISSN-2079-1562-110 (online), October 2010

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43.48 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC and ECHA guidance
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
434.78 mg/m³
Explanation for the modification of the dose descriptor starting point:
ECHA guidance recommends that a factor of 2 be applied when doing route to route extrapolation for oral to inhalation exposure, recognizing higher absorption via the lungs. Only a dermal study NOAEL is available but as more than 50% absorption through the skin is predicted, the same approach as used for oral data is appropriate. Therefore the NOAEL from the dermal study is divided by two before the route to route extrapolation. Allometric scaling is applied by taking account for the different breathing rates between rats and humans as described in ECHA technical guidance the oral NOAEL in the rat mg/kg/day *1/1.15 mg/m3 inhalation NOAEC for consumers.
AF for dose response relationship:
1
Justification:
No adverse effects were seen at the limit dose so a factor of 1 used
AF for differences in duration of exposure:
2
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study use an assessment factor of 2.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEC.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied.
AF for intraspecies differences:
5
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for the general population is 5 and not 10 as ECHA proposed. See discussion for detailed justification.
AF for the quality of the whole database:
1
Justification:
This DNEL is based on a NOAEL from a high quality modern 90 day dermal study on Hydroxyethyl urea; therefore we have used a factor of 1.
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC and ECHA guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The available data is a NOAEL from a 90 day dermal study so it is directly applicable.
AF for dose response relationship:
1
Justification:
No adverse effects were seen at the limit dose so a factor of 1 used
AF for differences in duration of exposure:
2
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study use an assessment factor of 2.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is applied based on ECHA guidance for allometric scaling of data from rats to humans.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied.
AF for intraspecies differences:
5
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for the general population is 5 and not 10 as ECHA proposed. See discussion for detailed justification.
AF for the quality of the whole database:
1
Justification:
This DNEL is based on a NOAEL from a high quality modern 90 day dermal study on Hydroxyethyl urea; therefore we have used a factor of 1.
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC and ECHA guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The DNEL is derived from a NOAEL in a 90 day dermal study; the Epiwin model predicts similar ca. 70% absorption via the skin and the gastrointestinal tract. Therefore it is considered acceptable to use route to route extrapolation of the NOAEL from the dermal study.
AF for dose response relationship:
1
Justification:
No adverse effects were seen at the limit dose so a factor of 1 used.
AF for differences in duration of exposure:
2
Justification:
ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study use an assessment factor of 2.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is applied based on ECHA guidance for allometric scaling of data from rats to humans.
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied.
AF for intraspecies differences:
5
Justification:
ECETOC reported in 2010 after an extensive scientific review that the appropriate fact for intraspecies differences for the general population is 5 and not 10 as ECHA proposed. See discussion for detailed justification.
AF for the quality of the whole database:
1
Justification:
This DNEL is based on a NOAEL from a high quality modern 90 day dermal study on Hydroxyethyl urea; therefore we have used a factor of 1.
AF for remaining uncertainties:
1
Justification:
All uncertainties are already included so a factor of 1 is applied.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Selection of Assessment factors for Intra – Inter species variation for workers and the general population (consumers)

  

ECHA (2010) has produced guidance on the assessment factors to use to derive a DNEL for human exposure based the application of assessment factors (safety factors) to an NOAEL or LOAEL in animal studies.

 

The ECHA guidance proposes an assessment factor of 4 for the allometric scaling from rats to humans when calculating oral and dermal DNELs. However it then proposes an additional factor of 2.5 to cover remaining differences (uncertainties). There is no clear scientific justification for this additional factor. ECETOC in itsGuidance on Assessment Factors to Derive a DNEL(2010) reviewed the scientific evidence and concluded that the factor of 4 for rats was sufficient to cover the allometric scaling from rats to humans and any remaining differences are of intra-species rather than interspecies variability. Based on this, the additional assessment factor of 2.5 for inter-species variability will not be used.

This ECETOC guidance also reviewed the intra-species assessment factors, which ECHA proposed as 5 for workers and 10 for the general population. ECETOC originally proposed in 2003, based on the scientific evidence, that assessment factors of 3 for workers and 5 for the general population are sufficient for covering any intra-species variability, which includes the remaining differences factor of 2.5. 

 

This was confirmed in the ECETOC (2010) Guidance.

 

After reviewing these proposals, we have adopted the proposal from ECETOC as our default assessment factors but consider possible additional factors on a case by case basis.

 

In this case we have decided to use an assessment factor of 3 for workers based on the ECETOC Guidance (ECETOC 2010). For Consumers we have taken the ECETOC recommended factor of 5.

 

References:

 

ECHA, 2010 Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2 December 2010

 

ECETOC, 2010Guidance on Assessment Factors to Derive a DNEL,Technical Report No.110,ISSN-0773-8072-110 (print),ISSN-2079-1562-110 (online), October 2010