Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
27.17 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
42.5
Modified dose descriptor starting point:
other: NAEC
DNEL value:
577.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
NAEC: [(660/4) x 70)/10]; NOAEL = 660 mg/kg on rat (Channon, 1926); 4 = allometric scaling factor rat; 70 kg/bw= standard human body weight; 10 m^3/person= default human breathing volume for workers in 8 h.
AF for dose response relationship:
1
Justification:
No scaling needed
AF for differences in duration of exposure:
3.4
Justification:
* ERASM Project: lower factor found based on RepDose study (factor 3.4 instead of 6 from subacute to chronic exposure). ** In addition, the study duratios is 42 days instead of 28. Then it is proposed to start from the NOAEL of the 42-day study, but to apply a lower duration factor of 3,4 instead of 6.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling needed because the starting point (NAEC) has just been corrected for the human evaluation.
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
Justification:
Based on the surfactant effect on epithelial tissues and absence of systemic effects, differences within species are expected to be limited. Therefore informed assessment factors of 3 and 5 are proposed instead of ECHA default values of 5 and 10 for workers and general population.
AF for the quality of the whole database:
1
Justification:
No GLP studies compliant, but many qualitative evaluations to support the end point
AF for remaining uncertainties:
1
Justification:
100% conservative adsorption for inhalative route for animal and human is assumed
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
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:
38.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
170
Modified dose descriptor starting point:
NOAEL
DNEL value:
6 600 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Oral to dermal AF = 10
AF for dose response relationship:
1
Justification:
No scaling needed
AF for differences in duration of exposure:
3.4
Justification:
* ERASM Project: lower factor found based on RepDose study (factor 3.4 instead of 6 from subacute to chronic exposure). ** In addition, the study duratios is 42 days instead of 28. Then it is proposed to start from the NOAEL of the 42-day study, but to apply a lower duration factor of 3,4 instead of 6.
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
No GLP studies compliant, but many qualitative evaluations to support the end point
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
85
Modified dose descriptor starting point:
other: NAEC
DNEL value:
577.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
NAEC= ((660 /4) x 70) /20; NOAEL = 660 mg/kg on rat (Channon, 1926); 4 = allometric scaling factor rat; 70 kg/bw= standard human body weight; 20 m^3/person= default human breathing volume for general population 24h.
AF for dose response relationship:
1
Justification:
No scaling needed
AF for differences in duration of exposure:
3.4
Justification:
* ERASM Project: lower factor found based on RepDose study (factor 3.4 instead of 6 from subacute to chronic exposure). ** In addition, the study duratios is 42 days instead of 28. Then it is proposed to start from the NOAEL of the 42-day study, but to apply a lower duration factor of 3,4 instead of 6.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling needed because the starting point (NAEC) has just been corrected for the human evaluation.
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Justification:
100% adsorption for inhalative route for animal and human is assumed
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:
19.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
340
Modified dose descriptor starting point:
NOAEL
DNEL value:
6 600 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Oral to dermal AF = 10
AF for dose response relationship:
1
Justification:
No scaling needed
AF for differences in duration of exposure:
3.4
Justification:
* ERASM Project: lower factor found based on RepDose study (factor 3.4 instead of 6 from subacute to chronic exposure). ** In addition, the study duratios is 42 days instead of 28. Then it is proposed to start from the NOAEL of the 42-day study, but to apply a lower duration factor of 3,4 instead of 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Rat
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
Based on the surfactant effect on epithelial tissues and absence of systemic effects, differences within species are expected to be limited. Therefore informed assessment factors of 3 and 5 are proposed instead of ECHA default values of 5 and 10 for workers and general population.
AF for the quality of the whole database:
1
Justification:
No GLP studies compliant, but many qualitative evaluations to support the end point
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
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:
1.94 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
340
Modified dose descriptor starting point:
NOAEL
DNEL value:
660 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No modification necessary
AF for dose response relationship:
1
Justification:
No scaling needing
AF for differences in duration of exposure:
3.4
Justification:
* ERASM Project: lower factor found based on RepDose study (factor 3.4 instead of 6 from subacute to chronic exposure). ** In addition, the study duratios is 42 days instead of 28. Then it is proposed to start from the NOAEL of the 42-day study, but to apply a lower duration factor of 3,4 instead of 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
Data on structural similar substances
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

References

[1]   Kroes R, Renwick AG,*, Feron V, Galli CL, Gibney M, Greim H,Guy RH, Lhuguenot JC, van de Sandt JJM. Application of the threshold of toxicological

concern (TTC) to the safety evaluation of cosmetic ingredients. Food and Chemical Toxicology 45 (2007) 2533–2562

[2]   Bartek, M J ; Labudde, J A ; Maibach, H I. Skin permeability in vivo: comparison in rat, rabbit, pig and man.The Journal of investigative

dermatology, 1972, Vol.58(3), pp.114-23.

[3]   SchenkL and Gunnar J. A Quantitative Comparison of the Safety Margins in the European Indicative Occupational Exposure Limits and the

Derived No-Effect Levels for Workers under REACH. Toxicological Sciences 2011, 12(12), 408-416.

[4]   ERASM Project: Safety Factors under REACH (June 2012); publications in progress.

[5]  Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I. Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129