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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
18.5 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):
18
Dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
332.36 mg/m³
Explanation for the modification of the dose descriptor starting point:

The oral NOAEL is 377 mg/kg bw and the modified NOAEC for the inhalation route is 332.36 mg/m3. The reasoning is presented below:

•       Route-to-route extrapolation: The data for Hyacinth body does not provide information on the percentage absorption after oral, dermal or inhalation exposure or the distribution of Hyacinth body. Therefore, default values of 50% and 100% for oral and inhalation absorption respectively, will be used for the exposure and risk assessment calculations. Modification factor: 0.5

•       Modification for exposure (animal to human): 8 h exposure /day = 1/sRV rat (8h) = 1/0.38 m3/kg/d. Modification factor for worker = 1/0.38 = 2.63 (ECHA’s guidance R.8, November, 2012).

•       Modification for respiratory volume (worker/general): 6.7/10 (ECHA Ch. R.8, 2012, p 20: Respiratory volume light activity), standard conditions for worker - 8 hour (sRV human = 6.7 m3/kg/d) with relevant duration of 8 h - respiratory volume / exposure of 10 m3 (wRV). Modification factor for worker =6.7/10= 0.67

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1 (ECHA, 2012, Chapter R8). As the NOAEL derived is the maximum tested dose, no serious dose-related adverse effects were observed. Therefore the AF 1 is acceptable.
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from an OECD TG 422 study, an additional assessment factor of 6 is used to take the extrapolation of subacute data to chronic exposure into account (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application of the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified complication of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.
AF for intraspecies differences:
3
Justification:
The intraspecies variation in humans is greater than that in the more homogenous experimental animal population. Based on an evaluation of the scientific literature by ECETOC, an AF of 3 (for workers) and of 5 (for the general population) is advised, after a detailed review of the literature. Hyacinth body does not give concern for specific intraspecies effects, or specific effects on the developing organ systems in early or late life phases. The ECETOC recommendations are followed for this substance until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
1
Justification:
An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity study with Hyacinth body has been well performed. The study report itself is available, results are well presented.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were identified.
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:
5.2 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):
72
Dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The oral NOAEL is 377 mg/kg bw and the modified NOAEL for the dermal route is 377 mg/kg bw for the following reasons:

•       Route-to-route extrapolation: For dermal absorption of Hyacinth body in humans, an absorption value of 50% is taken into account, based on experimental info. Modification factor: 0.5/0.5 = 1

•       Bioavailability differences between human and animal species: there is no evidence for a difference between species for oral exposure to test substance. Modification factor: 1

•       Bioavailability differences between test and target substances: the tested substance is the target substance. Modification factor: 1

•       Modification for exposure route (animal to human): Not applicable for the dermal route. Modification factor: 1.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1 (ECHA, 2012, Chapter R8). As the NOAEL is derived as the maximum tested dose, no serious dose-related adverse effects were observed.
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from an OECD TG 422 study, an additional assessment factor of 6 is used to take the extrapolation of subacute data to chronic exposure into account (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convert rat to human data in accordance with ECHA guidance (Table R.8-3, 2012).
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
3
Justification:
An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is likely due to potential differences in biological sensitivity between species, and includes intraspecies differences.
AF for the quality of the whole database:
1
Justification:
An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity study with Hyacinth body has been well performed. The study report itself is available, results are well presented (ECHA’s Guidance, R.8.4.3.1, November, 2012).
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.5 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):
30
Dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
163.91 mg/m³
Explanation for the modification of the dose descriptor starting point:

The oral NOAEL is 377 mg/kg bw and the modified NOAEC for the inhalation route is 163.9 mg/m3. The reasoning is presented below:

•       Route-to-route extrapolation: The data for Hyacinth body does not provide information on the percentage absorption after oral, dermal or inhalatory exposure or the distribution of Hyacinth body. Therefore, default values of 50% and 100% for oral and inhalation absorption respectively, will be used for the exposure and risk assessment calculations. Modification factor: 0.5

•       Modification for exposure (animal to human): Modification factor for general population = 1/1.15= 0.87 (ECHA’s guidance R.8, November, 2012).

•       Modification for respiratory volume (general): 1

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1 (ECHA, 2012, Chapter R8). As the NOAEL is derived as the maximum tested dose, no serious dose-related adverse effects were observed. Therefore the AF 1 is acceptable.
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from an OECD TG 422 study, an additional assessment factor of 6 is used to take the extrapolation of subacute data to chronic exposure into account (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application of the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified complication of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.
AF for intraspecies differences:
5
Justification:
The intraspecies variation in humans is greater than that in the more homogenous experimental animal population. Based on an evaluation of the scientific literature by ECETOC, an AF of 3 (for workers) and of 5 (for the general population) is advised, after a detailed review of the literature. As Hyacinth body does not give concern for specific intraspecies effects, or specific effects on the developing organ systems in early or late life phases. The ECETOC recommendations are followed for this substance until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
1
Justification:
An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity study with Hyacinth body has been well performed. The study report itself is available, results are well presented.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were identified.
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:
3.1 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):
120
Dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The oral NOAEL is 377 mg/kg bw and the modified NOAL for the dermal route is also 377 mg/kg bw. The reasoning is presented below:

•      Route-to-route extrapolation: For dermal absorption of Hyacinth body in humans, an absorption value of 50% is taken into account, based on experimental info. Modification factor: 0.5/0.5 = 1

•       Bioavailability differences between human and animal species: there is no evidence for a difference between species for oral exposure to test substance. Modification factor: 1

•       Bioavailability differences between test and target substances: the tested substance is the target substance. Modification factor: 1

•       Modification for exposure route (animal to human): Not applicable for the dermal route. Modification factor: 1.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1 (ECHA, 2012, Chapter R8).
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure (ECHA 2012, Chapter R8, p 29)
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convert rat to human data in accordance with ECHA guidance (Table R.8-3, 2012).
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.
AF for the quality of the whole database:
1
Justification:
An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity study with Hyacinth body has been well performed. The study report itself is available, results are well presented.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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:
3.1 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):
120
Dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
377 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

•       Route-to-route extrapolation: not applicable as the study is performed for the oral route. Modification factor: 1

•       Bioavailability differences between human and animal species: There is no evidence for a difference between species for oral exposure to test substance. Modification factor: 1

•       Bioavailability differences between test and target substances: the tested substance is the target substance. Modification factor: 1

•       Modification for exposure (animal to human): not applicable for the oral route. Modification factor: 1

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1 (ECHA, 2012, Chapter R8).
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from an OECD422 study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure (ECHA 2012, Chapter R8, p 29)
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convert rat to human data in accordance with ECHA guidance (Table R.8-3, 2012).
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.
AF for the quality of the whole database:
1
Justification:
An additional assessment factor of 1 is considered appropriate. The repeated dose toxicity study with Hyacinth body has been well performed.. The study report itself is available, results are well presented.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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

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