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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
49 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC Guidance on Assessment Factors to derive DNELs (2010)
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
Value:
881.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

Inhalation NOAEL = oral NOAEL * ABSoral-rat/ABSinh-human = 1000 * 50/100 = 500 mg/kg bw/day; Corrected inhalatory NOAEC = 500 mg/kg bw/day*(1/0.38 m3/kg/d)*(6.7 m3/10 m3) = 881.6 mg/m3 [8h exposure/day]

AF for dose response relationship:
1
Justification:
Default, as the starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
To correct for difference in study duration and actual exposure situation (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable, is taken into account in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
Default according to ECETOC guidance
AF for intraspecies differences:
3
Justification:
Default according to ECETOC guidance
AF for the quality of the whole database:
1
Justification:
All studies listed in REACH Annex VII and REACH Annex VIII have been conducted
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
69.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC Guidance on Assessment Factors to derive DNELs (2010)
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL * ABSoral-rat/ABSdermal-human = 1000 * 50/10 = 5000 mg/kg bw/day

AF for dose response relationship:
1
Justification:
Default, as the starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
To correct for the difference in study duration and actual exposure situation (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
To correct for metabolic rate
AF for other interspecies differences:
1
Justification:
Default according to ECETOC guidance
AF for intraspecies differences:
3
Justification:
Default according to ECETOC guidance
AF for the quality of the whole database:
1
Justification:
All studies listed in REACH Annex VII and REACH Annex VIII have been conducted
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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

Route-to-route extrapolation

For the derivation of the DNELs:

Long-term – dermal, systemic effects

Long-term – inhalation, systemic effects

Route-to-route extrapolation has been performed. In absence of relevant data, only differences between the different routes as determined by the assumed percentages of absorption into the systemic circulation could be accounted for. A certified toxicologist assessed the toxicokinetic behaviour of the substance (in accordance with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance) and concluded:

 

For risk assessment purposes:

Absorption oral = 50%

Absorption dermal = 10%

Absorption inhalation = 100%

Assessment factors

The assessment factors (AFs) that are applied to obtain the endpoint-specific DNELs for the relevant exposure pattern are based on the ECETOC report “Guidance on assessment factors to derive DNELs” (final draft). In the following overview the relevant AFs are shown:

Aspect

Assessment Factor (AF)

Interspecies extrapolation (rat to human), for the dermal and oral route (inhalation route: not applicable)

4

(to correct for metabolic rate)

 

Intraspecies extrapolation; worker

3

Intraspecies extrapolation; general population

5

Exposure duration (sub-acute to chronic)

6

(to correct for difference in study duration and actual exposure situation)

Dose-response

1

(default, as the starting point is a NOAEL)

Quality of whole database

1

(all studies listed in REACH Annex VII and REACH Annex VIII have been conducted)

 

Leading to the following Assessment Factors: 

 

Assessment Factor

DNEL

Worker

General population

Long-term – dermal, systemic effects

72

120

Long-term – inhalation, systemic effects (and acute – inhalation, systemic effects)

18

30

Long-term – oral, systemic effects

Not relevant

120

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC Guidance on Assessment Factors to derive DNELs (2010)
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Value:
434.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

Inhalation NOAEL = oral NOAEL * ABSoral-rat/ABSinh-human = 1000 * 50/100 = 500 mg/kg bw day; Corrected inhalatory NOAEC = 500 mg/kg bw/day*(1/1.15 m3/kg/d) = 434.8 mg/m3 [24h exposure/day]

AF for dose response relationship:
1
Justification:
Default, as the starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
To correct for difference in study duration and actual exposure situation (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable, is taken into account in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
Default according to ECETOC guidance
AF for intraspecies differences:
5
Justification:
Default according to ECETOC guidance
AF for the quality of the whole database:
1
Justification:
All studies listed in REACH Annex VII and REACH Annex VIII have been conducted
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
41.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC Guidance on Assessment Factors to derive DNELs (2010)
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL * ABSoral-rat/ABSdermal-human = 1000 * 50/10 = 5000 mg/kg bw/day

AF for dose response relationship:
1
Justification:
Default, as the starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
To correct for difference in study duration and actual exposure situation (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
To correct for metabolic rate
AF for other interspecies differences:
1
Justification:
Default according to ECETOC guidance
AF for intraspecies differences:
5
Justification:
Default according to ECETOC guidance
AF for the quality of the whole database:
1
Justification:
All studies listed in REACH Annex VII and REACH Annex VIII have been conducted
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
8.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC Guidance on Assessment Factors to derive DNELs (2010)
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

Not applicable, no route to route extrapolation applied

AF for dose response relationship:
1
Justification:
Default, as the starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
To correct for difference in study duration and actual exposure situation (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
To correct for metabolic rate
AF for other interspecies differences:
1
Justification:
Default according to ECETOC guidance
AF for intraspecies differences:
5
Justification:
Default according to ECETOC guidance
AF for the quality of the whole database:
1
Justification:
All studies listed in REACH Annex VII and REACH Annex VIII have been conducted
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
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

Please refer to the section Discussion under Workers for information about the applied route-to-route extrapolation and Assessment Factors.