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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.7 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):
75
Modified dose descriptor starting point:
NOAEC
Value:
352.63 mg/m³
Explanation for the modification of the dose descriptor starting point:
AF for oral-to-inhalation extrapolation = 1. Based on available toxicokinetic information, complete absorption of the substance following oral administration can be assumed. As a consequence, no assessment factor is required for oral-to-inhalation extrapolation.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Not used for inhalation results
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
5
Justification:
ECHA REACH standard AF for intraspecies differences to workers
AF for the quality of the whole database:
1
Justification:
no issues with the quality of the data base
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 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):
300
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Correction to NOAEL based on TK information on absorption. See below.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH standard AF for rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
5
Justification:
ECHA REACH standard AF for intraspecies differences to workers
AF for the quality of the whole database:
1
Justification:
no issues with the quality of the whole database
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Description of the calculation of the NOAEC used for the worker, systemic effects, long-term DNEL for the inhalation route

NOAEL = 200 mg/kg bw/d       taken from the 28d-repeated dose toxicity study in rats (oral administration).

NOAEC = NOAEL (mg/kg bw/d) * (1/0.38 m3/kg bw) * (6.7 m3/10 m3)

NOAEC = 200 * (1/0.38) * (6.7/10) = 352.63 mg/m3

Description of the calculation of the NOAEL used for the worker, systemic effects, long-term DNEL for the dermal route

NOAEL = 200 mg/kg bw/d       taken from the 28d-repeated dose toxicity study in rats (oral administration).

corr. NOAEL = NOAEL (mg/kg bw/d) * Abs (oral, rat) / Abs (dermal, human)

with:

- Abs (oral, rat) = 100% according to ECHA's Guidance on Information Requirements and Chemical Safety Assessment, Section R7c.12.2.4

- Abs (dermal, human) = 80% as modeled according to the equation by Kroes (Food and Chemical Toxicology 45 (2007) 2533 -2562)

corr. NOAEL = 200*100/80 = 250 mg/kg bw/d

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.16 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):
150
Modified dose descriptor starting point:
NOAEC
Value:
173.91 mg/m³
Explanation for the modification of the dose descriptor starting point:
AF for oral-to-inhalation extrapolation = 1. Based on available toxicokinetic information, complete absorption of the substance following oral administration can be assumed. As a consequence, no assessment factor is required for oral-to-inhalation extrapolation.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Not used for inhalation results
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
10
Justification:
ECHA REACH standard AF for the general population
AF for the quality of the whole database:
1
Justification:
no issues with the quality of the whole database
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.41 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Correction to NOAEL based on TK information on absorption. See below.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH standard AF for rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
10
Justification:
ECHA REACH default AF for the general population
AF for the quality of the whole database:
1
Justification:
no issues with the whole database
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.33 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation. No correction on the NOAEL applied; oral absorption by rat and human are assumed to be equal.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
ECHA REACH standard AF for sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH standard AF for rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
ECHA REACH standard AF for "differences not related to calorimetric differences"
AF for intraspecies differences:
10
Justification:
ECHA REACH default AF for the general population
AF for the quality of the whole database:
1
Justification:
no issues with the whole database
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties identified
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:
high hazard (no threshold derived)

Additional information - General Population

Description of the calculation of the NOAEC used for the general population, systemic effects, long-term DNEL for the inhalation route

NOAEL = 200 mg/kg bw/d       taken from the 28d-repeated dose toxicity study in rats (oral administration).

NOAEC = NOAEL(mg/kg bw/d) * (1/1.15 m3/kg bw)

NOAEC = 200 * (1/1.15) = 173.91 mg/m3

Description of the calculation of the NOAEL used for the general population, systemic effects, long-term DNEL for the dermal route

NOAEL = 200 mg/kg bw/d       taken from the 28d-repeated dose toxicity study in rats (oral administration).

corr. NOAEL = NOAEL (mg/kg bw/d) * Abs (oral, rat) / Abs (dermal, human)

with:

- Abs (oral, rat) = 100% according to ECHA's Guidance on Information Requirements and Chemical Safety Assessment, Section R7c.12.2.4

- Abs (dermal, human) = 80% as modeled according to the equation by Kroes (Food and Chemical Toxicology 45 (2007) 2533 -2562)

corr. NOAEL = 200*100/80 = 250 mg/kg bw/d

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