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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.28 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
128.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

Descriptor: The inhalation route was extrapolated by oral route information in the absence of data for this administration route. The calculation of the DNEL is based on the results of a 28-day repeat dose toxicity study in rats. NOAEL (oral) = 150 mg/kg/d. Corrected Descriptor: The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m3/kg for 8 hours exposure of workers, see Table R. 8-2 in Section R.8.4.2, REACH guidance, chapter r8). For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor derives from the inhalative volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity). NOAEL (corrected) = NOAEL (oral)÷0.38 m3/kg*0.5(ABS rat-oral ÷ ABS human-inhalation) x 6.7 ÷ 10.3 = 128.3 mg/m3.

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:
12.5 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:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Descriptor: The dermal route was extrapolated from oral route information in the absence of data for this administration route. The calculation of the DNEL is based on the results of a 28-day repeat dose toxicity study in rats. NOAEL (oral) = 150 mg/kg/d. Corrected Descriptor: NOAELhuman-dermal = NOAEL rat -oral *(ABS rat-oral÷ABS human-dermal) Assume ABS rat – oral is 100%. Dermal absorption values were derived by considering relevant data on the substance (e.g. molecular weight and log Kow), and using the following models. All the models showed low dermal penetration coefficient (Kp, predicted to range from 10^-5 to 10^-2 cm/h), and <10% of dermal absorption was justifiable.(1) Dermwin: log Kp = -2.72 + 0.71 log Kow - 0.0061 MW (2) Human Health Evaluation Manual: log Kp = -2.80 + 0.66 logKow – 0.0056 MW (3) Equations on page 60 of this document (http://www.rivm.nl/en/healthanddisease/productsafety/ConsExpo.jsp). Based on low dermal absorption, the corrected dose description for dermal endpoint was NOAEL (oral)/10% absorption, and NOAEL (dermal) was determined to be 1500 mg/kg/day.

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
160 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor:
other: EC3 value
AF for dose response relationship:
3
Justification:
Human exposure is expected in a matrix with no penetration enhancers or irritants.
AF for interspecies differences (allometric scaling):
1
Justification:
Sensitisation is a local immunological effect with a similar mechanism across mammalian species.
AF for intraspecies differences:
5
Justification:
Default value for workers because no difference in sensitisation potential is expected between workers and consumers.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
160 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor starting point:
other: EC 3 value
AF for dose response relationship:
3
Justification:
Human exposure is expected in a matrix with no penetration enhancers or irritants.
AF for interspecies differences (allometric scaling):
1
Justification:
Sensitisation is a local immunological effect with a similar mechanism across mammalian species.
AF for intraspecies differences:
5
Justification:
Default value for workers because no difference in sensitisation potential is expected between workers and consumers.

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

1. Relevant Toxicology Data, exposure pattern and route

The calculation of the DNEL is based on the results of a 28 day repeated dose toxicity study in rats (OECD 407).

The oral administration of the test material resulted in microscopic changes in the mid- and high-dose groups in the adrenals, kidneys, and stomach/forestomach. The effects on the adrenals were accompanied by an increased organ weight. The FOB (functional observational battery) identified decreased landing foot splay in the mid- and high-dose females, and also decreased rectal temperature in the high-dose females. A NOAEL for systemic toxicity was established at 150 mg/kg bw.

2. Mode of action

No non-threshold mode of action is associated with this substance, in particular, the test substance has no genotoxic potential.

3. Correction of dose descriptor

NOAEL (oral) is converted into a NOAEL(corrected) in accordance to Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose [concentration] - response for human health, ECHA, May 2008.

NOAEL (oral) = 150 mg/kg/d

NOAEL(corrected)= 1500 mg/kg/d for dermal exposure, dermal absorption less than 10% was justified.

NOAEL(corrected)=NOAELrat-oral÷0.38 m3/kg*0.5(ABSrat-oral÷ ABShuman-inhalation)*6.7÷10.3 (sRV human 8h/wRV 8h)= 128.3 mg/m3for inhalation exposure

 

4. Application of assessment factors

Dermal route: The following assessment factors were chosen: interspecies difference (4 for allometric scale, 1 for remaining difference), intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

Inhalation route: The following assessment factors were chosen: interspecies difference (1), intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

 

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.09 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):
60
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
65.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

Descriptor: The inhalation route was extrapolated by oral route information in the absence of data for this administration route. The calculation of the DNEL is based on the results of a 28-day repeat dose toxicity study in rats. NOAEL (oral) = 150 mg/kg/d. Corrected Descriptor: The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure of general public, see Table R. 8-2 in Section R.8.4.2, REACH guidance, chapter r8). NAEL (corrected) = NOAEL (oral) ÷1.15*0.5(ABSrat-oral÷ ABShuman-inhalation)= 65.2 mg/m3

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:
6.25 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):
240
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Descriptor: The calculation of the DNEL is based on the results of a 28-day repeat dose toxicity study in rats. NOAEL (oral) = 150 mg/kg/d. Corrected Descriptor: NOAELhuman-dermal = NOAEL rat -oral *(ABS rat-oral÷ABS human-dermal) Assume ABS rat – oral is 100%. The dermal route was extrapolated from oral route information in the absence of data for this administration route. Dermal absorption values were derived by considering relevant data on the substance (e.g. molecular weight and log Kow), and using the following models. All the models showed low dermal penetration coefficient (Kp, predicted to range from 10^-5 to 10^-2 cm/h), and <10% of dermal absorption was justifiable. (1) Dermwin: log Kp = -2.72 + 0.71 log Kow - 0.0061 MW; (2) Human Health Evaluation Manual: log Kp = -2.80 + 0.66 logKow – 0.0056 MW; (3) Equations on page 60 of this document (http://www.rivm.nl/en/healthanddisease/productsafety/ConsExpo.jsp). Based on low dermal absorption, the corrected dose description for dermal endpoint was NOAEL (oral)/10% absorption, and NOAEL (dermal) was determined to be 1500 mg/kg/day.

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
160 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor:
other: EC3 value
AF for dose response relationship:
3
Justification:
Human exposure is expected in a matrix with no penetration enhancers or irritants.
AF for interspecies differences (allometric scaling):
1
Justification:
Sensitisation is a local immunological effect with a similar mechanism across mammalian species.
AF for intraspecies differences:
5
Justification:
Default value for workers because no difference in sensitisation potential is expected between workers and consumers.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
160 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor starting point:
other: EC3 value
AF for dose response relationship:
3
Justification:
Human exposure is expected in a matrix with no penetration enhancers or irritants.
AF for interspecies differences (allometric scaling):
1
Justification:
Sensitisation is a local immunological effect with a similar mechanism across mammalian species.
AF for intraspecies differences:
5
Justification:
Default value for workers because no difference in sensitisation potential is expected between workers and consumers.

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Descriptor: The calculation of the DNEL is based on the results of a 28-day repeat dose toxicity study in rats. NOAEL (oral) = 150 mg/kg/d. Corrected Descriptor: No correction was needed.

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

1. Relevant Toxicology Data, exposure pattern and route

The calculation of the DNEL is based on the results of a 28 day repeated dose toxicity study in rats (OECD 407).

The oral administration of the test material resulted in microscopic changes in the mid- and high-dose groups in the adrenals, kidneys, and stomach/forestomach. The effects on the adrenals were accompanied by an increased organ weight. The FOB (functional observational battery) identified decreased landing foot splay in the mid- and high-dose females, and also decreased rectal temperature in the high-dose females. A NOAEL for systemic toxicity was established at 150 mg/kg bw.

2. Mode of action

No non-threshold mode of action is associated with this substance, in particular, the test substance has no genotoxic potential.

3. Correction of dose descriptor

NOAEL (oral) is converted into a NOAEL(corrected) in accordance to Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose [concentration] - response for human health, ECHA, May 2008.

NOAEL (oral) = 150 mg/kg/d

NOAEL(corrected)= 1500 mg/kg/d for dermal exposure, dermal absorption less than 10% was justified.

NOAEL(corrected)== NOAELrat-oral÷1.15 m3/kg*0.5(ABSrat-oral÷ ABShuman-inhalation) = 130.4 mg/ m3for inhalation exposure

4. Application of assessment factors

The following assessment factors were chosen:

Dermal route: interspecies difference (4 for allometric scale; for remaining difference 1 was used), intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

Inhalation route: interspecies difference (1), intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

Oral route: interspecies difference (4 for allometric scale; for remaining difference 2.5 was used), intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).