Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidace and ECETOC TR No.86 (2003)
Overall assessment factor (AF):
45
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
370 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available. Therefore, the worker-DNEL long-term for inhalation route - systemic is derived from the oral NOAEL of 300 mg/kg bw/day, obtained in the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Wistar rats [BASF, 2019]. The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 0.38 m³/kg/8h

- standard respiratory volume human = 6.7 m³/8h

- worker respiratory volume = 10 m³/8h

- absorption (oral, rat) = 50 % (default)

- absorption (inhalative, human) = 100 % (default)

- experimental exposure time = 7 days/week

- exposure time worker = 5 days/week

--> modified dose descriptor (corrected inhalatory NOAEC) = 300 mg/kg bw/day * (1/0.38 m³/kg/d) * (6.7 m³ (8h)/10 m³ (8h)) * (50%/100%) * (7 exposure days/week; rat/5 exposure days/week; worker) = 370 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance: no additional factor needed for extrapolation from oral to inhalation route
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended default AF for other interspecies differences is applied.
AF for intraspecies differences:
3
Justification:
ECETOC TR No.86 (2003): In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
2.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidace and ECETOC TR No.86 (2003)
Overall assessment factor (AF):
180
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the dermal route available. Therefore, the worker-DNEL long-term for dermal route - systemic is derived from the oral NOAEL of 300 mg/kg bw/day, obtained in the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Wistar rats [BASF, 2019]. The NOAELcorr. is calculated as follows:

- absorption (oral, rat) = 50 % (default)

- absorption (dermal, human) = 50 % (default)

- experimental exposure time = 7 days/week

- exposure time worker = 5 days/week

--> modified dose descriptor (corrected dermal NOAEL) = 300 mg/kg bw/day * (50%/50%) * (7 exposure days/week; rat/5 exposure days/week; worker) = 420 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended default AF for other interspecies differences is applied.
AF for intraspecies differences:
3
Justification:
ECETOC TR No.86 (2003): In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
1.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidace and ECETOC TR No.86 (2003)
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
130 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available. Therefore, the general population-DNEL long-term for inhalation route - systemic is derived from the oral NOAEL of 300 mg/kg bw/day, obtained in the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Wistar rats [BASF, 2019]. The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 1.15 m³/kg/24h

- absorption (oral, rat) = 50 % (default)

- absorption (inhalative, human) = 100 % (default).As worst case, inhalative absorption is assumed to be two times more than oral absorption which allows for a modification of the starting point by factor 2.

- experimental exposure time = 7 days/week

- exposure time general population = 7 days/week

--> modified dose descriptor (corrected inhalatory NOAEC) = 300 mg/kg bw/day * (1/1.15 m³/kg/d) * (50%/100%) * (7 exposure days/week; rat / 7 exposure days/week; general population) = 130 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance: no additional factor needed for extrapolation from oral to inhalation route.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended default AF for other interspecies differences is applied.
AF for intraspecies differences:
5
Justification:
ECETOC TR No.86 (2003): In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidace and ECETOC TR No.86 (2003)
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the dermal route available. Therefore, the general population-DNEL long-term for dermal route - systemic is derived from the oral NOAEL of 300 mg/kg bw/day, obtained in the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Wistar rats [BASF, 2019].

Modification of the dose descriptor starting point was not required, as no differences in the absorption rate and exposure between experimental animals and humans are expected:

- absorption (oral, rat) = 50 % (default)

- absorption (dermal, human) = 50 % (default)

- experimental exposure time = 7 days/week

- exposure time general population = 7 days/week

--> modified dose descriptor (corrected dermal NOAEL) = 300 mg/kg bw/day * (50%/50%) * (7 exposure days/week; rat / 7 exposure days/week; general population) = 300 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended default AF for other interspecies differences is applied.
AF for intraspecies differences:
5
Justification:
ECETOC TR No.86 (2003): In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidace and ECETOC TR No.86 (2003)
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The general population-DNEL long-term for the oral route - systemic is derived from the oral NOAEL of 300 mg/kg bw/day, obtained in the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Wistar rats [BASF, 2019].

Modification of the dose descriptor starting point was not required, as no differences in the absorption rate and exposure between experimental animals and humans are expected:

- absorption (oral, rat) = 50 % (default)

- absorption (oral, human) = 50 % (default)

- experimental exposure time = 7 days/week

- exposure time general population = 7 days/week

--> modified dose descriptor (corrected oral NOAEL) = 300 mg/kg bw/day * (50%/50%) * (7 exposure days/week; rat / 7 exposure days/week; general population) = 300 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended default AF for other interspecies differences is applied.
AF for intraspecies differences:
5
Justification:
ECETOC TR No.86 (2003): In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.
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