Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 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):
75
Dose descriptor starting point:
NOAEL
Value:
93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
114.8 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 93 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. 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). 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 worker = 5 days/week

--> modified dose descriptor (corrected inhalatory NOAEC) = 93 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) = 114.8 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:
ECHA REACH Guidance: The default value for the relatively homogenous group "worker" is used.
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:
4.3 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
Dose descriptor starting point:
NOAEL
Value:
93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 302 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 93 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. The NOAELcorr. is calculated as follows:

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

- absorption (dermal, human) = 10 % (*)

- experimental exposure time = 7 days/week

- exposure time worker = 5 days/week

--> modified dose descriptor (corrected dermal NOAEL) = 93 mg/kg bw/day * (100%/10%) * (7 exposure days/week; rat/5 exposure days/week; worker) = 1302 mg/kg bw/day.

(*) Based on the user manual for the internet version of the danish (Q)SAR database (version 1 may 2005), dermal penetration/absorption can be calculated with DERMWIN. According to this manual, with an Kp-value below 0.001 the dermal penetration of the test substance is considered to be very low (Kp-value calculated for disodium(sulphonatothio) acetate: 5*10 -8). Thus, based on this calculation dermal absorption compared to oral absorption is considered to be 10% as a worst case estimate. This is supported by acute toxicity data. In an acute dermal toxicity study at a dose of 2000 mg/kg bw no clinical signs and no mortality were seen, whereas in an acute oral toxicity study at a dose of 300 mg/kg bw all animals were found dead within one day. In a conservative approach, the dermal absorption was modified by factor 10.

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:
ECHA REACH Guidance: The default value for the relatively homogenous group "worker" is used.
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:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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
Dose descriptor starting point:
NOAEL
Value:
93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
40.4 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 93 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. 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) = 93 mg/kg bw/day * (1/1.15 m³/kg/d) * (50%/100%) * (7 exposure days/week; rat / 7 exposure days/week; general population) = 0.3 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:
10
Justification:
ECHA REACH Guidance: The default value for the relatively heterogenous group "general population" is used.
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:
1.6 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:
93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
930 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 93 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. The NOAELcorr. is calculated as follows:

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

- absorption (dermal, human) = 10 % (*)

- experimental exposure time = 7 days/week

- exposure time general population = 7 days/week

--> modified dose descriptor (corrected dermal NOAEL) = 93 mg/kg bw/day * (100%/10%) * (7 exposure days/week; rat/5 exposure days/week; general population) = 930 mg/kg bw/day.

(*) Based on the user manual for the internet version of the danish (Q)SAR database (version 1 may 2005), dermal penetration/absorption can be calculated with DERMWIN. According to this manual, with an Kp-value below 0.001 the dermal penetration of the test substance is considered to be very low (Kp-value calculated for disodium(sulphonatothio) acetate: 5*10 -8). Thus, based on this calculation dermal absorption compared to oral absorption is considered to be 10% as a worst case estimate. This is supported by acute toxicity data. In an acute dermal toxicity study at a dose of 2000 mg/kg bw no clinical signs and no mortality were seen, whereas in an acute oral toxicity study at a dose of 300 mg/kg bw all animals were found dead within one day. In a conservative approach, the dermal absorption was modified by factor 10.

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:
10
Justification:
ECHA REACH Guidance: The default value for the relatively heterogenous group "general population" is used.
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:
0.2 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):
600
Dose descriptor starting point:
NOAEL
Value:
93 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 93 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.

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) = 100 % (default)

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

- experimental exposure time = 7 days/week

- exposure time general population = 7 days/week

--> modified dose descriptor (corrected oral NOAEL) = 93 mg/kg bw/day * (100%/100%) * (7 exposure days/week; rat / 7 exposure days/week; general population) = 93 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:
10
Justification:
ECHA REACH Guidance: The default value for the relatively heterogenous group "general population" is used.
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:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population