Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 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:
176.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
Only oral route available
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure based on a sub-acute toxicity study
AF for interspecies differences (allometric scaling):
1
Justification:
Extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
AF for intraspecies differences:
5
Justification:
Default assessment factor for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Justification:
Default assessment factor
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:
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:
6.67 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:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only oral route available
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure based on a sub-acute toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in case of rat to human extrapolation.
AF for intraspecies differences:
5
Justification:
Default assessment factor for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Justification:
Default assessment factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since the substance is not classified for acute dermal, inhalation, and oral toxicity, no short-term DNELs needs to be derived for these routes of exposure. The substance is also not classified as irritating to the skin and therefore no derivation of the DNEL for acute local dermal effects needs to be derived. No data is available whether the test substance could cause irritation to the respiratory track and therefore no DNEL could be derived

 

Long-term toxicity

A subacute (28-days) oral toxicity study is available in rats. In this study a NOAEL of 200 mg/kg bw/day was established. This NOAEL is based on slightly lower mean body weights in males treated with 1000 mg/kg bw/day during the treatment period, passive fecal and urine discoloration, as well as minor macroscopical discoloration of some tissues of the excretory pathway. Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route.

 

According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. The low log Pow (<-1) value and the high water solubility (>10000 mg/L) suggest that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. In the absence of route-specific information a ratio of 0.1 for oral to dermal absorption is provisionally suggested for the risk assessment of the substance, based on its physico-chemical properties.

 

Worker DNELs

Long-term

 

Long-term – inhalation, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 200 mg/kg bw/day

Step 2) Modification of starting point

2

 

 

 

 

0.38 m3/kg bw

 

 

 

 

6.7 m3/10 m3

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation.

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.

Modified dose-descriptor

200 / 2 / 0.38 x (6.7/10) = 176.3 mg/m3

Step 3) Assessment factors

 

 

Interspecies

2.5

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.

Intraspecies

5

Default assessment factor for workers

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

176.3 / (2.5 x 5 x 6 x 1 x 1) = 2.4 mg/m3

 

Long-term – dermal, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 200 mg/kg bw/day

Step 2) Modification of starting point

0.1

Based on low log Kow and very high water solubility, dermal absorption is expected to be low. A ratio of 0.1 for oral to dermal absorption is therefore provisionally suggested for DNEL derivation.

Modified dose-descriptor

200 / 0.1 = 2000 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4 x 2.5

Assessment factor for allometric scaling.

Intraspecies

5

Default assessment factor for workers

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

2000 / (4 x 2.5 x 5 x 6 x 1 x 1) = 6.67 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 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:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:
Only oral route available
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure based on a sub-acute toxicity study
AF for interspecies differences (allometric scaling):
1
Justification:
Extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
AF for intraspecies differences:
10
Justification:
Default assessment factor
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Justification:
Default assessment factor
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:
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:
3.3 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only oral study available
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure based on a sub-acute toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in case of rat to human extrapolation.
AF for intraspecies differences:
10
Justification:
Default assessment factor
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Justification:
Default assessment factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
0.33 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
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure based on a sub-acute toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in case of rat to human extrapolation.
AF for intraspecies differences:
10
Justification:
Default assessment factor
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Justification:
Default assessment factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since the substance is not classified for acute dermal, inhalation, and oral toxicity, no short-term DNELs needs to be derived for these routes of exposure. The substance is also not classified as irritating to the skin and therefore no derivation of the DNEL for acute local dermal effects needs to be derived. No data is available whether the test substance could cause irritation to the respiratory track and therefore no DNEL could be derived

Long-term toxicity

A subacute (28-days) oral toxicity study is available in rats. In this study a NOAEL of 200 mg/kg bw/day was established. This NOAEL is based on slightly lower mean body weights in males treated with 1000 mg/kg bw/day during the treatment period, passive fecal and urine discoloration, as well as minor macroscopical discoloration of some tissues of the excretory pathway. Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route.

 

According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. The low log Pow (<-1) value and the high water solubility (>10000 mg/L) suggest that the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. In the absence of route-specific information a ratio of 0.1 for oral to dermal absorption is provisionally suggested for the risk assessment of the substance, based on its physico-chemical properties.

General population DNELs

Long-term

 

Long-term – inhalation, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 200 mg/kg bw/day

Step 2) Modification of starting point

2

 

 

 

 

1.15 m3/kg bw

 

 

 

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation.

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).

Modified dose-descriptor

200 / 2 / 1.15 = 87.0 mg/m3

Step 3) Assessment factors

 

 

Interspecies

2.5

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.

Intraspecies

10

Default assessment factor

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

87.0 / (2.5 x 10 x 6 x 1 x 1) = 0.58 mg/m3

 

Long-term – dermal, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 200 mg/kg bw/day

Step 2) Modification of starting point

0.1

Based on low log Kow and very high water solubility, dermal absorption is expected to be low. A ratio of 0.1 for oral to dermal absorption is therefore provisionally suggested for DNEL derivation.

Modified dose-descriptor

200 / 0.1 = 2000 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4 x 2.5

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

2000 / (4 x 2.5 x 10 x 6 x 1 x 1) = 3.3 mg/kg bw/day

 

Long-term – oral, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 200 mg/kg bw/day

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4 x 2.5

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

6

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

200 / (4 x 2.5 x 10 x 6 x 1 x 1) = 0.33 mg/kg bw/day