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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.35 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
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 dermal 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:
3.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Value:
1 000 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:
5
Justification:
Default assessment factor for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Justification:
Standard assessment factor
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

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 not sensitizing. Therefore no derivation of the DNEL for local dermal effects and for sensitization is needed. 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) dermal toxicity study is available in rats. In this study a NOAEL of 1000 mg/kg bw/day was established for systemic effects and a NOAEL of 40 mg/kg bw/day for local effect. No treatment related effects were observed on mortality, clinical signs, food consumption, body weight, ophthalmoscopic examinations, clinical laboratory investigations, and organ weights. Treatment-related gross and microscopic findings were observed at the application site at dose-dependent incidence and severity. Macroscopically, the lesions consisted in sores and scabs of varying size,microscopically, minimal to severe inflammation with slight to marked acanthosis was observed. Since treatment-related dose depended alterations were observed macroscopically and microscopically in the treated skin, the NOAEL for local effects was determined to be 40 mg/kg/bw, while the NOAEL for systemic effects was determined to be 1000 mg/kg bw/day. However, the administered test substance was dissolved in 4% aqueous sodium CMC and placed on the skin under occlusive dressing for 6 hours per day. The combination of exposure to a gel like formulation and the prevention of evaporation of moisture from the skin surface due to the occlusive condition will result in skin irritation regardless of the substance used.

Since only a sub-acute dermal toxicity study is available a route-to-route extrapolation is needed to derive the systemic DNELs for oral and inhalation route regarding long-term exposure.

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 factor on a case-by-case basis. 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. On the assumption that the physicochemical properties of the test substance reduces the absorption of the test substance, a factor of 10 is introduced when performing dermal to inhalation and dermal to oral extrapolation.

Worker DNELs

Long-term

 

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No adverse effects observed at any dose level.

Step 2) Modification of starting point

-

-

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

 

1000 / (4 x 2.5 x 5 x 6 x 1 x 1) =3.33 mg/kg bw/day

 

 

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No adverse effects observed at any dose level.

Step 2) Modification of starting point

10

 

 

 

 

0.38 m3/kg bw

 

 

 

 

6.7 m3/10 m3

On the assumption that the physicochemical properties of the test substance reduces the absorption of the test substance, a factor of 10 is introduced when performing dermal 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

1000 / 10 / 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) =2.35 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
580 µg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
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 dermal 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:
1.67 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Value:
1 000 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

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:
167 µg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only dermal 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:
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:
low 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 not sensitizing. Therefore no derivation of the DNEL for local dermal effects and for sensitization is needed. 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) dermal toxicity study is available in rats. In this study a NOAEL of 1000 mg/kg bw/day was established for systemic effects and a NOAEL of 40 mg/kg bw/day for local effect. No treatment related effects were observed on mortality, clinical signs, food consumption, body weight, ophthalmoscopic examinations, clinical laboratory investigations, and organ weights. Treatment-related gross and microscopic findings were observed at the application site at dose-dependent incidence and severity. Macroscopically, the lesions consisted in sores and scabs of varying size, microscopically, minimal to severe inflammation with slight to marked acanthosis was observed. Since treatment-related dose depended alterations were observed macroscopically and microscopically in the treated skin, the NOAEL for local effects was determined to be 40 mg/kg/bw, while the NOAEL for systemic effects was determined to be 1000 mg/kg bw/day. However, the administered test substance was dissolved in 4% aqueous sodium CMC and placed on the skin under occlusive dressing for 6 hours per day. The combination of exposure to a gel like formulation and the prevention of evaporation of moisture from the skin surface due to the occlusive condition will result in skin irritation regardless of the substance used. Since only a sub-acute dermal toxicity study is available a route-to-route extrapolation is needed to derive the systemic DNELs for oral and inhalation route regarding long-term exposure.

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 factor on a case-by-case basis.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.On the assumption that the physicochemical properties of the test substance reduces the absorption of the test substance, a factor of 10 is introduced when performing dermal to inhalation and dermal to oral extrapolation.

General population DNELs

Long-term

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No adverse effects observed at any dose level.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4 x 2.5

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment

Exposure duration

6

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

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

1000 / (4 x 2.5 x 10 x 6 x 1 x 1) =1.67 mg/kg bw/day

 

 

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No adverse effects observed at any dose level.

Step 2) Modification of starting point

10

 

 

 

 

1.15 m3/kg bw

 

 

 

On the assumption that the physicochemical properties of the test substance reduces the absorption of the test substance, a factor of 10 is introduced when performing dermal 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

1000 / 10 / 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) =580 µg/m3

 

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No adverse effects observed at any dose level.

Step 2) Modification of starting point

10

On the assumption that the physicochemical properties of the test substance reduces the absorption of the test substance, a factor of 10 is introduced when performing dermal to oral extrapolation.

Modified dose-descriptor

1000 / 10 = 100 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-chronic toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

100 / (4 x 2.5 x 10 x 6 x 1 x 1) =167 µg/kg bw/day

 

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