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Registration Dossier
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EC number: 451-490-1 | CAS number: -
Toxicological Summary
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
DNEL related information
- Overall assessment factor (AF):
- 75
- Modified dose descriptor starting point:
- NOAEC
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
DNEL related information
- Overall assessment factor (AF):
- 300
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high 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 local dermal effects needs to be derived. The test substance is classifies as sensitizing, however, since only limited data is available from a LLNA, no DNEL could 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 vacuolar tubulus cell degeneration observed in all test item-treated animals receiving 1000 mg/kg/day (after four weeks' treatment and recovery). and an increased incidence and mean grade of tubular basophilia recorded after recovery in animals treated with 1000 mg/kg/day. 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 available acute dermal study no effects were observed (RCC 2001). 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 – 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 |
Based on toxic effects observed in the kidney. |
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 |
|
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 |
Based on toxic effects observed in the kidney. |
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) =2.35 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
DNEL related information
- Overall assessment factor (AF):
- 150
- Modified dose descriptor starting point:
- NOAEC
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:
- 3.33 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 600
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high 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:
- 333 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 600
- Modified dose descriptor starting point:
- NOAEL
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 local dermal effects needs to be derived. The test substance is classifies as sensitizing, however, since only limited data is available from a LLNA, no DNEL could 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 vacuolar tubulus cell degeneration observed in all test item-treated animals receiving 1000 mg/kg/day (after four weeks' treatment and recovery). and an increased incidence and mean grade of tubular basophilia recorded after recovery in animals treated with 1000 mg/kg/day. 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 available acute dermal study no effects were observed (RCC 2001). 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 – 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 |
Based on toxic effects observed in the kidney. |
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. |
Step 3) Assessment factors |
200 / 0.1 = 2000 mg/kg bw/day |
|
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 |
|
|
2000 / (4 x 2.5 x 10 x 6 x 1 x 1) =3.33 mg/kg bw/day |
|
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 |
Based on toxic effects observed in the kidney. |
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 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 / (2.5 x 10 x 6 x 1 x 1) =580µg/m3 |
|
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 |
Based on toxic effects observed in the kidney. |
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) =333 µg/kg bw/day |
|
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