Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.05 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):
25
Modified dose descriptor starting point:
NOAEC
Value:
26.17 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long term inhalation studies are not available. The long term systemic DNEL for the inhalation route has been derived from the oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.
AF for dose response relationship:
1
Justification:
default - ECHA REACH Guidance
AF for differences in duration of exposure:
2
Justification:
default - ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
1
Justification:
default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default - ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
default - ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and were adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General considerations

Short-term data

No data on acute toxicity are available for the oral, inhalation and dermal route due to the corrosive nature of the substance.

 

Long-term data

Data relevant for long-term toxicity are available from an oral sub-chronic toxicity study, subacute toxicity study and a developmental toxicity study, all conducted in rats.

 

Selection of the relevant dose descriptors:

NOAEL = 30 mg/kg bw/day; 90 d Repeated Dose Toxicity Study, rat, oral (gavage)

NOEL = 50 mg/kg bw/d (systemic effects); 28 d Repeated Dose Toxicity Study, rat, oral (gavage)

NOAEL(embryotoxicity) = 100 mg/kg bw/d, NOEL(maternal toxicity)= 30 mg/kg bw/d; Prenatal Developmental Toxicity Test, rat, oral (gavage)

 

Hazard for the eyes

The substance is classified as corrosive.

Dermal DNELs have not been derived. Due to the severity of the local effects (skin corrosion and sensitisation) maximum PPE will have to be used. In case dermal exposure occurs, immediate washing is recommended. Thus, systemic exposure is unlikely. As none of the exposure software models takes that into consideration, and thereby overestimating exposure, a qualitative assessment is carried out. According to the Guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, the substance is of high hazard.

 

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

No data exist on differences in bioavailability following oral or dermal exposure between experimental animals and humans, and a similar bioavailability is assumed by default.

 

Oral to inhalation

For inhalation exposure as a worst case assumption a 100% absorption is assumed in absence of any experimental data (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

DNELs derived from oral repeated dose toxicity NOAEL (90-d study, rat, OECD Guideline 408) 

Worker-DNEL long-term for inhalation route (systemic): 1.05 mg/m³

Start value: 30 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 26.17 mg/m³

 

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV

                                             = 30 x 1/0.384 x 50/100 x 6.7/10

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 26.17 mg/m³ (8h-TWA)

Overall AF: 1*2.5*5*2*1*1*1 = 25

 

This DNEL does not address the potential for local irritation. The risk characterization will consider whether specific risk management measures are necessary to protect against local effects.

 

DNELs derived from oral prenatal developmental toxicity NOAEL (rat, OECD Guideline 414) 

No time extrapolation is required for this type of study, since the susceptible window is fully covered.

Worker-DNEL long-term for inhalation route (systemic): 6.98 mg/m³

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 87.24 mg/m³

 

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV

                                             = 100 x 1/0.384 x 50/100 x 6.7/10

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 87.24 mg/m³ (8h-TWA)

Overall AF: 1*2.5*5*1*1*1*1 = 12.5

 

This DNEL does not address the potential for local irritation. The risk characterization will consider whether specific risk management measures are necessary to protect against local effects.

 

The DNELs for developmental toxicity were higher than those for repeated dose toxicity. Thus, the repeated dose toxicity-DNELs are also protective for development. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.26 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):
50
Modified dose descriptor starting point:
NOAEC
Value:
13.02 mg/m³
Explanation for the modification of the dose descriptor starting point:
Long term inhalation studies are not available. The long term systemic DNEL for the inhalation route has been derived from the oral repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative.
AF for dose response relationship:
1
Justification:
default - ECHA REACH Guidance
AF for differences in duration of exposure:
2
Justification:
default - ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
1
Justification:
default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default - ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
default - ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and were adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.15 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
ECHA REACH Guidance
AF for dose response relationship:
1
Justification:
default - ECHA REACH Guidance
AF for differences in duration of exposure:
2
Justification:
default - ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
4
Justification:
default - ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
default - ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
default - ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
The available studies were conducted according to modern regulatory standards and were adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown (no further information necessary)

Additional information - General Population

DNELs for general population (for the oral and inhalation route) were only derived for assessment of risk related to exposure to man via the environment. No REACH-relevant consumer use has been identified.

 

General considerations

Short-term data

No data on acute toxicity are available for the oral, inhalation and dermal route due to the corrosive nature of the substance.

 

Long-term data

Data relevant for long-term toxicity are available from an oral sub-chronic toxicity study and a developmental toxicity study, both in rats.

 

Selection of the relevant dose descriptors:

NOAEL = 30 mg/kg bw/day; 90 d Repeated Dose Toxicity Study, rat, oral (gavage)

NOEL = 50 mg/kg bw/d (systemic effects); 28 d Repeated Dose Toxicity Study, rat, oral (gavage)

NOAEL(embryotoxicity) = 100 mg/kg bw/d, NOEL(maternal toxicity)= 30 mg/kg bw/d; Prenatal Developmental Toxicity Test, rat, oral (gavage)

 

 

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

No data exist on differences in bioavailability following oral or dermal exposure between experimental animals and humans, and a similar bioavailability is assumed by default.

 

Oral to inhalation

For inhalation exposure as a worst case assumption a 100% absorption is assumed in absence of any experimental data (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

 

DNELs derived from oral repeated dose toxicity NOAEL (90-d study, rat, OECD Guideline 408) 

General population-DNEL long-term for oral route (systemic): 0.15 mg/kg bw/d

Start value: 30 mg/kg bw/d

Route of original study: oral

Overall AF 4*2.5*10*2*1*1*1 = 200

 

General population -DNEL long-term for inhalation route (systemic): 0.26 mg/m³

Start value: 30 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 13.02 mg/m³

 

For general population the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-human

                                             = 30 x 1/1.152 x 50/100

The corrected inhalation NOAECgeneral population (24 h) is therefore:

                                             = 13.02 mg/m³ (24 h)

Overall AF: 1*2.5*10*2*1*1*1 = 50 

 

DNELs derived from oral prenatal developmental toxicity NOAEL (rat, OECD Guideline 414) 

No time extrapolation is required for this type of study, since the susceptible window is fully covered.

 

General population-DNEL long-term for oral route (systemic): 1 mg/kg bw/d

Start value: 100 mg/kg bw/d

Route of original study: oral

Overall AF 4*2.5*10*1*1*1*1 = 100

 

General population -DNEL long-term for inhalation route (systemic): 1.74 mg/m³

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 43.4 mg/m³

 

For general population the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human

                                             = 100 x 1/1.152 x 50/100

The corrected inhalation NOAECgeneral population (24 h) is therefore:

                                             = 43.4 mg/m³ (24 h)

Overall AF: 1*2.5*10*1*1*1*1 = 25 

 

The DNELs for developmental toxicity were higher than those for repeated dose toxicity. Thus, the repeated dose toxicity-DNELs are also protective for development.