Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.15 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
70 mg/kg bw/day
Value:
86.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Not required under Guidance R8 Appendix 8.8 as no distinct acute systemic effects have been established.

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:
0.327 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
70 mg/kg bw/day
Value:
98 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Not required under Guidance R8 Appendix 8.8 as no distinct acute systemic effects have been established.

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.01 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
15
Dose descriptor:
other: LOAEL
AF for dose response relationship:
3
Justification:
Default assessment factor when starting point is a LOAEL
AF for differences in duration of exposure:
1
Justification:
Not applicable to sensitisation
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable for local effects
AF for other interspecies differences:
1
Justification:
Not applicable for local effects
AF for intraspecies differences:
5
Justification:
Workers. Table R8-6
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Acute DNELs:

As the substance is classified for acute oral toxicity an acute DNEL should be derived for the general population. However, peak exposure is considered not possible and therefore an acute DNELsystemic will not be derived. The long term DNEL is considered sufficient to cover effects from acute exposure.As an acute toxicity hazard leading to Classification and Labelling of the substance has not been identified for dermal and inhalation exposure, the long-term DNEL is considered sufficient to ensure that effects from acute exposure to the substance do not occur (in accordance with ECHA Guidance on information requirements and chemical safety assessment: Chapter R.8: Characterisation of dose [concentration]-response for human health, and Part B: Hazard Assessment, Draft new chapter B.8 Scope of Exposure Assessment,).

 

Long term DNELs:

The following DNELs have been derived:

Systemic:

Long-term oral general population

Long-term inhalation general population and workers

Long-term dermal general population and workers

 

Route-to-route extrapolation

For the derivation of the DNELs:

Long-term – dermal, systemic effects

Long-term – inhalation, systemic effects

Route-to-route extrapolation has been performed. In absence of relevant data, only differences between the different routes as determined by the assumed percentages of absorption into the systemic circulation could be accounted for (see toxicokinetic assessment).

Absorption oral (rat) = Absorption oral (human) = 50%

Absorption dermal (human) = 50%

Absorption inhalation (human) = 100%

 

The DNELs for human exposure are derived according to the default assessment factors prescribed by ECHA. The automated calculation software within IUCLID 6 was used to derive the definitive DNELS .

 

Starting point for all DNELs: NOAEL 70 mg/kg bw/day from a developmental oral study in rats (LOAEL 175 mg/kg bw/d).

In a 28-day study with rats a NOAEL of 100 ppm (9.4 mg/kg bw/day) was observed with a LOAEL of 93.2 mg/kg bw/day (1000 ppm). The effect at the LOAEL in this study was only observed in females, the decreased kidney weight was dose-related but with a very flat curve (at 100, 1000, 3000 and 5000 ppm: 6, 9, 10 and 15%, respectively for relative and 7, 9, 10 and 13% for absolute kidney weights). No gross lesions were observed, however no histopathology was performed. At 3000 ppm clear other adverse effects were observed, such as decreased kidney weights in males, in males and females increased liver weights, decreased body weight gain and food consumption, severe clinical signs. In a 90-day study with rats conducted according to current OECD and EU guidelines, the NOAEL was 150 mg/kg bw (the highest dose tested); the adverse effects observed in the 28-day study were not observed in this 90 day study. Therefore, it is considered appropriate to use the NOAEL of the developmental study of 70 mg/kg bw/day. Justification of this is detailed in Section 13.2 "Justification of DNEL starting point" which presents an expert opinion for the justification of the 90-day NOAEL.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.203 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
70 mg/kg bw/day
Value:
30.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Not required under Guidance R8 Appendix 8.8 as no distinct acute systemic effects have been established.

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:
0.117 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
70 mg/kg bw/day
Value:
70 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
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:
DNEL (Derived No Effect Level)
Value:
0.007 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
30
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
3
Justification:
Default assessment factor when starting point is a LOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable for sensitisation
AF for other interspecies differences:
1
Justification:
Not applicable for local effects
AF for intraspecies differences:
1
Justification:
Not applicable for local effects
AF for the quality of the whole database:
10
Justification:
Default assessment factor for general population
AF for remaining uncertainties:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.117 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
70 mg/kg bw/day
Value:
70 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Acute DNELs:

As the substance is classified for acute oral toxicity an acute DNEL should be derived for the general population. However, peak exposure is considered not possible and therefore an acute DNELsystemic will not be derived. The long term DNEL is considered sufficient to cover effects from acute exposure.As an acute toxicity hazard leading to Classification and Labelling of the substance has not been identified for dermal and inhalation exposure, the long-term DNEL is considered sufficient to ensure that effects from acute exposure to the substance do not occur (in accordance with ECHA Guidance on information requirements and chemical safety assessment: Chapter R.8: Characterisation of dose [concentration]-response for human health, and Part B: Hazard Assessment, Draft new chapter B.8 Scope of Exposure Assessment,).

 

Long term DNELs:

The following DNELs have been derived:

Systemic:

Long-term oral general population

Long-term inhalation general population and workers

Long-term dermal general population and workers

 

Route-to-route extrapolation

For the derivation of the DNELs:

Long-term – dermal, systemic effects

Long-term – inhalation, systemic effects

Route-to-route extrapolation has been performed. In absence of relevant data, only differences between the different routes as determined by the assumed percentages of absorption into the systemic circulation could be accounted for (see toxicokinetic assessment).

Absorption oral (rat) = Absorption oral (human) = 50%

Absorption dermal (human) = 50%

Absorption inhalation (human) = 100%

 

The DNELs for human exposure are derived according to the default assessment factors prescribed by ECHA. The automated calculation software within IUCLID 6 was used to derive the definitive DNELS .

 

Starting point for all DNELs: NOAEL 70 mg/kg bw/day from a developmental oral study in rats (LOAEL 175 mg/kg bw/d).

In a 28-day study with rats a NOAEL of 100 ppm (9.4 mg/kg bw/day) was observed with a LOAEL of 93.2 mg/kg bw/day (1000 ppm). The effect at the LOAEL in this study was only observed in females, the decreased kidney weight was dose-related but with a very flat curve (at 100, 1000, 3000 and 5000 ppm: 6, 9, 10 and 15%, respectively for relative and 7, 9, 10 and 13% for absolute kidney weights). No gross lesions were observed, however no histopathology was performed. At 3000 ppm clear other adverse effects were observed, such as decreased kidney weights in males, in males and females increased liver weights, decreased body weight gain and food consumption, severe clinical signs. In a 90-day study with rats conducted according to current OECD and EU guidelines, the NOAEL was 150 mg/kg bw (the highest dose tested); the adverse effects observed in the 28-day study were not observed in this 90 day study. Therefore, it is considered appropriate to use the NOAEL of the developmental study of 70 mg/kg bw/day. Justification of this is detailed in Section 13.2 "Justification of DNEL starting point" which presents an expert opinion for the justification of the 90-day NOAEL.