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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:
16.4 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 230 mg/m³
Explanation for the modification of the dose descriptor starting point:

A dose of 1000 mg/kg bw/d, corresponding to the highest tested dose in a reproductive toxicity study (2013), was identified as NOAEL and selected as starting dose for DNEL based on: study duration (ca. 4 weeks in males, ca. 7 weeks in females); type of observations and parameters taken into account to identify effect levels. It should be noted that a NOAEL of 1000 mg/kg was also identified in a repeated dose toxicity study (1979).

Starting from an oral dose of 1000 mg/kg (NOAEL), a corrected value is obtained, based on: 8-h breathing volume of rat (0.38 m3/kg) and 8-h breathing volume of human (6.7 m3/kg in general population and 10 m3/kg in worker); days per week of exposure in experimental animals (7 d/w) and in humans (5 d/w in workers).

No experimental data on absorption via oral and inhalation route was available. Worst case assumption for absorption was: 50 % orally and 100 % by inhalation.

NOAEC = ((1000 mg/kg : 0.38 m3/kg) × (6.7 m3: 10 m3)) × (7 d/w : 5 d/w) × 0.5 = 1230 mg/m3

AF for dose response relationship:
1
Justification:
NOAEL was identified
AF for differences in duration of exposure:
6
Justification:
extrapolation from a duration comparable to subacute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
implicitly included in the corrected starting point.
AF for other interspecies differences:
2.5
Justification:
toxicokinetics differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
5
Justification:
workers.
AF for the quality of the whole database:
1
Justification:
good quality and reliability.
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties.
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.67 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEL value was corrected considering the time of exposure of workers, i.e. 5 days per week, compared to experimental animals.

NOAEL = 1000 mg/kg × 7 d / 5 d = 1400 mg/kg

No experimental data on dermal absorption and bioavailability is available; by default, no correction factor for extrapolation from oral to dermal route was applied.

AF for dose response relationship:
1
Justification:
NOAEL was identified.
AF for differences in duration of exposure:
6
Justification:
extrapolation from a duration comparable to subacute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
rat.
AF for other interspecies differences:
2.5
Justification:
toxicokinetics differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
5
Justification:
workers.
AF for the quality of the whole database:
1
Justification:
good quality and reliability.
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties.
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
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

In general, the calculation of a DNEL is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. If there is no basis for setting a DNEL or DMEL for a given human health endpoint, i.e. due to the lack of quantitative dose-response information, but there exists toxicity data of a qualitative nature, a qualitative risk assessment is performed. This kind of situation typically occurs with data on irritation/corrosion, sensitisation, acute toxicity, mutagenicity, and carcinogenicity.

INHALATION ROUTE

Systemic effects after long term exposure

Despite exposure is unlikely due to the physicochemical properties of the substance, a DNEL is derived.

The starting point to derive a long term DNEL for inhalation route was a NOAEC of 1230 mg/m3 derived from a NOAEL of 1000 mg/kg (highest tested dose in a reproductive toxicity study in rats by oral route) properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (worker) breathing volume. Worst case for absorption rate was assumed, namely 50 % by oral route and 100 % by inhalation. Assessment factors were used to derive the DNEL:

- dose response 1, because corrected starting point is derived from a NOAEL

- remaining interspecies differences 2.5

- intraspecies differences 5, for workers

- differences in duration of exposure 6, because the starting value resulted from a subacute study.

Systemic effects after acute exposure

Inhalation is unlikely. Moreover, the substance is not classified for acute toxicity according to the CLP Regulation (EC 1272/2008). Therefore, based on ECHA Guidance Chapter R.8, no DNEL for acute toxicity should be derived.

Local effects after acute and long term exposure

No test on local effects is available, however no irritating effect on mucous lining the respiratory tract is expected, as the substance resulted as not irritant to eyes.

DERMAL ROUTE

Systemic effects after acute and long term exposure

Systemic effects upon dermal exposure were assessed starting from a NOAEL of 1000 mg/kg (highest tested dose in a reproductive toxicity study in rats by oral route).

The starting point to derive a long term DNEL for dermal route was a NOAEL of 1400 mg/kg, derived from a NOAEL of 1000 mg/kg properly corrected for exposure conditions in experimental animals and workers. Assessment factors were used to derive the DNEL:

- dose response 1, because corrected starting point is derived from a NOAEL

- interspecies differences between rats and humans 4

- remaining interspecies differences 2.5

- intraspecies differences 5, for workers

- differences in duration of exposure 6, because the starting value resulted from a subacute study.

Systemic effects after acute exposure

The substance is not classified for acute toxicity according to the CLP Regulation (EC 1272/2008). Therefore, based on ECHA Guidance Chapter R.8, no DNEL for acute toxicity should be derived.

Local effects after long term and acute exposure

No test on local effects is available, however no effects were noted in skin irritation studies, thus no local hazard is expected.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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:
1 000 mg/kg bw/day
Value:
435 mg/m³
Explanation for the modification of the dose descriptor starting point:

A dose of 1000 mg/kg bw/d, corresponding to the highest tested dose in a reproductive toxicity study (2013), was identified as NOAEL and selected as starting dose for DNEL based on: study duration (ca. 4 weeks in males, ca. 7 weeks in females); type of observations and parameters taken into account to identify effect levels. It should be noted that a NOAEL of 1000 mg/kg was also identified in a repeated dose toxicity study (1979).

Starting from an oral dose of 1000 mg/kg (NOAEL), a corrected value is obtained, based on: 8-h breathing volume of rat (0.38 m3/kg) and 8-h breathing volume of human (6.7 m3/kg in general population and 10 m3/kg in worker); days per week of exposure in experimental animals (7 d/w) and in humans (5 d/w in workers).

No experimental data on absorption via oral and inhalation route was available. Worst case assumption for absorption was: 50 % orally and 100 % by inhalation.

NOAEC = ((1000 mg/kg : 1.15 m3/kg) × 0.5 = 435 mg/m3

AF for dose response relationship:
1
Justification:
NOAEL was identified.
AF for differences in duration of exposure:
6
Justification:
extrapolation from a duration comparable to subacute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
implicitly included in the corrected starting point.
AF for other interspecies differences:
2.5
Justification:
toxicokinetics differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
general population.
AF for the quality of the whole database:
1
Justification:
good quality and reliability.
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties.
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
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:
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:
1 000 mg/kg bw/day
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No experimental data on dermal absorption and bioavailability is available; by default, no correction factor for extrapolation from oral to dermal route was applied.

AF for dose response relationship:
1
Justification:
NOAEL was identified.
AF for differences in duration of exposure:
6
Justification:
extrapolation from a duration comparable to subacute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
rats.
AF for other interspecies differences:
2.5
Justification:
toxicokinetics differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability.
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties.
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:
1.67 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:
1 000 mg/kg bw/day
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOEAL was identified.
AF for differences in duration of exposure:
6
Justification:
extrapolation from a duration comparable to subacute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
rats.
AF for other interspecies differences:
2.5
Justification:
toxicokinetics differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).
AF for intraspecies differences:
10
Justification:
general population.
AF for the quality of the whole database:
1
Justification:
good quality and reliability.
AF for remaining uncertainties:
1
Justification:
no significative remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

In general, the calculation of a DNEL is based on the observed effect level and has to be corrected for the differences between effect assessment data and the real human exposure situation, taking into account variability and uncertainty within and between species. If there is no basis for setting a DNEL or DMEL for a given human health endpoint, i.e. due to the lack of quantitative dose-response information, but there exists toxicity data of a qualitative nature, a qualitative risk assessment is performed. This kind of situation typically occurs with data on irritation/corrosion, sensitisation, acute toxicity, mutagenicity, and carcinogenicity.

INHALATION ROUTE

Systemic effects after long term exposure

Despite exposure is unlikely due to the physicochemical properties of the substance, a DNEL is derived.

The starting point to derive a long term DNEL for inhalation route was a NOAEC of 1230 mg/m3 derived from a NOAEL of 1000 mg/kg (highest tested dose in a reproductive toxicity study in rats by oral route) properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (worker) breathing volume. Worst case for absorption rate was assumed, namely 50 % by oral route and 100 % by inhalation. Assessment factors were used to derive the DNEL:

- dose response 1, because corrected starting point is derived from a NOAEL

- remaining interspecies differences 2.5

- intraspecies differences 10, for general population

- differences in duration of exposure 6, because the starting value resulted from a subacute study.

Systemic effects after acute exposure

Inhalation is unlikely. Moreover, the substance is not classified for acute toxicity according to the CLP Regulation (EC 1272/2008). Therefore, based on ECHA Guidance Chapter R.8, no DNEL for acute toxicity should be derived.

Local effects after acute and long term exposure

No test on local effects is available, however no irritating effect on mucous lining the respiratory tract is expected, as the substance resulted as not irritant to eyes.

DERMAL ROUTE

Systemic effects after acute and long term exposure

Systemic effects upon dermal exposure were assessed starting from a NOAEL of 1000 mg/kg (highest tested dose in a reproductive toxicity study in rats by oral route).

The starting point to derive a long term DNEL for dermal route was a NOAEL of 1400 mg/kg, derived from a NOAEL of 1000 mg/kg properly corrected for exposure conditions in experimental animals and workers. Assessment factors were used to derive the DNEL:

- dose response 1, because corrected starting point is derived from a NOAEL

- interspecies differences between rats and humans 4

- remaining interspecies differences 2.5

- intraspecies differences 10, for general population

- differences in duration of exposure 6, because the starting value resulted from a subacute study.

Systemic effects after acute exposure

The substance is not classified for acute toxicity according to the CLP Regulation (EC 1272/2008). Therefore, based on ECHA Guidance Chapter R.8, no DNEL for acute toxicity should be derived.

Local effects after long term and acute exposure

No test on local effects is available, however no effects were noted in skin irritation studies, thus no local hazard is expected.

ORAL ROUTE

Systemic effects after long term exposure

The starting point to derive a DNEL for oral long-term exposure was a NOAEL of 1000 mg/kg (highest tested dose in a reproductive toxicity study in rats by oral route).

Assessment factors were used to derive the DNEL:

- dose response 1, because corrected starting point is derived from a NOAEL

- interspecies differences 4, from rat to human

- remaining interspecies differences 2.5

- intraspecies differences 10, for general population

- differences in duration of exposure 6, because the starting value resulted from a subacute study.

Systemic effects after acute exposure

The substance is not classified for acute toxicity according to the CLP Regulation (EC 1272/2008). Therefore, based on ECHA Guidance Chapter R.8, no DNEL for acute toxicity should be derived.