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Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.29 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):

75

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

246.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as the most representative starting dose based on: presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

In comparison, in a study of toxicity to reproduction, a NOAEL of 265 mg/kg bw/day was identified for toxic effects in male rats; observations were mainly focused on reproductive parameters.

Starting from an oral dose of 200 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.

Based on these considerations, the following formula is applied:

NOAEC = (200 ÷ 0.38 m³/kg) × (6.7 m³ ÷ 10 m³) × (7 d/w : 5 d/w) × 0.5 = 246.5 mg/m³

AF for dose response relationship:

1

Justification:

AF for dose-response relation is 1 as a NOAEL can be identified

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is 6 as the source study is a sub-acute toxicity study (28-day; OECD 407)

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences are already considered in the original formula

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

5

Justification:

AF for intraspecies differences in workers

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

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:

9.33 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):

300

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 800 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as the most representative starting dose based on: presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

In comparison, in a study of toxicity to reproduction, a NOAEL of 265 mg/kg bw /day was identified for toxic effects in male rats; observations were mainly focused on reproductive parameters.

Starting from an oral dose of 200 mg/kg (NOAEL), a corrected value is obtained, based on: days per week of exposure in experimental animals (7 d/w) and in humans (5 d/w in workers); 10 % dermal absorption due to a low log Pow, a high water solubility and a high molecular weight.

Based on these considerations, the following formula is applied:

NOAEL = 200 mg/kg × (7 d/w : 5 d/w) : 0.1 = 2800 mg/kg

AF for dose response relationship:

1

Justification:

AF for dose-response relation is 1 as a NOAEL can be identified.

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (28-day, OECD 407)

AF for interspecies differences (allometric scaling):

4

Justification:

AF value of 4 for interspecies differences between rat and human

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

5

Justification:

AF for intraspecies differences in workers

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

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:

acute toxicity

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 assessement 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

The substance is manufactured and used in non solid form and it has a negligible vapour pressure. Despite a low potential for systemic exposure via inhalation, a DNEL is derived.

The starting point to derive a long term DNEL for inhalation route was a NOAEC of 246.5 mg/m³ derived from a NOAEL of 200 mg/kg bw/d, 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:

- 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

No acute inhalation toxicity study was available. However, as the inhaled substance may likely enter the gastrointestinal tract via clearance mechanism and the substance is not classified for acute oral toxicity (CLP Regulation), no DNEL is derived.

Local effects after acute and long term exposure

The substance is not irritant to eye and did not cause damage to the gastrointestinal tract in studies by oral route, thus an effect on mucous of respiratory tract upon inhalation may be excluded.

DERMAL ROUTE

Physicochemical properties, i.e. water solubility and partition coefficient, are indicative of a low potential for absorption by dermal route.

Systemic effects after long term exposure

A DNEL was calculated starting from a NOAEL of 200 mg/kg bw/day. Worst case for absorption rate was assumed, namely 10 % by dermal route and 100 % by oral route. Assessment factors were used to derive the DNEL:

- interspecies differences 4, for rat to human

- 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

An acute dermal toxicity study was available, where no acute toxicity was seen and no classification was required (CLP Regulation), thus no DNEL is derived.

Local effects after long term and acute exposure

No long term studies upon dermal exposure were available. As no local effects were noted in skin irritation studies and in an acute toxicity test by dermal route, the substance resulted as non irritant and 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:

0.58 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):

150

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

87 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as the most representative starting dose based on: study duration; presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

In comparison, in a study of toxicity to reproduction, a NOAEL of 265 mg/kg bw/day was identified for toxic effects in male rats; observations were mainly focused on reproductive parameters.

Starting from an oral dose of 200 mg/kg (NOAEL), a corrected value is obtained, based on: 24-h breathing volume of rat (1.15 m³/kg). Exposure conditions of experimental animals and humans (general population) are the same, i.e. 7 days per week. No data on absorption via oral and inhalation route was available. Worst case assumption for absorption was: 50 % orally and 100 % by inhalation.

NOAEC = ((200 mg/kg bw/day : 1.15 m³/kg) × 0.5 = 87 mg/m³

AF for dose response relationship:

1

Justification:

AF for dose-response relation is 1 as a NOAEL can be identified

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (28-day; OECD 407)

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences are already included

AF for other interspecies differences:

2.5

Justification:

A default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences in the general population such as age, health, race

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

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:

3.33 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):

600

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as the most representative starting dose based on: presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

In comparison, in a study of toxicity to reproduction, a NOAEL of 265 mg/kg bw /day was identified for toxic effects in male rats; observations were mainly focused on reproductive parameters.

Starting from an oral dose of 200 mg/kg (NOAEL), a corrected value is obtained, based on a 10 % dermal absorption due to a low log Pow and a high molecular weight (log Pow < -1 and molecular weight > 500 g/mol), leading to:

NOAEL = 200 mg/kg / 0.1 = 2000 mg/kg

AF for dose response relationship:

1

Justification:

AF for dose-response relation is 1 as a NOAEL can be identified

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is 6 as the source study is a sub-acute toxicity study (28-day; OECD 407)

AF for interspecies differences (allometric scaling):

4

Justification:

AF value of 4 for interspecies differences between rat and human

AF for other interspecies differences:

2.5

Justification:

A default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences in the general population such as age, health, race

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

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:

0.33 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):

600

Dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A NOAEL of 200 mg/kg bw/day, obtained in a 28 -day study in rats, was selected as the most representative starting dose based on: presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

In comparison, in a study of toxicity to reproduction, a NOAEL of 265 mg/kg bw/day was identified for toxic effects in male rats; observations were mainly focused on reproductive parameters.

AF for dose response relationship:

1

Justification:

AF for dose-response relation is 1 as a NOAEL can be identified

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is 6 as the source study is a sub-acute toxicity study (28-day; OECD 407)

AF for interspecies differences (allometric scaling):

4

Justification:

AF value of 4 for interspecies differences between rat and human

AF for other interspecies differences:

2.5

Justification:

A default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences in the general population such as age, health, race

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties identified

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 assessement 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

The substance has a negligible vapour pressure and is manufactured and used in non-solid form. Despite the low potential for systemic exposure via inhalation, a DNEL is derived.

The starting point to derive a long term DNEL for inhalation route was a NOAEC of 246.5 mg/m³derived from a NOAEL of 200 mg/kg bw/d, properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human 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:

- 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

No acute inhalation toxicity study was available. However, as the inhaled substance may likely enter the gastrointestinal tract via clearance mechanism and the substance is not classified for acute oral toxicity (CLP Regulation), no DNEL is derived.

Local effects after acute and long term exposure

The substance is not irritant to eye and did not cause damage to the gastrointestinal tract in studies by oral route, thus an effect on mucous of respiratory tract upon inhalation may be excluded.

DERMAL ROUTE

Physicochemical properties, i.e. water solubility and partition coefficient, are indicative of a low potential for absorption by dermal route.

Systemic effects after long term exposure

A DNEL was calculated starting from a NOAEL obtained in a repeated dose oral toxicity study. Worst case for absorption rate was assumed, namely 10 % by dermal route and 100 % by oral route. Assessment factors were used to derive the DNEL:

- interspecies differences 4, for 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

An acute dermal toxicity study was available, where no acute toxicity was seen and no classification was required (CLP Regulation), thus no DNEL is derived.

Local effects after long term and acute exposure

No long term studies upon dermal exposure were available. As no local effects were noted in skin irritation studies and in an acute toxicity test by dermal route, the substance resulted as non irritant and 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 200 mg/kg bw/d obtained from a 28 -day toxicity study. Assessment factors were used to derive DNEL:

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

- interspecies differences 4, from rat to human

- remaining differences 2.5

- intraspecies differences 10, for general population.

Systemic effects after acute exposure

The substance is not classified for acute toxicity within the CLP Regulation (EC 1272/2008), thus no DNEL is derived.