1-amino-4-hydroxy-2-phenoxyanthraquinone

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.53 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:

300 mg/kg bw/day

Modified dose descriptor starting point:

other: NAEC

Value:

264.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting from an oral dose of 300 mg/kg bw/d (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 normal population and 10 m³/kg in worker).

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

DNEL = ((300 mg/kg bw/day : 0.38 m³/kg) x (6.7 m³ : 10 m³)) x 0.5 = 264.5 mg/m³

AF for dose response relationship:

1

Justification:

starting point is a NAEC.

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

implicitly included in the correct starting point.

AF for other interspecies differences:

2.5

Justification:

toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).

AF for intraspecies differences:

5

Justification:

default value.

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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

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:

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 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 a powder and particles have a mass-median diameter of 21 µm and all particles are below 100 µm size. The fraction of respirable particles, which may enter the alveolar region and become systemically available upon absorption, is less than 7 %. 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 NAEC of 264.5 mg/m³ derived from a NOAEL of 300 mg/kg bw/d (mid tested dose in a combined repeated dose toxicity and reproduction/developmental 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:

- 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 acute and long term exposure

The substance is a powder and particles have a mass-median diameter of 21 µm. Based on the particle size distribution, all particles have diameter below 100 µm. Mucous lining the respiratory tract may be exposed to the substance. No test on local effects are available, however no irritating effect on mucous is expected since the substance was found as not irritant to eyes.

DERMAL ROUTE

Partition coefficient and molecular weight of test substance indicates that the substance may be absorbed by dermal route. However, in an in vitro test with human epidermis, absorption rate resulted to be low. Following a precautionary approach, 100 % bioavailability is assumed.

Systemic effects after long term and acute exposure

Systemic effects upon dermal exposure were assessed in a skin sensitisation study. The substance resulted as highly sensitising, with positive responses to challenge in all tested animals and no threshold for either induction or elicitation, based on available data.

Based on the potency categorisation for guinea pig maximisation test, reported in ECHA guidance R.8, the substance is considered a strong sensitiser and a high hazard is expected.

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, 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:

0.87 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

Modified dose descriptor starting point:

other: NAEC

Value:

130.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting from an oral dose of 300 mg/kg bw/d (NOAEL), a corrected value is obtained, based on 24-h breathing volume of rat (1.15 m³/kg).

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

DNEL = ((300 mg/kg bw/day : 1.15 m³/kg) x 0.5 = 130.4 mg/m³

AF for dose response relationship:

1

Justification:

starting point is a NAEC.

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

implicitly included in the correct starting point.

AF for other interspecies differences:

2.5

Justification:

toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part).

AF for intraspecies differences:

10

Justification:

default value.

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:

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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:

0.5 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

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no extrapolation.

AF for dose response relationship:

1

Justification:

NOAEL clearly identified.

AF for differences in duration of exposure:

6

Justification:

extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

rat.

AF for other interspecies differences:

2.5

Justification:

toxicokinetic 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

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 is a powder and particles have a mass-median diameter of 21 µm and all particles are below 100 µm size. The fraction of respirable particles, which may enter the alveolar region and become systemically available upon absorption, is less than 7 %. 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 NAEC of 130.4 mg/m³derived from a NOAEL of 300 mg/kg bw/d (low tested dose in a combined repeated dose toxicity and reproduction/developmental toxicity study in rats by oral route) properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (general population) 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

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

The substance is a powder and particles have a mass-median diameter of 21 µm. Based on the particle size distribution, all particles have diameter below 100 µm. Mucous lining the respiratory tract may be exposed to the substance. No test on local effects are available, however no irritating effect on mucous is expected since the substance was found as not irritant to eyes.

DERMAL ROUTE

Based on partition coefficient, absorption by dermal route may occur. However, in an in vitro test with human epidermis, absorption rate resulted to be low. However, following a very precautionary approach, 100 % bioavailability is assumed.

Systemic effects after long term and acute exposure

Systemic effects upon dermal exposure were assessed in a skin sensitisation study. The substance resulted as highly sensitising, with positive responses to challenge in all tested animals and no threshold for either induction or elicitation, based on available data.

Based on the potency categorisation for guinea pig maximisation test, reported in ECHA guidance R.8, the substance is considered a strong sensitiser and a high hazard is expected.

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, 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 300 mg/kg bw/d obtained from a combined repeated dose toxicity and reproduction/developmental toxicity study. This was the mid tested dose, at which no indications of neither systemic nor reproductive toxicity were reported. 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 according to the CLP Regulation (EC 1272/2008). Therefore, based on ECHA Guidance Chapter R.8, no DNEL for acute toxicity should be derived.