Trisodium 1-(1-naphthylazo)-2-hydroxynaphthalene-4',6,8-trisulphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24.7 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

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

616.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 90-day study in rats was selected as the most representative starting dose based on the study duration, the identification of an effect level (LOAEL) at 1000 mg/kg bw/d, and the number of observations and parameters taken into account to identify effect levels.

In comparison, in studies on toxicity to reproduction, animals were dosed for a shorter period, adverse effect levels were not identified, observations were mainly focused on reproductive parameters, resulting in NOAELs significantly higher than those obtained with respect to general toxicity in the repeated dose study.  

Starting from an oral dose of 500 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 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.

DNEL = ((500 mg/kg bw/day : 0.38 m³/kg) × (6.7 m³: 10 m³)) × (7 d/w : 5 d/w) × 0.5 = 616.7 mg/m³

AF for dose response relationship:

1

Justification:

starting point is a NOAEC

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic 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:

toxicokinetic 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:

7 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):

100

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

700 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 90-day study in rats was selected as the most representative starting dose based on the study duration, the identification of an effect level (LOAEL) at 1000 mg/kg bw/d, and the number of observations and parameters taken into account to identify effect levels.

In comparison, in studies on toxicity to reproduction, animals were dosed for a shorter period, adverse effect levels were not identified, observations were mainly focused on reproductive parameters, resulting in NOAELs significantly higher than those obtained with respect to general toxicity in the repeated dose study.  

Starting from an oral dose of 500 mg/kg bw/d (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).

No experimental data on absorption via oral and dermal route is available, thus same absorption rate is assumed for both routes.

DNEL = 500 mg/kg bw/day × (7 d/w : 5 d/w) = 700 mg/m³

AF for dose response relationship:

1

Justification:

starting point is a NOAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default value

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:

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

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 42.5 µm. The fraction of respirable particles, which may enter the alveolar region and become systemically available upon absorption, is less than 14 %. 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 616.7 mg/m³derived from a NOAEL of 500 mg/kg bw/d (mid tested dose in a repeated dose 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, and for differences in exposure conditions, i.e. days per week of exposure of experimental animals and workers. 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 2, because the starting value resulted from a subchronic 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 42.5 µm. Based on the particle size distribution, ca. 90 % of 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

Systemic effects after long term exposure

Partition coefficient and molecular weight of test substance make dermal absorption unlikely. However, following a precautionary approach, dermal and oral bioavailabilities are assumed to be the same.

Despite the low potential for systemic exposure via deraml route, a DNEL is derived.

The starting point to derive a long term DNEL for dermal route was a NOAEL of 700 mg/kg derived from a NOAEL of 500 mg/kg bw/d (mid tested dose in a repeated dose toxicity study in rats by oral route) properly corrected for differences in exposure conditions, namely 7 days per week in experimental animals and 5 days per week in workers. Assessment factors were used to derive the DNEL:

- remaining interspecies differences 2.5

- intraspecies differences 5, for workers

- differences in duration of exposure 2, because the starting value resulted from a subchronic 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.

Based on the lack of skin sensitising effects by the substance, no 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:

3.7 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

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

185 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 90-day study in rats was selected as the most representative starting dose based on the study duration, the identification of an effect level (LOAEL) at 1000 mg/kg bw/d, and the number of observations and parameters taken into account to identify effect levels.

In comparison, in studies on toxicity to reproduction, animals were dosed for a shorter period, adverse effect levels were not identified, observations were mainly focused on reproductive parameters, resulting in NOAELs significantly higher than those obtained with respect to general toxicity in the repeated dose study.  

Starting from an oral dose of 500 mg/kg bw/d (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.

DNEL = ((500 mg/kg bw/day : 1.35 m³/kg) x 0.5 = 185 mg/m³

AF for dose response relationship:

1

Justification:

starting point is a NOAEC

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic 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:

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

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:

2.5 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):

200

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 90-day study in rats was selected as the most representative starting dose based on the study duration, the identification of an effect level (LOAEL) at 1000 mg/kg bw/d, and the number of observations and parameters taken into account to identify effect levels.

In comparison, in studies on toxicity to reproduction, animals were dosed for a shorter period, adverse effect levels were not identified, observations were mainly focused on reproductive parameters, resulting in NOAELs significantly higher than those obtained with respect to general toxicity in the repeated dose study.  

No experimental data on absorption via oral and dermal route is available, thus same absorption rate is assumed for both routes.

Exposure conditions of experimental animals and humans (general population) are the same, i.e. 7 days per week.

AF for dose response relationship:

1

Justification:

starting dose is a NOAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation form subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

default value

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

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:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 90-day study in rats was selected as the most representative starting dose based on the study duration, the identification of an effect level (LOAEL) at 1000 mg/kg bw/d, and the number of observations and parameters taken into account to identify effect levels.

In comparison, in studies on toxicity to reproduction, animals were dosed for a shorter period, adverse effect levels were not identified, observations were mainly focused on reproductive parameters, resulting in NOAELs significantly higher than those obtained with respect to general toxicity in the repeated dose study.  

Exposure conditions of experimental animals and general population were the same, i.e. 7 days per week. No extrapolation was applied.

AF for dose response relationship:

1

Justification:

starting dose is a NOAEL

AF for differences in duration of exposure:

2

Justification:

extrapolation for subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

default value

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, particles have a mass-median diameter of 42.5 µm and ca. 90 % of 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 14 %. 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 616.7 mg/m³derived from a NOAEL of 500 mg/kg bw/d (mid tested dose in a repeated dose 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, and exposure conditions. 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 2, because the starting value resulted from a subchronic 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 42.5 µm. Based on the particle size distribution, ca. 90 % of particles are below 100 µm size. 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

DERMAL ROUTE

Systemic effects after long term exposure

Partition coefficient and molecular weight of test substance make dermal absorption unlikely. However, following a precautionary approach, dermal and oral bioavailabilities are assumed to be the same.

Despite the low potential for systemic exposure via deraml route, a DNEL is derived.

The starting point to derive a long term DNEL for dermal route was a NOAEL of 500 mg/kg (mid tested dose in a repeated dose toxicity study in rats by oral route). A precautionary approach for absorption rate was assumed, namely equal absorption by oral and dermal route. Assessment factors were used to derive the DNEL:

- remaining interspecies differences 2.5

- intraspecies differences 5, for workers

- differences in duration of exposure 2, because the starting value resulted from a subchronic 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.

Based on the lack of skin sensitising effects by the substance, no 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 500 mg/kg bw/d obtained from a repeated dose toxicity study. This was the mid tested dose, at which no indications of systemic toxicity were reported. Assessment factors were used to derive DNEL:

- differences in duration of exposure 2, because the starting value resulted from a subchronic 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.