disodium 7-{[4-chloro-6-(dodecylamino)-1,3,5-triazin-2-yl]amino}-4-hydroxy-3-[{4-[(4-sulfonatophenyl)diazen-1-yl]phenyl}diazen-1-yl]naphthalene-2-sulfonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

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 (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 data on absorption via oral and inhalation route. Worst case assumption for absorption: 50 % orally and 100 % by inhalation.

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:

DNEL (Derived No Effect Level)

Value:

1 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

100 % bioavailability for both oral and dermal routes.

AF for dose response relationship:

1

Justification:

NOAEL.

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:

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:

DNEL (Derived No Effect Level)

Value:

40 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Value:

2 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no extrapolation.

AF for dose response relationship:

1

Justification:

NOAEL.

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:

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.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.9 mg/cm²

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

other: NOAEL

AF for dose response relationship:

1

Justification:

NOAEL.

AF for interspecies differences (allometric scaling):

1

Justification:

local effects.

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.

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

In general, calculation of a DNEL is based on the observed effect level and has to be corrected for the differences between effect assessment data and real human exposure situation, taking into account variability and uncertainty within and between species.

INHALATION ROUTE

Systemic effects after acute exposure

No hazard identified, since the substance is a powder and particles have a mass-median diameter between 63 and 250 µm, meaning that only a small fraction may be inhaled. Moreover, fraction of respirable particles, i.e. diameter < 4 µm, is less than 4 %. Systemic effects upon acute exposure are unlikely to occur.

Systemic effects after long term exposure

Despite exposure is unlikely, a DNEL is computed. The starting point to derive a long term DNEL for inhalation route was a NAEC of 264.5 mg/kg bw/day derived from a NOAEL of 300 mg/kg bw/day (mid tested dose in a reproduction/developmental toxicity screening test in rats by oral route) properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (worker) breathing volume. 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.

Local effects after acute and long term exposure

The substance is a powder and particles have a mass-median diameter between 63 and 250 µm. Due to the particle size, only a small fraction may be inhaled, but mucous 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 is expected to be low. However, following a precautionary approach, 100 % bioavailability is assumed.

Systemic effects after acute exposure

The starting point to derive an acute DNEL for dermal exposure was a NOAEL of 2000 mg/kg obtained in an acute study in rats by dermal route. This was the maximum tested dose.

Assessment factors were used to derive the DNEL:

-interspecies differences 4, from rat to human

- remaining interspecies differences 2.5

- intraspecies differences 5, for workers

Systemic effects after long term exposure

The starting point to derive a long term DNEL for dermal exposure was a NOAEL of 300 mg/kg bw/day obtained in a reproduction/developmental toxicity screening test with rats by oral route. This was the mid tested dose.

Assessment factors were used to derive the DNEL:

- interspecies differences 4, from rat to human

- remaining differences 2.5

- intraspecies differences 5, for workers

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

Local effects after acute exposure

The starting point to derive an acute DNEL for dermal exposure was a NOAEL of 2000 mg/kg, derived from an acute study in rats by dermal route. This was the maximum tested dose. It corresponds to 11.2 mg/cm² considering an average body weight of 0.25 kg and a body surface of 445 cm², where ca. 10 % is exposed to the substance.

Assessment factors were used to derive the DNEL:

- remaining interspecies differences 2.5

- intraspecies differences 5, for workers

Local effects after long term exposure

No DNEL for repeated dermal exposure was derived due to the lack of data. However, no local effects, except for pink discoloration of the treated skin, were seen in studies assessing acute dermal toxicity, skin irritation and skin sensitisation.

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:

effect on fertility

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 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting from an oral dose of 300 mg/kg (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.

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:

DNEL (Derived No Effect Level)

Value:

0.5 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

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:

100 % bioavailability for both oral and dermal routes.

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:

DNEL (Derived No Effect Level)

Value:

20 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

2 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no extrapolation.

AF for dose response relationship:

1

Justification:

NOAEL.

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.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.45 mg/cm²

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

other: NOAEL

AF for dose response relationship:

1

Justification:

NOAEL.

AF for interspecies differences (allometric scaling):

1

Justification:

local effects.

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.

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:

effect on fertility

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:

DNEL (Derived No Effect Level)

Value:

20 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

2 000 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 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.

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.

INHALATION ROUTE

Systemic effects after acute exposure

No hazard identified, since the substance is a powder and particles have a mass-median diameter between 63 and 250 µm, meaning that only a small fraction may be inhaled. Moreover, fraction of respirable particles, i.e. diameter < 4 um, is less than 4 %. Systemic effects upon acute exposure are unlikely to occur.

Systemic effects after long term exposure

Despite the exposure is unlikely, a DNEL is computed. The starting point to derive a long term DNEL for inhalation route was a NOAEL of 130 mg/kg bw/day derived from a NOAEL of 300 mg/kg bw/day (mid tested dose in reproduction/developmental toxicity screening test with rats by oral route) properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (general population) breathing volume.

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.

Local effects after acute and long term exposure

The substance is a powder and particles have a mass-median diameter between 63 and 250 µm. Due to the particle size, only a small fraction may be inhaled, but mucous 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, dermal absorption is expected to be low. However, following a precautionary approach, 100 % bioavailability is assumed.

Systemic effects after acute exposure

The starting point to derive an acute DNEL for dermal exposure was a NOAEL of 2000 mg/kg obtained in an acute study in rats by dermal route. This was the maximum tested dose.

Assessment factors were used to derive the DNEL:

-interspecies differences 4, from rat to human

- remaining interspecies differences 2.5

- intraspecies differences 10, for general population

Systemic effects after long term exposure

The starting point to derive a long term DNEL for dermal exposure was a NOAEL of 300 mg/kg bw/day obtained in a reproduction/developmental toxicity screening test with rats by oral route. This was the mid tested dose.

Assessment factors were used to derive the DNEL:

- interspecies differences 4, from rat to human

- remaining differences 2.5

- intraspecies differences 10, for general population

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

Local effects after acute exposure

The starting point to derive an acute DNEL for dermal exposure was a NOAEL of 2000 mg/kg, derived from an acute study in rats by dermal route. This was the maximum tested dose. It corresponds to 11.2 mg/cm² considering an average body weight of 0.25 kg and a body surface of 445 cm², where ca. 10 % is exposed to the substance.

Assessment factors were used to derive the DNEL:

- dose-response 3

- remaining interspecies differences 2.5

- intraspecies differences 10, for general population

Local effects after long term exposure

No DNEL for repeated dermal exposure was derived due to the lack of data. However, no local effects, except for pink discoloration of the treated skin, were seen in studies assessing acute dermal toxicity, skin irritation and skin sensitisation.

ORAL ROUTE

Systemic effects after acute exposure

The starting point to derive an acute DNEL for oral exposure was a NOAEL of 2000 mg/kg obtained in an acute oral study in rats. This was the maximum tested dose.

Assessment factors were used to derive the DNEL:

-interspecies differences 4, from rat to human

- remaining interspecies differences 2.5

- intraspecies differences 10, for general population

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/day obtained from a reproduction/developmental toxicity screening test. This was the mid tested dose, at which no indications of systemic or 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.