m,m'-[carbonylbis[imino(3-methoxy-p-phenylene)azo]]bis(benzenesulphonic) acid, compound with 2,2'-iminodiethanol (1:2)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.16 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:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

12.34 mg/m³

Explanation for the modification of the dose descriptor starting point:

For the inhalation route there is no reliable animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to chapter R.8.4.2 of the ECHA guidance on information requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012). According to Figure R. 8-3 in ECHA guidance R.8 additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 50%/100% * 1/0.38 m³ per kg and day * 6.7 m³/10 m³ * 1.4 (based on the oral NOAEL of 10 mg/kg bw/day for systemic toxicity obtained in the Guideline compliant subacute gavage study on rats the starting point is calculated with 12.34 mg/m³. Differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers).

Corrected inhalation NOAEC for workers = 12.34 mg/m³

AF for dose response relationship:

1

Justification:

Since the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1

AF for differences in duration of exposure:

6

Justification:

Difference in the experimental exposure duration (= sub-acute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8 as default.

AF for intraspecies differences:

5

Justification:

According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

AF for remaining uncertainties:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

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:

0.15 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:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

46.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

- Explanation for the modification of the dose descriptor starting point:

For the dermal route there is no reliable animal study available. Therefore, oral rat data is used to calculate a corresponding dermal dose for humans. On the assumption that in general dermal absorption will not be higher than oral absorption no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (chapter 4.2 of the ECHA guidance on information requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012). Differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers).

Overall, based on the physicochemical data, in particular a molecular weight well above 500 g/mol and the low log P / log D values it can be assumed that dermal absorption is lower than oral absorption. For the human risk assessment we calculated with 100% absorption after oral exposure and 30% absorption after dermal exposure (see chapter Toxicokinetcs for more information)

Cited from the guidance document	Cited from the guidance document	Conclusion drawn  for Bayscript Gelb GGN
Data source	What it tells us
Physical State	Liquids and substances in solution are taken up more readily than dry particulates. Dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin.	Bayscript Gelb GGN was  isolated as a solid for testing under REACH. The commercial form which is used throughout the supply chain is an aqueous solution. During service life (use of printed or coated article [paper, plastic]) Bayscript Gelb GGN exists as a solid though.
Molecular Weight	Less than 100 favours dermal uptake. Above 500 the molecule may be too large.	The free acid (CAS 25712-08-7)  of Bayscript Gelb GGN has a molecular weight of 640.64 g/mol.
Water Solubility	The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. Between 1-100 mg/l absorption is anticipated to be low to moderate and between 100-10,000 mg/l moderate to high. However, if water solubility is above 10,000 mg/l and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low.	Water solubility of Gelb GGN is high: 150.2 g/l with low calculated log P (0.835) and negative log D (-3.6) over a wide range of pH values.
Log P	For substances with log P values <0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low. Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow.	Calculated log P (0.835) is low and negative log D (-3.6) over a wide range of pH values*.
Vapour Pressure	Vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally may be more than 10% of the amount that would be absorbed by inhalation.	Vapor Pressure: 8.9E-8 Pa
Skin irritation /corrosion	If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration	Bayscript Gelb GGN is not irritating to the skin or eye
Dermal toxicity data	Signs of systemic toxicity indicate that absorption has occurred. However, if steps have not been taken to prevent grooming, the substance may have been ingested and therefore signs of systemic toxicity could be due to oral rather than dermal absorption.	LD50 > 2000 mg/kg bw No signs of systemic toxicity
Skin sensitization data	If the substance has been identified as a skin sensitizer then, provided the challenge application was to intact skin, some uptake must have occurred although it may only have been a small fraction of the applied dose.	Bayscript Yellow GGN did not reveal any skin sensitising properties in the mouse local lymph node assay and can thus be regarded as non-sensitizer

* log D:  Log P only correctly describes the partition coefficient of neutral (uncharged) molecules. Log D, the distribution constant, is a better descriptor of the lipophilicity of a molecule and applied in areas involving partition phenomena in biological systems such as the human body, e.g. in drug discovery.

The distribution coefficient, log D, is the ratio of the sum of the concentrations of all forms of the compound (ionized plus un-ionized) in each of the two phases, one essentially always aqueous and at a specific pH.

Overall, based on the physicochemical data, in particular a molecular weight well above 500 g/mol and the low log P / log D values it can be assumed that dermal absorption is lower than oral absorption. For the human risk assessment we calculated with 100% absorption after oral exposure and 30% absorption after dermal exposure.

AF for dose response relationship:

1

Justification:

As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

6

Justification:

Difference in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

4

Justification:

According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for rats when compared with humans is 4.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8

AF for intraspecies differences:

5

Justification:

According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

AF for remaining uncertainties:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

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

DNELs/Hazards - worker (systemic and local effects):

Route	Type of effect	Hazard conclusion	Most sensitive endpoint
Inhalation	Systemic effects - Long-term	DNEL 0.16 mg/m³	Repeated subacute oral dose toxicity, NOAEL 10 mg/kg bw/day
Inhalation	Systemic effects - Acute	No hazard	LD50 oral and dermal > 2000 mg/kg bw
Inhalation	Local effects - Long-term	No hazard	Not irritating to skin or eyes
Inhalation	Local effects - Acute	No hazard	Not irritating to skin or eyes
Dermal	Systemic effects - Long-term	DNEL 0.15 mg/kg bw/day	Repeated subacute oral dose toxicity, NOAEL 10 mg/kg bw/day
Dermal	Systemic effects - Acute	No hazard	LD50 > 2000 mg/kg bw
Dermal	Local effects - Long-term	No hazard	Not irritating to skin or eyes
Dermal	Local effects - Acute	No hazard	Not irritating to skin or eyes
Eyes		No hazard	Not irritating to skin or eyes

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.029 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:

NOAEC

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

4.34 mg/m³

Explanation for the modification of the dose descriptor starting point:

For the inhalation route there is no reliable animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to chapter R.8.4.2 of ECHA guidance R.8. According to Figure R. 8-3 in ECHA guidance R.8 additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 0.5 * 1/1.15 m³ per kg and day (based on the oral NOAEL of 10 mg/kg bw/day for systemic toxicity obtained in a sub-acute screening study on rats).

Corrected inhalation NOAEC for the General Population = 4.34 mg/m³.

AF for dose response relationship:

1

Justification:

As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

6

Justification:

Difference in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.

AF for intraspecies differences:

10

Justification:

According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

AF for remaining uncertainties:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

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:

0.055 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:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

33.3 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal Systemic effects - Long-term: For the dermal route there is no reliable animal study available. Therefore, oral rat data is used to calculate a corresponding dermal dose for humans. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation (ECHA guidance R.8, chapter 8.4.2). No differences in experimental/human exposure conditions were considered (7 days/week in the animal study and for the general population.

Based on the physicochemical data, in particular the molecular weight well above 500 g/mol and the low log P / log D values it can be assumed that dermal absorption is lower than oral absorption. For the human risk assessment we calculated with 100% absorption after oral exposure and 30% absorption after dermal exposure (see discussion in the worker chapter for detailed information)

AF for dose response relationship:

1

Justification:

As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

6

Justification:

Difference in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

4

Justification:

According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.

AF for intraspecies differences:

10

Justification:

According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

AF for remaining uncertainties:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

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:

0.017 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:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral data from the rat are used to decide on a corresponding oral dose for humans. Therefore a route-to-route extrapolation is not necessary and the NOAEL from the rat study is used as starting point.

AF for dose response relationship:

1

Justification:

As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.

AF for differences in duration of exposure:

6

Justification:

Difference in the experimental exposure duration (= subacute) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8.

AF for interspecies differences (allometric scaling):

4

Justification:

According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8

AF for intraspecies differences:

10

Justification:

According to chapter R.8.4.3.1 of ECHA guidance R.8 the default AF to be applied for intraspecies differences in the general population is 10.

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

AF for remaining uncertainties:

1

Justification:

Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.

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

DNELs/Hazards – General  population (systemic and local effects):

Route	Type of effect	Hazard conclusion	Most sensitive endpoint
Inhalation	Systemic effects - Long-term	DNEL 0.029 mg/m³	Repeated subacute oral dose toxicity, NOAEL 10 mg/kg bw/day
Inhalation	Systemic effects - Acute	No hazard	LD50 oral and dermal > 2000 mg/kg bw
Inhalation	Local effects - Long-term	No hazard	Not irritating to skin or eyes
Inhalation	Local effects - Acute	No hazard	Not irritating to skin or eyes
Dermal	Systemic effects - Long-term	DNEL 0.055 mg/kg bw/day	Repeated subacute oral dose toxicity, NOAEL 10 mg/kg bw/day
Dermal	Systemic effects - Acute	No hazard	LD50 > 2000 mg/kg bw
Dermal	Local effects - Long-term	No hazard	Not irritating to skin or eyes
Dermal	Local effects - Acute	No hazard	Not irritating to skin or eyes
Oral	Systemic effects - Long-term	DNEL 0.017 mg/kg bw/day	Repeated subacute screening study, NOAEL 10 mg/kg bw/day
Oral	Systemic effects - Acute	No hazard	LD50 > 2000 mg/kg bw
Eyes		No hazard	Not irritating to skin or eyes