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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
240
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Kinetics (absorption for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach was taken forward to DNEL derivation. For dermal absorption, based on the physical-chemical properties of the substance (molecular weight > 500 g/mol [1061 g/mol], log Kow < -1 [-4.2 at 23C], water solubility > 10000 mg/L [218 g/L}) low uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with Direct Red 239. Based on the above physical-chemical properties, oral absorption is also expected to be low. The absence of systemic effects at the high doses tested in the available oral toxicity studies with Direct Red 239 supports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation.

 

Acute toxicity

Direct Red 239 does not have to be classified for acute toxicity and therefore derivation of a DNELacuteis not necessary.

 

Repeated dose toxicity

A subacute oral toxicity study is available for the read across substance Analogue substance 1. In this study male and female rats received the substance by oral gavage at 1000 mg/kg bw/day on 5 days per week over a 30-day period.The treatment period was followed by a 2-wk recovery period.No treatment-related reactions were observed with respect to clinical symptoms, mortality, food consumption, body weight, clinical laboratory investigations and pathology. Furthermore, eye examination did not reveal any ocular changes and no loss of hearing ability was observed. The NOAEL from this study was 1000 mg/kg bw/day. This NOAEL is supported by the absence of adverse effects at 1000 mg/kg bw/day, the highest dose tested, in an oral reproduction/developmental toxicity screening study with Direct Red 239. Hence, a NOAEL of 1000 mg/kg bw/day for systemic effects was used as starting point for the DNEL derivation.

 

Mutagenicity

Direct Red 329 was not mutagenic in the Ames test. No chromosome aberration or gene mutation test in mammalian cells is available for Direct red 239. However, for a structural analogue of Direct Red 239 (Analogue substance 1) a gene mutation test in mouse lymphoma L5178Y cells is available. This gene mutation test also covers chromosome aberrations because during evaluation small and large colonies were distinguished. Under the conditions of this gene mutation test with the structural analogue, the test substance was non-mutagenic and non-clastogenic.

 

Reproduction toxicity

No adverse effects on parents or offspring were observed in areproduction/developmental toxicity screening test (OECD 421) in which rats received Direct Red 239by oral gavage at 0, 100, 300 or 1000 mg/kg bw/day. Thus, the NOAEL for reproductive toxicity was 1000 mg/kg bw/day. As this NOAEL is the same as that for repeated dose toxicity (derived from the subacute oral toxicity study with Analogue substance 1), no specific DNEL has to be derived for developmental and reproductive toxicity.

 

DNEL derivation

Short-term toxicity (systemic and local):

No DNEL needs to be derived for all routes of exposure.

 

Long-term toxicity:

Inhalation long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 2 for oral-to-inhalation extrapolation was used as proposed inChapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNELlong-termfor the inhalation route.

 

Inhalation long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

 

Dermal long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 1 for oral-to-dermal extrapolation was used as proposed inChapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNELlong-termfor the dermal route.

 

Dermal long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating or sensitizing to skin, no local effects are expected for repeated dermal exposure. 

 

Oral long-term exposure, systemic effects

The NOAEL of 1000 mg/kg bw/day for systemic toxicity obtained in the repeated dose oral toxicity study with the read across substance, which was supported by the results of the reproduction / developmental toxicity screening test (OECD TG 421) with Direct red 239, was used for DNEL derivation.

  

Worker DNELs

 

Long-term –inhalation, systemic effects(based on repeated dose oral toxicity study with read across substance in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

2

 

 

 

0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Modified dose-descriptor

(1000 / 2 / 0.38) x (6.7/10) =  882 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

5

Default assessment factor for worker

Exposure duration

6

Extrapolation from subacute to chronic

Dose response

1

 

Quality of database

2

Read across

DNEL

Value

 

 882 / (1 x 5 x 6 x 1 x 2) = 882 / 60 = 15 mg/m3

 

 

Long-term – dermal, systemic effects(based on repeated dose oral toxicity study with read across substance in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

1

As both oral and dermal absorption are expected to be low adefault factor of 1 for oral-to-dermal extrapolation was used.

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor for worker

Exposure duration

6

Extrapolation from subacute to chronic

Dose response

1

 

Quality of database

2

Read across

DNEL

Value

 

1000 / (4 x 5 x 6 x 1 x 2) =1000 / 240 = 4.2 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
480
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
480
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Kinetics (absorption for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach was taken forward to DNEL derivation. For dermal absorption, based on the physical-chemical properties of the substance (molecular weight > 500 g/mol [1061 g/mol], log Kow < -1 [-4.2 at 23C], water solubility > 10000 mg/L [218 g/L}) low uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with Direct Red 239. Based on the above physical-chemical properties, oral absorption is also expected to be low. The absence of systemic effects at the high doses tested in the available oral toxicity studies with Direct Red 239 supports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation.

 

Acute toxicity

Direct Red 239 does not have to be classified for acute toxicity and therefore derivation of a DNELacuteis not necessary.

 

Repeated dose toxicity

A subacute oral toxicity study is available for the read across substance Analogue substance 1. In this study male and female rats received the substance by oral gavage at 1000 mg/kg bw/day on 5 days per week over a 30-day period.The treatment period was followed by a 2-wk recovery period.No treatment-related reactions were observed with respect to clinical symptoms, mortality, food consumption, body weight, clinical laboratory investigations and pathology. Furthermore, eye examination did not reveal any ocular changes and no loss of hearing ability was observed. The NOAEL from this study was 1000 mg/kg bw/day. This NOAEL is supported by the absence of adverse effects at 1000 mg/kg bw/day, the highest dose tested, in an oral reproduction/developmental toxicity screening study with Direct Red 239. Hence, a NOAEL of 1000 mg/kg bw/day for systemic effects was used as starting point for the DNEL derivation.

 

Mutagenicity

Direct Red 329 was not mutagenic in the Ames test. No chromosome aberration or gene mutation test in mammalian cells is available for Direct red 239. However, for a structural analogue of Direct Red 239 (Analogue substance 1) a gene mutation test in mouse lymphoma L5178Y cells is available. This gene mutation test also covers chromosome aberrations because during evaluation small and large colonies were distinguished. Under the conditions of this gene mutation test with the structural analogue, the test substance was non-mutagenic and non-clastogenic.

 

Reproduction toxicity

No adverse effects on parents or offspring were observed in areproduction/developmental toxicity screening test (OECD 421) inwhich rats received Direct Red 239by oral gavage at 0, 100, 300 or 1000 mg/kg bw/day. Thus, the NOAEL for reproductive toxicity was 1000 mg/kg bw/day. As this NOAEL is the same as that for repeated dose toxicity (derived from the subacute oral toxicity study with Analogue substance 1), no specific DNEL has to be derived for developmental and reproductive toxicity.

 

DNEL derivation

Short-term toxicity (systemic and local):

No DNEL needs to be derived for all routes of exposure.

 

Long-term toxicity:

Inhalation long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 2 for oral-to-inhalation extrapolation was used as proposed inChapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNELlong-termfor the inhalation route.

 

Inhalation long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

 

Dermal long-term exposure, systemic effects

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 1 for oral-to-dermal extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the repeated-dose oral toxicity study with the read across substance was used for derivation of the DNELlong-termfor the dermal route.

 

Dermal long-term exposure, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating or sensitizing to skin, no local effects are expected for repeated dermal exposure. 

 

Oral long-term exposure, systemic effects

The NOAEL of 1000 mg/kg bw/day for systemic toxicity obtained in the repeated dose oral toxicity study with the read across substance, which was supported by the results of the reproduction / developmental toxicity screening test (OECD TG 421) with Direct red 239, was used for DNEL derivation.

General population DNELs

 

Long-term – oral, systemic effects (based on repeated dose oral toxicity study with read across substance in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor for general population

Exposure duration

6

Extrapolation from subacute to chronic

Dose response

1

 

Quality of database

2

Read across

DNEL

Value

 

1000 / (4 x 10 x 6 x 1 x 2) =1000 / 480 = 2.1 mg/kg bw/day

 

 

Long-term – inhalation, systemic effects (based on repeated dose oral toxicity study with read across substance in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

2

 

 

 

1.15 m3/kg bw

 

 

Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Modified dose-descriptor

(1000 / 2) x (1/1.15) = 435 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

10

Default assessment factor for general population

Exposure duration

6

Extrapolation from subacute to chronic

Dose response

1

 

Quality of database

2

Read across

DNEL

Value

 

435 / (1 x 10 x 6 x 1 x 2) = 435 / 120 = 3.6 mg/m3

 

 

Long-term – dermal, systemic effects (based on repeated dose oral toxicity study with read across substance in rats)

 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

Highest dose tested. No effects observed.

Step 2) Modification of starting point

1

As both oral and dermal absorption are expected to be low adefault factor of 1 for oral-to-dermal extrapolation was used

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor for general population

Exposure duration

6

 

Extrapolation from subacute to chronic

Dose response

1

 

Quality of database

2

Read across

DNEL

Value

 

1000 / (4 x 10 x 6 x 1 x 2) =1000 / 480 = 2.1 mg/kg bw/day

 

 

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