Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.9 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
other: NOEL
DNEL value:
1 763.1 mg/m³
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
1
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
3
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.9 mg/m³
DNEL related information
DNEL extrapolated from long term DNEL

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:
13.8 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
other: NOEL
DNEL value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
4
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
3
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.8 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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

Reinblau RLW (CAS 41611-71-1)

DNELs (worker)

I. Introduction:

EU/MAK occupational exposure limit:

There is no occupational limit available

Classification (R-phrases) according to Regulation 67/548/EEC (DSD)

A classification is not justified (self classification)

II. DNEL systemic

Basis for delineation of the DNELs systemic:

A subacute oral gavage study rats with Reinblau RLW Tr. was evaluated for the derivation of DNELs of Reinblau RLW and Reinblau BLW.

Due to the close structural similarity of Reinblau RLW and Reinblau BLW (1,4-bis[(2,6-diethyl-4-methyl- phenyl)amino]anthraquinone (CAS-No. 32724-62-2) has an additional ethylgroup in the aromatic side chains in relation to 1,4-bis(2-ethyl-6-methy1anilino) anthraquinone (CAS-No. 41611-76-1), the similar physicochemical and toxicological properties a read-across between the 2 compounds is justified.

There is no long term study available using the inhalation or dermal route. Thus, as starting point for the calculation, the NOAEL of the subacute oral gavage study has to be taken into account.

No evidence of systemic exposure is observed also in the developmental toxicity study. Based on the results of the embryo-fetal developmental toxicity study in rats, it was concluded that the No-Observed-Adverse- Effect-Level (NOAEL) of Macrolex Blau 3R for maternal toxicity and embryo-fetal development was the limit dose of 1000 mg/kg/day. No evidence of toxicity to reproductive organs was observed in a subacute repeated dose study as no treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination. On the basis of this study no effects on fertility were expected (NOEL, rat: 1000 mg/kg bw/day). In conclusion, there is no hazard to reproductive toxicity and the the DNEL for systemic toxicity covers reproductive toxicity.

Study (rat study)

Repeated dose study

rat, male, female,

subacute oral gavage study for 28 days

rat: 0 (control), 8, 40, 200 or 1000 mg/kg bw/d – male, female via gavage

Effects, NOAEL

NOEL = 1000 mg/kg bw/d (male + female rats)

Effects:

There were no test substance-related toxic changes in clinical sign, body weight, food consumption, hematology, blood chemistry, urinalysis, organ weight, necropsy, or histopathology.

Reference

Sudo M (1988)

A 28-day repeated dose oral toxicity study of Reinblau RLW Tr. in rats

Mitsubishi Chemical Safety Institute Ltd., 1-30, Shiba 2-chome, Minato-ku, Tokyo, Japan

Long-term toxicity – systemic effects (worker)

Long-term inhalation route – systemic effects (worker) using extrapolation factors:

NOAEL (rat) from a subacute oral toxicity study: 1000 mg/kg bw

Correction of the starting point according ECHA Guidance Chapter R.8:

Corrected inhalatory NOAEC = Oral NOAEL (1000 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1

=> NOAEC worker = 1763.15 mg/m³

Factors to be applied                                                               Justification

AF for dose response relationship               1       There are no effects up to the limit dose

AF for differences in duration of exposure 6        Default value (ECHA)

AF for interspecies differences                    1        Allometric scaling: rat versus human the AF of 4 is already included in the route to route extrapolation

AF for intraspecies differences                    3        Based on the consideration by ECETOC Report TR110, 2010: furthermore, there are no toxic effects up to the limit dose

AF for other interspecies differences           1        The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw without mortality or relevant clinical findings. Therefore, It can be assumed that also other animals tolerate the test item without any harm

AF for quality of the whole database        1        There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP

AF for remaining differences                      1        In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a default factor. The view is supported by data generated by ERASM project (Barke et al 2010)

Overall factor                                           18

Worker DNEL long-term for inhalation exposure: 97.9 mg/m³

Short-term toxicity (inhalation) – systemic effects (worker)

No exceeding factor related to the DNEL for long term exposure is applied.

Long-term dermal route-systemic effects (worker) using extrapolation factors:

Factors to be applied                                                        Justification

AF for dose response relationship              1        There are no effects up to the limit dose

AF for differences in duration of exposure 6        Default value (ECHA)

AF for interspecies differences                   4        Allometric scaling: rat versus human

AF for intraspecies differences: worker      3        Based on the consideration by ECETOC Report TR110, 2010: furthermore, there are no toxic effects up to the limit dose

AF for other interspecies differences        1        The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw without mortality or relevant clinical findings. Therefore It can be assumed that also other animals tolerate the test item without any harm

AF for quality of the whole database        1        There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP

AF for remaining differences                     1        In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a default factor. The view is supported by data generated by ERASM project (Barke et al 2010)

Overall factor                                          72

Worker DNEL long-term for route-systemic: 13.8 mg/kg bw/day

Short-term toxicity (dermal) – systemic effects (worker)

No exceeding factor related to the DNEL for long term exposure is applied.

Therefore:

Worker DNEL short-term for inhalation exposure:        97.9 mg/m³

Worker DNEL short-term for dermal exposure:           13.8 mg/kg bw/day

General dust limit:

For insoluble particles, the general threshold value for dust has to be taken into account:

For general dust in Germany the current binding national Occupational Exposure Limit is 10 mg/m³ for inhalable and 3 mg/m³ for respirable dust (TRGS900; http://www.baua.de/cae/servlet/contentblob/666764/publicationFile/55580/TRGS-900.doc).

For the respirable and inhalable fraction of Reinblau RLW+BLW the general dust limit has to be considered.

III. DNEL local

Basis for delineation of the DNELs local (long and short term toxicity):

Irritation/corrosion

In rabbits, Reinblau RLW and Reinblau BLW were not irritating to the skin, and not irritating to the eyes

Sensitization

Reinblau RLW was not sensitising in a LLNA.

A classification is therefore not necessary

Result:

For local effects no DNEL can be set (No hazard identified).

IV: Conclusion (systemic and local effects):

Route of exposure        DNEL; local effect        DNEL; systemic effect

Oral (long term)                      -                                           -

Oral (short term)                    -                                           -

Dermal (long term)        No hazard identified             13.8 mg/kg bw/day

Dermal (short term)       No hazard identified             13.8 mg/kg

Inhalation (long term) No hazard identified 97.9 mg/m³

Inhalation (short term) No hazard identified 97.9 mg/m³

Inhalation (general dust limit) 10 mg/m³                             -

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
28.98
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
DNEL value:
869.56 mg/m³
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
1
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
5
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
28.98 mg/m³
Route of original study:
Oral
DNEL related information
DNEL extrapolated from long term DNEL

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:
8.33 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
4
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
5
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

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:
8.33 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
see 'Discussion'
AF for differences in duration of exposure:
6
Justification:
see 'Discussion'
AF for interspecies differences (allometric scaling):
4
Justification:
see 'Discussion'
AF for other interspecies differences:
1
Justification:
see 'Discussion'
AF for intraspecies differences:
5
Justification:
see 'Discussion'
AF for the quality of the whole database:
1
Justification:
see 'Discussion'
AF for remaining uncertainties:
1
Justification:
see 'Discussion'
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL extrapolated from long term DNEL
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'
Justification:
see 'Discussion'

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Reinblau RLW (CAS 41611-71-1)

DNELs (general population)

I. Introduction:

EU/MAK occupational exposure limit:

There is no occupational limit available

Classification (R-phrases) according to Regulation 67/548/EEC (DSD)

A classification is not justified (self classification)

II. DNEL systemic

Basis for delineation of the DNELs systemic:

A subacute oral gavage study rats with Reinblau RLW Tr. was evaluated for the derivation of DNELs of Reinblau RLW and Reinblau BLW.

Due to the close structural similarity of Reinblau RLW and Reinblau BLW (1,4-bis[(2,6-diethyl-4-methyl- phenyl)amino]anthraquinone (CAS-No. 32724-62-2) has an additional ethylgroup in the aromatic side chains in relation to 1,4-bis(2-ethyl-6-methy1anilino) anthraquinone (CAS-No. 41611-76-1), the similar physicochemical and toxicological properties a read-across between the 2 compounds is justified.

There is no long term study available using the inhalation or dermal route. Thus, as starting point for the calculation, the NOAEL of the subacute oral gavage study has to be taken into account.

No evidence of systemic exposure is observed also in the developmental toxicity study. Based on the results of the embryo-fetal developmental toxicity study in rats, it was concluded that the No-Observed-Adverse- Effect-Level (NOAEL) of Macrolex Blau 3R for maternal toxicity and embryo-fetal development was the limit dose of 1000 mg/kg/day. No e

vidence of toxicity to reproductive organs was observed in a subacute repeated dose study as no treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination. On the basis of this study no effects on fertility were expected (NOEL, rat: 1000 mg/kg bw/day). In conclusion, there is no hazard to reproductive toxicity and the the DNEL for systemic toxicity covers reproductive toxicity.

Study (rat study)

Repeated dose study

rat, male, female,

subacute oral gavage study for 28 days

rat: 0 (control), 8, 40, 200 or 1000 mg/kg bw/d – male, female

via gavage

Effects, NOAEL

NOEL = 1000 mg/kg bw/d (male + female rats)

Effects:

There were no test substance-related toxic changes in clinical sign, body weight, food consumption, hematology, blood chemistry, urinalysis, organ weight, necropsy, or histopathology.

Reference

Sudo M (1988)

A 28-day repeated dose oral toxicity study of Reinblau RLW Tr. in rats

Mitsubishi Chemical Safety Institute Ltd., 1-30, Shiba 2-chome, Minato-ku, Tokyo, Japan

Long-term toxicity – systemic effects (general population)

Long-term inhalation route – systemic effects (general population) using extrapolation factors:

NOAEL(rat) from a subacute oral toxicity study: 1000 mg/kg bw/day

Correction of the starting point according ECHA Guidance Chapter R.8:

Corrected inhalatory NOEC = Oral NOAEL (1000 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOAEC general population = 869.56 mg/m³

Factors to be applied                                                                      Justification

AF for dose response relationship                     1       There are no effects up to the limit dose

AF for differences in duration of exposure 6        Default value (ECHA)

AF for interspecies differences                      1        Allometeric scaling: rat versus human the AF of 4 is already included in the route to route extrapolation

AF for intraspecies differences                          5        Based on the consideration by ECETOC Report TR110, 2010: furthermore, there are no toxic effects up to the limit dose

AF for other interspecies differences               1        The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw without mortality or relevant clinical findings. Therefore, It can be assumed that also other animals tolerate the test item without any harm

AF for quality of the whole database               1        There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP

AF for remaining differences                             1        In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a default factor. The view is supported by data generated by ERASM project (Barke et al 2010

Overall factor                                                 30

General population DNEL long-term for inhalation exposure 28.98 mg/m³

Short-term toxicity (inhalation) – systemic effects (general population)

No exceeding factor related to the DNEL for long term exposure is applied.

Long-term oral and dermal route-systemic effects (general population) using extrapolation factors:

Factors to be applied                                                                      Justification

AF for dose response relationship              1        There are no effects up to the limit dose

AF for differences in duration of exposure 6       Default value (ECHA)

AF for interspecies differences                   4        Allometric scaling: rat versus human

AF for intraspecies differences                   5        Based on the consideration by ECETOC Report TR110, 2010: furthermore, there are no toxic effects up to the limit dose

AF for other interspecies differences        1        The rats tolerated the dosing up to and including the limit dose of 1000 mg/kg bw without mortality or relevant clinical findings. Therefore It can be assumed that also other animals tolerate the test item without any harm

AF for quality of the whole database        1        There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP

AF for remaining differences                      1        In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a default factor. The view is supported by data generated by ERASM project (Barke et al 2010

Overall factor                                           120

General population DNEL long term for dermal route - systemic 8.33 mg/kg bw/day

Short-term toxicity (dermal) – systemic effects (general population)

No exceeding factor related to the DNEL for long term exposure is applied.

Therefore:

General population DNEL short-term for inhalation exposure: 28.98 mg/m³

General population DNEL short-term for dermal exposure: 8.33 mg/kg bw/day

General dust limit:

The only critical exposure pathway to humans is the inhalation of the dust of the compound. Therefore it is only necessary to consider this way of exposure as a threshold mode of action for the general population. However, consumers are not exposed via inhalation as the substance is bound physically in the matrix of an article. Therefore, no relevant exposure via inhalation is expected for consumers.

2.) Reproductive Toxicity – systemic effects (general population)

There was no fertility study with 1,4-bis[(2-ethyl-6-methylphenyl)amino]anthraquinone available. No effects on reproductive organs were observed in a 28 day study in rats. The pathologic evaluation consisted of organ weight, gross and microscopic examination of reproductive organs, incl. tetes and ovaries. No treatment-related changes were observed for any reproductive organ investigated during macroscopic and microscopic examination of all major organs (NOAEL, rat: 1000 mg/kg bw/day; males and females).

On the basis of this study no effects on fertility were expected (NOEL, rat: 1000 mg/kg bw/day).

NOEL= 1000 mg/kg bw

As the NOEL for reproductive toxicity (1000 mg/kg bw/day) is identical as the NOEL for repeated dose toxicity (1000 mg/kg bw/day), the derivation of a separate DNEL for reproductive toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

For developmental/teratogenicity no NOAEL is available – a study according OECD 414 will be conducted.

III. DNEL local

Basis for delineation of the DNELs local (long and short term toxicity):

Irritation/corrosion

In rabbits, Reinblau RLW and Reinblau BLW were not irritating to the skin, and not irritating to the eyes

Sensitization

Reinblau RLW was not sensitising in a LLNA.

A classification is therefore not necessary.

Result:

For local effects no DNEL can be set (No hazard identified).

IV: Conclusion (systemic and local effects):

Route of exposure DNEL;        local effect DNEL;              systemic effect

Oral (long term)                      No hazard identified        8.33 mg/kg bw/day

Oral (short term)                      No hazard identified        8.33 mg/kg

Dermal (long term)                   No hazard identified        8.33 mg/kg bw/day

Dermal (short term)                  No hazard identified        8.33 mg/kg

Inhalation (long term)               No hazard identified       28.98 mg/m³

Inhalation (short term)               No hazard identified       28.98 mg/m³