Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.29 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:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
247 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a repeated dose toxicity study in rats was selected as representative starting dose based on: study duration; presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

 

Starting from an oral dose of 200 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 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.

 

NOAEC = ((200 mg/kg : 0.38 m3/kg) × (6.7 m3: 10 m3)) × (7 d/w : 5 d/w) × 0.5 = 247 mg/m3

AF for dose response relationship:
1
Justification:
NOAEL identified
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
already included in the modified dose starting point
AF for other interspecies differences:
2.5
Justification:
other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)
AF for intraspecies differences:
5
Justification:
intraspecies differences in the population of workers
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.933 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:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
280 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as representative starting dose based on: study duration; presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

Starting from an oral dose of 200 mg/kg (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).

Based on these considerations, the following formula is applied:

NOAEL = 200 mg/kg × (7 d/w : 5 d/w) = 280 mg/kg

AF for dose response relationship:
1
Justification:
NOAEL identified
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
differences between rats and humans
AF for other interspecies differences:
2.5
Justification:
other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)
AF for intraspecies differences:
5
Justification:
differences in population of workers
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

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 manufactured and used in non solid form and it has a negligible vapour pressure.

Despite a 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 247 mg/m3 derived from a NOAEL of 200 mg/kg bw/d, properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human (worker) breathing volume. Worst case for absorption rate was assumed, namely 50 % by oral route and 100 % by inhalation. Assessment factors were used to derive 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.

Systemic effects after acute exposure

No acute inhalation toxicity study was available. However, as the inhaled substance may likely enter the gastrointestinal tract via clearance mechanism and the substance is not classified for acute oral toxicity (CLP Regulation), no DNEL is derived.

Local effects after acute and long term exposure

Basic Orange 064 is considered as able to cause serious eye damage and skin irritation, due to the content of lactic acid as impurity. In a long-term toxicity study (OECD 421) by oral route, effects of irritation of the mucous membrane of stomach were reported.

Accordingly, an effect on mucous of respiratory and gastrointestinal tracts upon inhalation may not be excluded.

DERMAL ROUTE

Physicochemical properties, i.e. water solubility and partition coefficient, are indicative of a low potential for absorption by dermal route.

Systemic effects after long term exposure

A DNEL was calculated starting from a NOAEL obtained in a repeated dose oral toxicity study.

Assessment factors were used to derive the DNEL:

- interspecies differences 4, for rat to human

- 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.

Systemic effects after acute exposure

No acute dermal toxicity study was available. However, based on an acute study by oral route, no classification is required (CLP Regulation), thus no DNEL is derived.

Local effects after long term and acute exposure

No long term studies upon dermal exposure were available. However, Basic orange 064 is considered as able to cause serious eye damage and skin irritation, due to the content of lactic acid as impurity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 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:
NOAEL
Value:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a repeated dose toxicity study in rats was selected as representative starting dose based on: study duration; presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

 

Starting from an oral dose of 200 mg/kg (NOAEL), a corrected value is obtained, based on: 24 -h breathing volume of rat (1.15 m3/kg); days per week of exposure in experimental animals and humans are the same, i.e. 7 d/w.

No experimental data on absorption via oral and inhalation route was available. Worst case assumption for absorption was: 50 % orally and 100 % by inhalation.

 

NOAEC = ((200 mg/kg : 1.15 m3/kg) × 0.5 = 87 mg/m3

AF for dose response relationship:
1
Justification:
NOAEL identified
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
already included in the modified dose starting point
AF for other interspecies differences:
2.5
Justification:
other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)
AF for intraspecies differences:
10
Justification:
differences in general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.333 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:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEL obtained in a 28 -day study in rats was selected as representative starting dose basedon: study duration; presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

AF for dose response relationship:
1
Justification:
NOAEL identified
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
differences between rats and humans
AF for other interspecies differences:
2.5
Justification:
other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)
AF for intraspecies differences:
10
Justification:
differences in general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.333 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:
200 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 200 mg/kg bw/day, obtained in a 28 -day study in rats, was selected as the most representative starting dose based on: study duration; presence of adverse effects; type of observations and parameters taken into account to identify effect levels.

AF for dose response relationship:
1
Justification:
NOAEL identified
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
differences between rats and humans
AF for other interspecies differences:
2.5
Justification:
other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)
AF for intraspecies differences:
10
Justification:
differences in general population
AF for the quality of the whole database:
1
Justification:
good quality and reliability
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

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 manufactured and used in non solid form and it has a negligible vapour pressure.

Despite a 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 87 mg/m3derived from a NOAEL of 200 mg/kg bw/d, properly corrected for route-to-route extrapolation, namely accounting for rat breathing volume and human breathing volume. Worst case for absorption rate was assumed, namely 50 % by oral route and 100 % by inhalation. Assessment factors were used to derive 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.

Systemic effects after acute exposure

No acute inhalation toxicity study was available. However, as the inhaled substance may likely enter the gastrointestinal tract via clearance mechanism and the substance is not classified for acute oral toxicity (CLP Regulation), no DNEL is derived.

Local effects after acute and long term exposure

Basic Orange 064 is considered as able to cause serious eye damage and skin irritation, due to the content of lactic acid as impurity. In a long-term toxicity study (OECD 421) by oral route, effects of irritation of the mucous membrane of stomach were reported.

Accordingly, an effect on mucous of respiratory and gastrointestinal tracts upon inhalation may not be excluded.

DERMAL ROUTE

Physicochemical properties, i.e. water solubility and partition coefficient, are indicative of a low potential for absorption by dermal route.

Systemic effects after long term exposure

A DNEL was calculated starting from a NOAEL obtained in a repeated dose oral toxicity study.

Assessment factors were used to derive the DNEL:

- interspecies differences 4, for rat to human

- 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.

Systemic effects after acute exposure

No acute dermal toxicity study was available. However, based on an acute study by oral route, no classification is required (CLP Regulation), thus no DNEL is derived.

Local effects after long term and acute exposure

No long term studies upon dermal exposure were available. However, Basic orange 064 is considered as able to cause serious eye damage and skin irritation, due to the content of lactic acid as impurity.

ORAL ROUTE

Systemic effects after long term exposure

A DNEL was calculated starting from a NOAEL obtained in a repeated dose oral toxicity study.

Assessment factors were used to derive the DNEL:

- interspecies differences 4, for rat to human

- 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.

Systemic effects after acute exposure

Based on an acute study by oral route, no classification is required (CLP Regulation); thus, no DNEL is derived.