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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.98 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
18
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:
0.14 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Toxicokinetics (absorption, metabolism, distribution and elimination)

No data on toxicokinetics are available. Therefore for the DNEL derivation the default values for absorption as reported in the REACH guidance will be used.

 

Acute toxicity

Ethylviolet acetate is classified for acute oral toxicity (Xn, R22). However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure (peaks; in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Practically relevant peak exposure therefore does not occur for ethylviolet acetate and as ethylviolet acetate does not have to be classified based on the acute inhalation and dermal toxicity data, no acute DNEL is needed.

 

Irritation

Ethylviolet acetate is classified as corrosive (C, R34). The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin and eye corrosion.

 

Sensitisation

Ethylviolet acetate is classified as sensitising to skin (Xi, R43). It is not possible to derive a DNEL for skin sensitisation. Whilst there is an EC3 value derived from a LLNA in mice this information alone is not enough to allow derivation of a DNEL. Therefore a qualitative approach will be followed.

 

Long-term toxicity

Ethylviolet acetate was administered daily by gavage over a period of 4 weeks to five male and five female Wistar rats at dose levels of 0, 10, 30 and 100 mg/kg bw/day at the beginning of the study. Because of severe findings in test group 3 (100 mg/kg bw/day) at study day 4, the dose was reduced to 60 mg/kg bw/d from study day 5 onwards. For the same reasons the dose was reduced for test group 2 (30 mg/kg bw/day) from study day 13 onwards to 20 mg/kg bw/day.

 

Regarding clinical examinations, signs of general systemic toxicity were observed at dose levels of 100 and 60 mg/kg bw/day as well as 30 and 20 mg/kg bw/day as mortalities ahead of schedule, poor general state and piloerection accompanied with body weight loss were observed. No signs of general systemic toxicity were seen in animals of test group 1 (10 mg/kg bw/day).

Salivation was seen after dosing all male and most female rats of test groups 1-3. From the temporary, short appearance immediately after dosing it is likely, that this finding was induced by a bad taste of the test substance or local affection of the upper digestive tract. This finding was not considered to be an adverse and toxicologically relevant effect.

 

Concerning clinical pathology no treatment-related, adverse effects were observed up to a dose of 30 and 20 mg/kg bw/day.

 

(Clinical) pathology examinations were not performed for animals of test group 3 (100 and 60 mg/kg bw/day) as all animals died or were sacrificed moribund before study termination.

 

Regarding pathology, the terminal body weight was decreased in males of test group 2 (30 and 20 mg/kg bw/day), resulting in secondary weight changes in the thymus and liver. No clear histopathological correlate was found for the liver weight increase in female rats of test group 2 (30 and 20 mg/kg bw/day). However, a treatment-related effect could not be completely ruled out.

The blue discoloration observed macroscopically in carcass, organs and gastrointestinal contents was attributed to the colour of the test substance. The discoloration disappeared from the tissues after histotechnical processing. Since no histopathological correlate, such as substance deposits or tissue damage was detected in any organ of animals of test groups 1 (10 mg/kg bw/day) and 2(30 and 20 mg/kg bw/day), the discoloration was regarded as non-adverse.

In the proximal duodenum, a minimal crypt cell hyperplasia occurred in males and females of test group 2 (30 and 20 mg/kg bw/day) with addition of villi edema starting from test group 1 (10 mg/kg bw/day). Both findings were considered to be treatment-related. While the crypt cell hyperplasia may reflect a slight irritant effect on the duodenal mucosa and was regarded as adverse, the presence of edema with lack of inflammatory reaction was considered to be non-adverse.

 

Under the conditions of the present study, the no observed adverse effect level (NOAEL) was 10 mg/kg bw/day for male and female Wistar rats.

 

Mutagenicity

EVA is assessed as being non-mutagenic. Based on this, no separate risk characterisation for mutagenicity is needed.

 

Reproduction toxicity

In aprenatal developmental toxicity study, the oral administration of Ethylviolet Acetate to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at doses as high as 12 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity. The high dose was selected based on a previous dose range-finding study in which pronounced maternal toxicity was observed at 20 mg/kg bw/d. In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is 12 mg/kg bw/d.

 

Long-term – dermal, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 10 mg/kg bw/day

Oral administration of ethylviolet acetate by gavage over a period of 4 weeks revealed severe signs of toxicity in male and female Wistar rats at dose levels of 100 and 60 mg/kg bw/day as well as 30 and 20 mg/kg bw/day.

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

3

Default assessment factor (ECETOC Technical Report No. 86, 2003)

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

10 / (4 x 3 x 6 x 1 x 1) =0.14 mg/kg bw/day

 

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived.

 

 

Long-term – inhalation, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 10 mg/kg bw/day

Oral administration of ethylviolet acetate by gavage over a period of 4 weeks revealed severe signs of toxicity in male and female Wistar rats at dose levels of 100 and 60 mg/kg bw/day as well as 30 and 20 mg/kg bw/day.

Step 2) Modification of starting point

: 0.38 m3/kg bw

 

 

 

x 6.7 m3/10 m3

 

 

An 8 h respiratory volume of 0.38 m3/kg bw for rats was used for conversion into a NAEC upon inhalation exposure

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest

 

An additional factor of 2 for oral-to-inhalation extrapolation is not considered necessary. Modification of the starting point for respiratory volume and activity-driven differences is considered to be sufficient.

Modified dose-descriptor

10 x 6.7 / (0.38 x 10) = 17.6 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

3

Default assessment factor (ECETOC Technical Report No. 86, 2003)

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

17.6 / (1 x 3 x 6 x 1 x 1) =0.98mg/m3

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived.

Remark regarding Quality of database assessment factor

 

In the REACH Guidance on DNEL derivation the following is mentioned on Quality of database:

An assessment factor on the quality of the whole database should, if justified, be applied to compensate for the potential remaining uncertainties in the derived DNEL.

Firstly, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database).

To account for deficiencies in the available data set and in identifying its magnitude, the assessor should consider both the data lacking and the data available. When there are deficiencies in the toxicity studies considered crucial to provide useful information for establishing the starting point, extra caution should be taken to address this scientific uncertainty in deriving the DNEL. Further, in order to account for data gaps and deficiencies in the available data set and in identifying its magnitude, the assessor should consider the nature of the effect occurring in particular organ systems, endpoints as well as at different life stages.

 

Even though the tonnage driven data requirements for ethylviolet acetate are not met, i.e. there is no data for subchronic repeated dose toxicity, an additional assessment factor for Quality of database is currently not applied. The basis for this decision is that the substance is classified for acute oral toxicity, skin irritation, serious damage to eyes and skin sensitisation which will result in very strict RMMs. Furthermore, the DNELs based on the sub acute repeated dose toxicity study are already very low and it is not expected that the results of a sub chronic repeated dose toxicity study or reproduction toxicity studies will lead to even lower DNELs.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.29 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
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:
0.083 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
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:
0.083 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Long-term – dermal, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 10 mg/kg bw/day

Oral administration of ethylviolet acetate by gavage over a period of 4 weeks revealed severe signs of toxicity in male and female Wistar rats at dose levels of 100 and 60 mg/kg bw/day as well as 30 and 20 mg/kg bw/day.

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

5

Default assessment factor (ECETOC Technical Report No. 86, 2003)

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

10 / (4 x 5 x 6 x 1 x 1) =0.083 mg/kg bw/day

 

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived.

 

Long-term – inhalation, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 10 mg/kg bw/day

Oral administration of ethylviolet acetate by gavage over a period of 4 weeks revealed severe signs of toxicity in male and female Wistar rats at dose levels of 100 and 60 mg/kg bw/day as well as 30 and 20 mg/kg bw/day.

Step 2) Modification of starting point

: 1.15

 

A 24 h respiratory volume of 1.15 m3/kg bw for rats was used for conversion into a NAEC upon inhalation exposure

 

An additional factor of 2 for oral-to-inhalation extrapolation is not considered necessary. Modification of the starting point for respiratory volume is considered to be sufficient.

Modified dose-descriptor

10 / 1.15 = 8.7 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 (ECETOC Technical Report No. 86, 2003)

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

8.7 / (1 x 5 x 6 x 1 x 1) =0.29mg/m3

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived.

 

Long-term – oral, systemic effects (based on sub-acute oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 10 mg/kg bw/day

Oral administration of ethylviolet acetate by gavage over a period of 4 weeks revealed severe signs of toxicity in male and female Wistar rats at dose levels of 100 and 60 mg/kg bw/day as well as 30 and 20 mg/kg bw/day.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

5

Default assessment factor (ECETOC Technical Report No. 86, 2003)

Exposure duration

6

Extrapolation to chronic exposure based on a sub-acute toxicity study

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

10 / (4 x 5 x 6 x 1 x 1) =0.083mg/kg bw/day

Remark regarding Quality of database assessment factor

 

In the REACH Guidance on DNEL derivation the following is mentioned on Quality of database:

An assessment factor on the quality of the whole database should, if justified, be applied to compensate for the potential remaining uncertainties in the derived DNEL.

Firstly, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database).

To account for deficiencies in the available data set and in identifying its magnitude, the assessor should consider both the data lacking and the data available. When there are deficiencies in the toxicity studies considered crucial to provide useful information for establishing the starting point, extra caution should be taken to address this scientific uncertainty in deriving the DNEL. Further, in order to account for data gaps and deficiencies in the available data set and in identifying its magnitude, the assessor should consider the nature of the effect occurring in particular organ systems, endpoints as well as at different life stages.

 

Even though the tonnage driven data requirements for ethylviolet acetate are not met, i.e. there is no data for subchronic repeated dose toxicity, an additional assessment factor for Quality of database is currently not applied. The basis for this decision is that the substance is classified for acute oral toxicity, skin irritation, serious damage to eyes and skin sensitisation which will result in very strict RMMs. Furthermore, the DNELs based on the sub acute repeated dose toxicity study are already very low and it is not expected that the results of a sub chronic repeated dose toxicity study or reproduction toxicity studies will lead to even lower DNELs.