Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.4 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):

10

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

44 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used. For details, please refer to "additional information - worker".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

1

Justification:

There is no evidence for species differences in the general mode of action or kinetics.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

0.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose dermal toxicity study is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling.
There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, FeNaEDDHA displays low acute toxicity as evidenced by LD50 values of >2000 mg/kg bw determined in rats for both the oral and the dermal route, and a 4-h LC50 value of >4200 mg/m³ determined in rats for the inhalation route. Therefore, FeNaEDDHA is not subject to classification for acute toxicity according to Regulation (EC) No 1272/2008 (as amended for the ninth time in Regulation (EC) No 2016/1179), and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

 

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, FeNaEDDHA is not subject to classification for skin, eye and/or respiratory irritation and skin sensitisation and no worker DNEL for local effects following acute/short-term or long-term exposure is derived. This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-repsonse for human health".

 

Long-term exposure - systemic effects

Using a conservative approach, the NOELs determined in the repeated dose toxicity studies for the oral and dermal routes are also identified as NOAELs.

For the dermal route, the NO(A)EL of 100 mg/kg bw/day from the key subacute repeated dose dermal toxicity study (CIBA-GEIGY Limited, 1996b) is regarded as the relevant dose descriptor for systemic effects associated with long-term exposure to FeNaEDDHA. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted.

For the inhalation route, the NOAEL of 25 mg/kg bw/day from the recently performed extended OECD 422 key subchronic oral toxicity study (CRL, 2022) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to FeNaEDDHA.

 

Estimation of NOAEL:

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human)

with:

oral NO(A)EL: 25 mg/kg bw/day

sRV(rat): 0.38 m³/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

sRV(human)/wRV(human): 6.7 m³/10 m³ [ratio of human standard respiratory volume to worker respiratory volume]

Accordingly, the oral NO(A)EL of 25 mg/kg bw/day is transformed in an inhalation NO(A)EC of 44 mg/m³.

 

The following assessment factors are used for the derivation of worker DNELs for dermal or inhalation exposure to FeNaEDDHA:

Interspecies factor (rat to human): 4 [used for the dermal route only]

Intraspecies factor (worker): 5

Exposure duration factor: 6 (subacute to chronic) [for the dermal route], 2 (subchronic to chronic) [for the inhalation route]

Dose-response factor: 1

Quality of whole database factor: 1

 

The resulting worker DNELs are:

worker DNEL (dermal exposure) = 100 mg/kg bw/day / (4 × 5 × 6 × 1 × 1) = 100 mg/kg bw/day / 120 = 0.83 mg/kg bw/day, rounded to 0.8 mg/kg bw/day

worker DNEL (inhalation exposure) = 17.636 mg/m³ / (5 × 2 × 1 × 1) = 44 mg/m³ / 10 = 4.4 mg/m³

 

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health".

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 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):

20

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

22 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used. For details, please refer to "additional information - worker"

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

1

Justification:

There is no evidence for species differences in the general mode of action or kinetics.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

417 µg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

240

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

312 µg/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):

80

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose oral toxicity study is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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

Acute/short-term exposure - systemic effects

According to ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, FeNaEDDHA displays low acute toxicity as evidenced by LD50 values of >2000 mg/kg bw determined in rats for both the oral and the dermal route, and a 4-h LC50 value of >4200 mg/m³ determined in rats for the inhalation route. Therefore, FeNaEDDHA is not subject to classification for acute toxicity according to Regulation (EC) No 1272/2008 (as amended for the ninth time in Regulation (EC) No 2016/1179) , and consequently the derivation of general population DNELs for acute/short-term exposure - systemic effects is not required.

 

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, FeNaEDDHA is not subject to classification for skin, eye and/or respiratory irritation and skin sensitisation and no general population DNEL for local effects following acute/short-term or long-term exposure is derived.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-repsonse for human health".

 

Long-term exposure - systemic effects

Using a conservative approach, the NOELs determined in the repeated dose toxicity studies for the oral and dermal routes are also identified as NOAELs.

For the dermal route, the NO(A)EL of 100 mg/kg bw/day from the key subacute repeated dose dermal toxicity study (CIBA-GEIGY Limited, 1996b) is regarded as the relevant dose descriptor for systemic effects associated with long-term exposure to FeNaEDDHA. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted.

 

For the inhalation route, the NOAEL of 25 mg/kg bw/day from the recently performed extended OECD 422 key subchronic oral toxicity study (CRL, 2022) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to FeNaEDDHA. In order to derive a general population DNEL and under the assumption of a daily exposure period of 24 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human)

with:

oral NO(A)EL: 25 mg/kg bw/day

sRV(rat): 1.15 m³/kg bw/day [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

Accordingly, the oral NO(A)EL of 25 mg/kg bw/day is transformed in an inhalation NO(A)EC of 22 mg/m³.

 

For the oral route, the NO(A)EL of 25 mg/kg bw/day from the same study (CRL, 2022) is used as the dose descriptor for systemic effects after long-term exposure to FeNaEDDHA. 

 

Estimation of NOAEL:

The following assessment factors are used for the derivation of general population DNELs for oral, dermal or inhalation exposure to FeNaEDDHA:

Interspecies factor (rat to human): 4 [used for the oral and dermal routes only]

Intraspecies factor (general population): 10

Exposure duration factor: 6 (subacute to chronic) [for the dermal route], 2 (subchronic to chronic) [for the oral and inhalation routes]

Dose-response factor: 1

Quality of whole database factor: 1

 

The resulting general population DNELs are:

general population DNEL (dermal exposure) = 100 mg/kg bw/day / (4 × 10 × 6 × 1 × 1) = 100 mg/kg bw/day / 240 = 0.417 mg/kg bw/day, 416.7 µg/kg bw/day

general population DNEL (inhalation exposure) = 22 mg/m³ / (10 × 2 × 1 × 1) = 1.1 mg/m³

general population DNEL (oral exposure) = 25 mg/kg bw/day / (4 × 10 × 2 × 1 × 1) = 25 mg/kg bw/day / 80 = 312 µg/kg bw/day

 

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health".