Iron tris(2-ethylhexanoate)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.9 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:

300 mg/kg bw/day

Modified dose descriptor starting point:

other: NAEC

Value:

367.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the inhalation route, therefore, the NOAEL resulted from an animal study after an oral administration of the substance for at least 28 days to rats, is used. Route-to-route extrapolation is therefore needed from the oral to the inhalation route. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test.

The highest dose administered to treatment animals was 300 mg/kg bw/day, which resulted to be non toxic neither for repeated expoure nor for reproductive/developmental parameters. Therefore, the NOAEL value is considered 300 mg/kg bw/day.

To calculate the DNEL it is necessary first to calculate the NAEC_{workers, inhalation} applying the following formula:

NAEC_{workers, inhalation}= NOAEL_{rat, oral}÷ 4 × 70 kg ÷ 10 m³× 1.4 × 0.5 = 300 mg/kg bw/day ÷ 4 × 70 kg ÷ 10 m³× 1.4 × 0.5 = 367.5 mg/m³

As the NOAEL value was particular to rats, it is necessary to apply an factor of 4 to consider inter-species differences; the standard body weight considered for workers is 70 kg, therefore, the NOAEL is multiplied by a factor of 70 kg. A worker is considered to be exposed to 10 m3 for 8 hours per day for 5 days out of 7, therefore, the NOAEL value is multiplied by 10 m3 and a factor of 1.4 to account for weekends.

Finally, absorption of a substance by the inhalation route is considered to be 100 % once it reaches the alveolar level, whereas absorption via the oral route is considered generically to be 50 %, therefore, the NOAEL value is multiplied by 0.5 to account for absorption differences.

The DNEL_workers was then calculated as follows:

DNEL_{workers, inhalation} = NAEC_{workers,inhalation}/Overall AF = 367.5 mg/m³ / 75 = 4.9 mg/m³

The overall assessment factors (AF) is calculated multiplying the AFs detailed below.

AF for dose response relationship:

1

Justification:

AF for dose response relationship is considered 1 as the source study uses a NOAEL

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (63-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences are already considered in the original formula (above), whereby the NOAEL was multiplied by a factor of 4 to allow for differences between rats and humans

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

5

Justification:

AF for intraspecies differences is considered 5 to allow for potential differences in the population of workers

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14 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:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

4 200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the dermal route, therefore, the NOAEL resulted from an animal study after an oral administration of the substance for at least 28 days to rats, is used. Route-to-route extrapolation is therefore needed from the oral to the dermal route. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test.

The highest dose administered to treatment animals was 300 mg/kg bw/day, which resulted to be non toxic neither for repeated expoure nor for reproductive/developmental parameters. Therefore, the NOAEL value is considered 300 mg/kg bw/day.

To calculate the DNEL it is necessary first to calculate the NOAEC_{workers, dermal} applying the following formula:

NOAEL_{workers, dermal}= NOAEL_{rat, oral} × 1.4 /0.1 = 4200 mg/kg bw

A worker is considered to be exposed to a substance for 5 days out of 7, therefore, the NOAEL value is multiplied by a factor of 1.4.

A default value of 100 % skin absorption is allocated to substances with a molar mass below 500 and a partition coefficient between log P_ow-1 and 4. In the case of iron tris(2 -ethylhexanoate) the molecular mass and/or partition coefficient values are outside the given range, therefore a skin absorption value of 10 % is allocated.

The DNEL_{workers, dermal} was then calculated as follows:

DNEL_{workers, dermal}= NOAEC_{workers,dermal}/Overall AF = 4200 mg/kg bw/ 300 = 14 mg/kg bw

The overall assessment factors (AF) is calculated multiplying the AFs detailed below.

AF for dose response relationship:

1

Justification:

AF for dose response relationship is considered 1 as the source study uses a NOAEL

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (63-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

4

Justification:

An AF value of 4 is provided for interspecies differences between the rat and human

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

5

Justification:

AF for intraspecies differences is considered 5 to allow for potential differences in the population of workers

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 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:

NOAEC

Value:

300 mg/m³

Modified dose descriptor starting point:

other: NAEC

Value:

112.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the inhalation route, therefore, the NOAEL resulted from an animal study after an oral administration of the substance for at least 28 days to rats, is used. Route-to-route extrapolation is therefore needed from the oral to the inhalation route. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test.

The highest dose administered to treatment animals was 300 mg/kg bw/day, which resulted to be non toxic neither for repeated expoure nor for reproductive/developmental parameters. Therefore, the NOAEL value is considered 300 mg/kg bw/day.

To calculate the DNEL it is necessary first to calculate the NAEC_{human, inhalation}applying the following formula:

NAEC_{human, inhalation}= NOAEL_{rat, oral}÷ 4 × 60 kg ÷ 20 m³× 0.5 = 300 mg/kg bw/day ÷ 4 × 60 kg ÷ 20 m³× 0.5 = 112.5 mg/m³

As the NOAEL value was particular to rats, it is necessary to apply an factor of 4 to consider inter-species differences; the standard body weight considered for the general population is 60 kg, therefore, the NOAEL is multiplied by a factor of 60 kg. A person is considered to be exposed to 20 m3 for 24 hours per day for 7 days a week, therefore, the NOAEL value is multiplied by 20 m3..

Finally, absorption of a substance by the inhalation route is considered to be 100 % once it reaches the alveolar level, whereas absorption via the oral route is considered generically to be 50 %, therefore, the NOAEL value is multiplied by 0.5 to account for absorption differences.

The DNEL_humans was then calculated as follows:

DNEL_{humans, inhalation}= NAEC_{humans,inhalation}/Overall AF = 112.5 mg/m³/ 150 = 0.75 mg/m³

The overall assessment factors (AF) is calculated multiplying the AFs detailed below.

AF for dose response relationship:

1

Justification:

AF for dose response relationship is considered 1 as the source study uses a NOAEL

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (63-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences are already considered in the original formula (above), whereby the NOAEL was multiplied by a factor of 4 to allow for differences between rats and humans

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences is considered 10 to allow for potential differences in the general population such as age, health, race

AF for the quality of the whole database:

1

Justification:

Good/standard quality data base

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 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:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

3 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the dermal route, therefore, the NOAEL resulted from an animal study after an oral administration of the substance for at least 28 days to rats, is used. Route-to-route extrapolation is therefore needed from the oral to the dermal route. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test.

The highest dose administered to treatment animals was 300 mg/kg bw/day, which resulted to be non toxic neither for repeated expoure nor for reproductive/developmental parameters. Therefore, the NOAEL value is considered 300 mg/kg bw/day.

To calculate the DNEL it is necessary first to calculate the NOAEC_{humans, dermal}applying the following formula:

NOAEL_{humans, dermal}= NOAEL_{rat, oral}/0.1 = 3000 mg/kg bw

A default value of 100 % skin absorption is allocated to substances with a molar mass below 500 and a partition coefficient between log P_ow-1 and 4. In the case of iron tris(2 -ethylhexanoate) the molecular mass and/or partition coefficient values are outside the given range, therefore a skin absorption value of 10 % is allocated.

The DNEL_{humans, dermal}was then calculated as follows:

DNEL_{humans, dermal}= NOAEC_{humans,dermal}/Overall AF = 3000 mg/kg bw/ 600 = 5 mg/kg bw

The overall assessment factors (AF) is calculated multiplying the AFs detailed below.

AF for dose response relationship:

1

Justification:

AF for dose response relationship is considered 1 as the source study uses a NOAEL

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (63-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

4

Justification:

An AF value of 4 is provided for interspecies differences between the rat and human

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences is considered 10 to allow for potential differences in the general population

AF for the quality of the whole database:

1

Justification:

Good/standard quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 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:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL value used resulted from an animal study whereby the substance was administered orally for at least 28 days to rats. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test.

The highest dose administered to treatment animals was 300 mg/kg bw/day, which resulted to be non toxic neither for repeated expoure nor for reproductive/developmental parameters. Therefore, the NOAEL value is considered 300 mg/kg bw/day.

The overall assessment factors (AF) is calculated multiplying the AFs detailed below.

AF for dose response relationship:

1

Justification:

AF for dose response relationship is considered 1 as the source study uses a NOAEL

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (63-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

4

Justification:

An AF value of 4 is provided for interspecies differences between the rat and human

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences is considered 10 to allow for potential differences in the general population

AF for the quality of the whole database:

1

Justification:

Good/standard quality database

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:

no hazard identified