Sodium O,O-diisobutyl dithiophosphate

Toxicological Summary

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:

NOAEC

Value:

200 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

246.84 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic inhalative effects was estimated via route-to-route-extrapolation and assessment factors were applied, all according to ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health and ECHA: How to prepare toxicological summaries in IUCLID and how to derive DNELs Practical Guide 14. 

A NOAEL of 200 mg/kg bw /day was derived based on a sub-acute oral Combined Repeated Dose Toxicity Study with the Reproductive/Developmental Screening Test in rats according to OECD Test Guideline 422. This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/0.38 m³/kg/day, the absorption rates (based on the ECHA Guidance R.8 the inhalative absorption is considered to be higher by a factor of 2 than the oral absorption as worst-case assumption) and the standard respiratory volume in humans/ worker respiratory volume (6.7 m³ (8 h) / 10 m³ (8 h)) and the correction factor between human and experimental exposure conditions of workers (5 working days vs. 7 days continuous exposure) of 1.4.

NOAEC corrected = 200 mg/kg bw/day * 1/0.38 m³/kg/day * 0.5 * (6.7 m³/10 m³) * 1.4 = 246.84 mg/m³

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL/NOAEC

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic. DNEL is based on a (oral) OECD 422 (28 d) (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default for remaining interspecies differences

AF for intraspecies differences:

5

Justification:

Worker

AF for the quality of the whole database:

1

Justification:

high quality of the database

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.93 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:

The DNEL for systemic dermal effects was estimated via route-to-route-extrapolation and assessment factors were applied, all according to ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health and ECHA: How to prepare toxicological summaries in IUCLID and how to derive DNELs Practical Guide 14.

A NOAEL of 200 mg/kg bw /day was derived based on a sub-acute oral Combined Repeated Dose Toxicity Study with the Reproductive/Developmental Screening Test in rats according to OECD Test Guideline 422. This value was converted into the corrected dermal NOAEL taking into account the absorption rates (based on the physicochemical properties and toxicological profile, an oral absorption rate of 100 %, and a dermal absorption rate of 100 % are assumed as worst-case assumptions) and the correction factor between human and experimental exposure conditions of workers (5 working days vs. 7 days continuous exposure) of 1.4.

NOAEL corrected = 200 mg/kg bw/day * 100/100 * 1.4 = 280 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL/NOAEC

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic. DNEL is based on a (oral) OECD 422 (28 d) (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

AF for interspecies differences (allometric scaling):

4

Justification:

Rat to human

AF for other interspecies differences:

2.5

Justification:

Default for remaining interspecies differences

AF for intraspecies differences:

5

Justification:

Worker

AF for the quality of the whole database:

1

Justification:

high quality of the database

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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

Consideration on the selected POD:

Two ‘Combined Repeated Dose Toxicity’ studies according to OECD Guideline 422 are available for IBP1-Na and EP1-Na. When comparing the NOAELs alone IBP1-Na appears to be a slightly more toxic than EP1-Na and thus represent a “worst case” source substance. However, the test conditions were not identical in these tests with regard to tester strain and vehicle used. In the OECD 422 study with IBP1-Na some slight liver effects (hypertrophy) and variations of some clinical chemistry parameter as well as slight reduction for the hind limb grip strength were noted at the highest test dose of 600 mg/kg bw/day. However, in the also available 90 day study according to OECD Guideline 408 those effects were not confirmed/seen after administration of IBP1-Na (at the same dose level), although the study implies a significant longer exposure and higher number of animals. Thus, the statistically significant “effects” noted in the OECD 422 study with the source substance are most likely accidental findings. Nevertheless, in order to follow a worst-case approach, the NOAEL of 200 mg/kg bw/d is selected for the derivation of the DNELs to be most protective.

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:

86.96 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic inhalative effects was estimated via route-to-route-extrapolation and assessment factors were applied, all according to ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health and ECHA: How to prepare toxicological summaries in IUCLID and how to derive DNELs Practical Guide 14. Details are given in the discussion. The DNEL for systemic inhalative effects was estimated via route-to-route-extrapolation and assessment factors were applied, all according to ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health and ECHA: How to prepare toxicological summaries in IUCLID and how to derive DNELs Practical Guide 14. 

A NOAEL of 200 mg/kg bw /day was derived based on a sub-acute oral Combined Repeated Dose Toxicity Study with the Reproductive/Developmental Screening Test in rats according to OECD Test Guideline 422. This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/1.15 m³/kg/day and the absorption rates (based on the ECHA Guidance R.8 the inhalative absorption is considered to be higher by a factor of 2 than the oral absorption as worst-case assumption).

NOAEC corrected = 200 mg/kg bw/day * 1/1.15 m³/kg/day * 0.5 = 86.96 mg/m³

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL/NOAEC

AF for differences in duration of exposure:

6

Justification:

subacute to chronic. DNEL is based on a (oral) OECD 422 (28 d) (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

high quality of the database

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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:

0.33 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:

The DNEL for systemic dermal effects was estimated via route-to-route-extrapolation and assessment factors were applied, all according to ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health and ECHA: How to prepare toxicological summaries in IUCLID and how to derive DNELs Practical Guide 14.
A NOAEL of 200 mg/kg bw /day was derived based on a sub-acute oral Combined Repeated Dose Toxicity Study with the Reproductive/Developmental Screening Test in rats according to OECD Test Guideline 422. No correction of this value is needed, as the absorption rates via dermal and oral routes are expected to be identical (100 % as worst-case for both routes).

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL/NOAEC

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic. DNEL is based on a (oral) OECD 422 (28 d) (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

AF for interspecies differences (allometric scaling):

4

Justification:

Rat to human

AF for other interspecies differences:

2.5

Justification:

Default for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

high quality of the database

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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:

0.33 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 was derived based on a sub-acute oral Combined Repeated Dose Toxicity Study with the Reproductive/Developmental Screening Test in rats according to OECD Test Guideline 422. No correction of this value is needed, as the oral absorption rates are considered to be identical between rats and humans. 

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL/NOAEC

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic. DNEL is based on a (oral) OECD 422 (28 d) (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

AF for interspecies differences (allometric scaling):

4

Justification:

Rat to human

AF for other interspecies differences:

2.5

Justification:

Default for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

General population

AF for the quality of the whole database:

1

Justification:

high quality of the database

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Consideration on the selected POD:

Two ‘Combined Repeated Dose Toxicity’ studies according to OECD Guideline 422 are available for IBP1-Na and EP1-Na. When comparing the NOAELs alone IBP1-Na appears to be a slightly more toxic than EP1-Na and thus represent a “worst case” source substance. However, the test conditions were not identical in these tests with regard to tester strain and vehicle used. In the OECD 422 study with IBP1-Na some slight liver effects (hypertrophy) and variations of some clinical chemistry parameter as well as slight reduction for the hind limb grip strength were noted at the highest test dose of 600 mg/kg bw/day. However, in the also available 90 day study according to OECD Guideline 408 those effects were not confirmed/seen after administration of IBP1-Na (at the same dose level), although the study implies a significant longer exposure and higher number of animals. Thus, the statistically significant “effects” noted in the OECD 422 study with the source substance are most likely accidental findings. Nevertheless, in order to follow a worst-case approach, the NOAEL of 200 mg/kg bw/d is selected for the derivation of the DNELs to be most protective.