Phosphorodithioic acid, O,O-di-dodecyl-esters, zinc salts, neutral and basic

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.11 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

308.55 mg/m³

Explanation for the modification of the dose descriptor starting point:

DNEL calculation was based on the results of a 28-day repeat dose toxicity study with the source substance in rats, resulting in a NOAEL (oral) = 125 mg/kg bw/day

Corrected Descriptor: The inhalation route was extrapolated by oral route information in the absence of data for this administration route. The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 hours exposure of workers, see Table R. 8-2 in Section R.8.4.2, REACH guidance, chapter R8). For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor derives from the inhalative volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity).

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h) * (days of exposure per week in rats / days of exposure per week worker)

= 125 mg/kg bw/day * (1/0.38 m³/kg) * 6.7/10 m³ * 7/5 = 308.55 m³/kg

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for the inhalation route

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACh Guidance

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.83 mg/kg bw/day

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL calculation was based on the results of a 28-day repeat dose toxicity study with the source substance in rats, resulting in a NOAEL (oral) = 125 mg/kg bw/day

Assume ABS rat – oral is 100%. The dermal route was extrapolated from oral route information in the absence of data for this administration route. Basic physicochemical properties of the source substance were taken into consideration when estimating dermal absorption, (e.g. low water solubility, molecular weight and log Kow), and < 10% dermal absorption was predicted (please refer to toxicokinetics, metabolism and distribution). As the physicochemical properties of the target substance are similar to that of the source substance this assumption is also valid for the target substance.

Corrected starting point for the dermal route for workers:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (days of exposure per week in rats / days of exposure per week worker)

= 125 mg/kg bw/day * (1/0.1) * 7/5 = 1750 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study.

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default value for workers

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

1. Relevant Toxicology Data, exposure pattern and route

The oral repeated dose toxicity of the source substance was evaluated in rats at levels up to 500 mg/kg/day according to OECD 407. Treatment-related deaths occurred at 500 mg/kg/day in both sexes. All of these animals had reddened adrenal and pituitary glands and yellow contents in the stomach. Microscopic examinations found edema and inflammation of the stomach in all 500 mg/kg/day group females and thickened mucosa in the nonglandular portion of the stomach in one male. In the 250 mg/kg/day group, one male also had edema and inflammation of the stomach. Clinical signs were toxicologically significant at 250 mg/kg/day and 500 mg/kg/day dose levels. The occurrence of soft stools, diarrhea, mucoid diarrhea, and a decrease in the general condition of the animals was greater than in the controls and lower dose. Significant decreases in body weight gain occurred only in the 500 mg/kg/day group males and females. Food consumption showed a slightly decrease in the 500 mg/kg/day groups although only the food consumption for females was significantly different from the controls. These findings are primary orsecondary effects dueto the local irritation via the experimental route of administration Treatment-related increases in mean absolute and relative adrenal gland weights occurred at the 250 and 500 mg/kg/day dose levels. However, no test article-related histopathological lesions were observed in the adrenal glands to account for the increases. Based on these findings, the No Adverse Effect Level NOAEL was determined to be 125 mg/kg/day. 

 

2. Mode of action

No non-threshold mode of action is associated with the source substance, in particular, the test substance has no genotoxic potential.

 

3. Correction of dose descriptor

NOAEL_oral is converted into a NOAEL_corrected in accordance to Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose [concentration] - response for human health, ECHA, May 2008.

Corrected starting point for the dermal route for workers:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (days of exposure per week in rats / days of exposure per week worker)

= 125 mg/kg bw/day * (1/0.1) * 7/5 = 1750 mg/kg bw/day

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h) * (days of exposure per week in rats / days of exposure per week worker)

= 125 mg/kg bw/day * (1/0.38 m³/kg) * 6.7/10 m³ * 7/5 = 308.55 m³/kg

 

4. Application of assessment factors

Dermal route: The following assessment factors were chosen: interspecies difference (4 for allometric scale, 2.5 for remaining difference), intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

Inhalation route: The following assessment factors were chosen: interspecies difference (2.5), intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.72 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

108.69 mg/m³

Explanation for the modification of the dose descriptor starting point:

DNEL calculation was based on the results of a 28-day repeat dose toxicity study with the source substance in rats, resulting in a NOAEL (oral) = 125 mg/kg bw/day

Corrected Descriptor: The inhalation route was extrapolated by oral route information in the absence of data for this administration route.

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/1.15 m³/kg bw/day) * (ABSoral-rat/ABSinh-human)

= 125 mg/kg bw/day * (1/1.15 m³/kg) = 108.69 m³/kg

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for the inhalation route

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.08 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

125 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL calculation was based on the results of a 28-day repeat dose toxicity study with the source substance in rats, resulting in a NOAEL (oral) = 125 mg/kg bw/day

Assume ABS rat – oral is 100%. The dermal route was extrapolated from oral route information in the absence of data for this administration route. Basic physicochemical properties of the source substance were taken into consideration when estimating dermal absorption, (e.g. low water solubility, molecular weight and log Kow), and < 10% dermal absorption was predicted (please refer to toxicokinetics, metabolism and distribution). As the physicochemical properties of the target substance are similar to that of the source substance this assumption is also valid for the target substance.

Corrected starting point for the dermal route for workers:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal)

= 125 mg/kg bw/day * (1/0.1) = 1250 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

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:

0.208 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation necessary.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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

1. Relevant Toxicology Data, exposure pattern and route

The oral repeated dose toxicity of the source substance was evaluated in rats at levels up to 500 mg/kg/day according to OECD 407. Treatment-related deaths occurred at 500 mg/kg/day in both sexes. All of these animals had reddened adrenal and pituitary glands and yellow contents in the stomach. Microscopic examinations found edema and inflammation of the stomach in all 500 mg/kg/day group females and thickened mucosa in the nonglandular portion of the stomach in one male. In the 250 mg/kg/day group, one male also had edema and inflammation of the stomach. Clinical signs were toxicologically significant at 250 mg/kg/day and 500 mg/kg/day dose levels. The occurrence of soft stools, diarrhea, mucoid diarrhea, and a decrease in the general condition of the animals was greater than in the controls and lower dose. Significant decreases in body weight gain occurred only in the 500 mg/kg/day group males and females. Food consumption showed a slightly decrease in the 500 mg/kg/day groups although only the food consumption for females was significantly different from the controls. These findings are primary orsecondary effects dueto the local irritation via the experimental route of administration Treatment-related increases in mean absolute and relative adrenal gland weights occurred at the 250 and 500 mg/kg/day dose levels. However, no test article-related histopathological lesions were observed in the adrenal glands to account for the increases. Based on these findings, the No Adverse Effect Level NOAEL was determined to be 125 mg/kg/day. 

 

2. Mode of action

No non-threshold mode of action is associated with this substance, in particular, the test substance has no genotoxic potential.

 

3. Correction of dose descriptor

NOAEL_oral is converted into a NOAEL_corrected in accordance to Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose [concentration] - response for human health, ECHA, May 2008.

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/1.15 m³/kg bw/day) * (ABSoral-rat/ABSinh-human)

= 125 mg/kg bw/day * (1/1.15 m³/kg) = 108.69 m³/kg

Corrected starting point for the dermal route for workers:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal)

= 125 mg/kg bw/day * (1/0.1) = 1250 mg/kg bw/day

 

4. Application of assessment factors

Dermal route: The following assessment factors were chosen: interspecies difference (4 for allometric scale, 2.5 for remaining difference), intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

Inhalation route: The following assessment factors were chosen: interspecies difference (2.5), intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).

Oral route: The following assessment factors were chosen: interspecies difference (4 for allometric scale, 2.5 for remaining difference), intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure duration), and quality of the data (1 for a reliable study).