Triisotridecyl phosphite

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):

25

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

110.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

  Inhalation - Long-Term Systemic Effects

 

Key Study: JRF (2019), 90-day oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 125 mg/kg/day

 

Corrected Inhalation NOAEL = Oral NOAEL x (1/sRV_rat)[a]x (ABS_oral-rat/ ABS_inhl-human)

 

= 125 mg/kg/day x (1 / 0.38m³kg^-18hr^-1) x (0.5)[b]

 

Corrected Inhalation NOAEL = 164.5 mg/m3 for 8hr

 

Corrected Inhalation NOAEL (workers) = 164.5 x (sRV_human/ wRV)[c]

 

= 164.5 x (6.7 / 10)

 

Corrected Inhalation NOAEL (workers) = 110.2 mg/m3 for 8hr

 

Assessment Factors:  Interspecies                2.5 (remaining differences)

                                   Intraspecies                5 (ECTOC recommendation)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response          1

                                   Quality of Database   1

 

Total Assessment Factor:                              25

 

DNEL_{Inhl - Long-Term Systemic}= 110.2 mg/m3 for 8hr ÷ 25

 

DNEL_{Inhl - Long-Term Systemic}= 4.4 mg/m3 for 8hr

 

[a]Standard respiratory volume (rat) = 0.38 m³/kg for 8 hours.

[b]Default assumption: inhalation absorption in humans is twice the oral absorption in rats.

[c]Standard respiratory volume (human) = 6.7 m³for 8 hours; worker respiratory volume = 10 m³for 8 hours

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.25 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):

100

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

625 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Extrapolated from oral study (assume 50% oral and 10% dermal absorption). Standard assessment factors used.

Dermal - Long-Term Systemic Effects

 

Key Study: JRF (2019), 90-day oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 125 mg/kg/day

 

Corrected Dermal NOAEL = Oral NOAEL x (ABS_oral-rat/ ABS_dermal-human)

 

= 125 mg/kg/day x (0.5/0.1)[1]

 

Corrected Dermal NOAEL = 625 mg/kg/day

 

Assessment Factors:  Interspecies               4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                5 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response          1

                                   Quality of Database   1

 

Total Assessment Factor:                              100

 

DNEL_{Dermal - Long-Term Systemic}= 625 mg/kg/day ÷ 100

 

DNEL_{Dermal - Long-Term Systemic}= 6.25 mg/kg/day

[1]Default assumption: dermal absorption in humans = 10%; oral absorption in rats = 50%.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

767.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor:

other: EC3, EC3 [%]*250 [μg/cm2/% ] = EC3 [μg/cm2]

Value:

23 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

10

AF for intraspecies differences:

3

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

767.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor starting point:

other: EC3, EC3 [%]*250 [μg/cm2/% ] = EC3 [μg/cm2]

Value:

23 mg/m³

AF for dose response relationship:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

10

AF for intraspecies differences:

3

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Acute DNELs

There were no signs of acute toxicity by either the oral, inhalation or dermal routes. As such, it is not necessary or appropriate to establish acute DNELs.

Dermal Local DNELs

TiTDP test positive in an LLNA skin sensitisation study. The EC3 concentration was 92.1%. The DNEL has derived as follows:

DNEL = EC3[%] * 250 [µg/cm²/%] / AF = 92.1% * 250 µg/cm²/% / 30 = 767.5 µg/cm²

Long-Term Systemic DNELs

The basis for the long-term systemic DNELs is the NOAEL of 125 mg/kg/day (top dose) from the JRF (2019) oral gavage 90 -day subchronic study in rats.The inhalation and dermal DNELs were extrapolated from the oral study using standard route-to-route extrapolations and assuming 50% oral and inhalation absorption and 10% dermal absorption.

Substance Class

TiTDP is one of several structurally related alkyl phosphites. Alkyl phosphites are characterized by a phosphorus atom connected to three alkyl ester groups (oxygen connected to an alkyl chain). The closest alkyl phosphite structural analog to TiTDP is triisodecyl phosphite (TDP). The alkyl groups on TDP are branched,C10, isomers and the alkyl groups on TiTDP are branched, C13, isomers. TDP as a data-rich member of this class of phosphites is an important source of analog or read-across data for TiTDP.

Relationship Between Alkyl Phosphites and Alkyl Alcohols

These alkyl phosphites are manufactured using a class of alkyl alcohols that have been well studied and previously accepted as a category (Long Chain Alcohols Category under the OECD SIDS program; Alkyl Alcohols C6 to C13 Category under the U. S. High Production Volume (HPV) program). The category assessment and associated use of read-across data for these alkyl alcohols is particularly relevant for the alkyl phosphites because these phosphites readily hydrolyze into the associated alcohol used in the manufacture of the phosphite – TDP to isodecanol (C10), TiTDP to isotridecanol (C13). Given this, it appears appropriate to consider both the category approach that was used to assess the alkyl alcohols under REACH as well as the data on the relevant alcohols as analogs to TITDP and the related phosphites.

Read-Across Justification

A matrix comparing TDP data, TiTDP data, and their associated alkyl alcohol data is provided in as separate report in Section 13. For toxicity endpoints where there are corresponding data between TDP and TiTDP – acute oral toxicity, skin irritation, eye irritation, skin sensitisation, repeat-dose toxicity, in vitro genetic toxicity, in vivo genetic toxicity – the two chemicals generally have similar results with the same resulting classifications. Likewise in hydrolysis testing, both TDP and TiTDP showed the ability to rapidly hydrolyse in simulated stomach acid. Given the similarities in toxicities and hydrolytic characteristics plus the established relationship between their corresponding alkyl alcohols, it is appropriate to treat these substances as chemical analogues.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.7 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):

50

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

287.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard adjustment assuming 50% absorption of human inhaled dose and 100% absorption of rat ingested dose. See full derivation below.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.125 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):

200

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

625 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Extrapolated from oral study assumes 50% oral and 10% dermal absorption.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

767.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor:

other: EC3,

Value:

23 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

10

Acute/short term exposure

Hazard assessment conclusion:

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.625 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):

200

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified