Triphenylphosphine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEC

Value:

10 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The worker-DNEL long-term for inhalation route - systemic is derived from the NOAEC of 10 mg/m³, obtained in the sub-acute inhalation study in dogs (M&T Chemicals, 1983) in which TPP was administered as a xylene-based aerosol. The NOAECcorr is calculated as follows: NOAECcorr = 10 mg/m³*((6 h/d)/(8 h/d))*(6.7 m³ (8h)/10 m³ (8h)) = 5 mg/m³, with: 10 mg/m³: NOAEC, ((6 h/d)/(8 h/d)): correction factor for duration of exposure, (6.7 m³ (8h)/10 m³ (8h)): correction factor for light physical activity of workers.

AF for dose response relationship:

1

Justification:

The dose response was unremarkable (no additional factor needed).

AF for differences in duration of exposure:

2

Justification:

The most sensitive endpoint was observed in a sub-acute inhalation study. Of note, neurotoxic effects were already observed after 2 dosages in this study suggesting a non time dependend effect, in which TPP's toxicity doesn't increase gradually with exposure time. Therefore the AF was set at 2. The factor wasn't waived completely in order to account for remaining uncertainties since only 2 animals per dose were used in this study.

AF for interspecies differences (allometric scaling):

1

Justification:

The dose descriptor (NOAEC) was expressed as a concentration (ppm, mg/m³) and was thus scaled according to the allometric principle (no additional factor required).

AF for other interspecies differences:

1

Justification:

The insensitivity of the rat in a 12-day inhalation study, in which aerosol from molten TPP was administered (Waritz, 1975), suggests that the dog study is representing a worst case scenario. Therefore, no additional interspecies factors were considered.

AF for intraspecies differences:

5

Justification:

The default factor for worker was used.

AF for the quality of the whole database:

1

Justification:

Two sub-acute studies on different species using different vehicles revealed varying NOAECs. According to a conservative approach the lower NOAEC was used for DNEL derivation. No additional factor is needed.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is already conservative (no further assessment factor needed).

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:

0.07 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

14

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The worker-DNEL long-term for dermal route - systemic is derived from the NOAEL of 1 mg/kg bw/d, obtained in the sub-acute oral study in dogs (M&T Chemicals, 1983) in which TPP was administered in oil. The NOAEL didn't need to be corrected since there were no deviations in absorption rate (100%) and exposure conditions (5 days/per week) between the worker (default values) and the laboratory animal.

AF for dose response relationship:

1

Justification:

The dose response was unremarkable (no additional factor needed).

AF for differences in duration of exposure:

2

Justification:

The most sensitive endpoint was observed in a sub-acute oral study. Of note, neurotoxic effects were already observed after 2 dosages in this study suggesting a non time dependend effect, in which TPP's toxicity doesn't increase gradually with exposure time. Therefore the AF was set at 2. The factor wasn't waived completely in order to account for remaining uncertainties since only 2 animals per dose were used in this study.

AF for interspecies differences (allometric scaling):

1.4

Justification:

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

AF for other interspecies differences:

1

Justification:

The insensitivity of the rat towards neurotoxic effects in a 90-day oral study, in which a water based vehicle was used (BASF, 2002), suggests that the dog study is representing a worst case scenario. Therefore, no additional interspecies factors were considered.

AF for intraspecies differences:

5

Justification:

The default factor for worker was used.

AF for the quality of the whole database:

1

Justification:

No repeated-dose study for the dermal route was available. However, sub-acute oral and inhalation studies and a sub-chronic oral study on different species using different vehicles were available for route-to-route extrapolation. Similar DNELs were calculated from all three studies. No additional factor is needed.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is already conservative (no further assessment factor needed).

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)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Conclusions from existing experimental data for DNEL settings

a) Local effects after short term and long term exposure

A DNEL derivation of local effects after inhalation exposure is not required since TPP does not cause respiratory irritation. Only weak indications of respiratory irritation were documented in one single study (Waritz, 1975). The authors observed salivation, lacrimation, dyspnea and red ears as the only adverse effects during a sub-acute inhalation study on in which an aerosol of molten TPP of approx. 2400

mg/m³ was administered to 6 rats for 12 days and concluded TPP to cause slight respiratory irritation. In this publication, however, neither the incidence nor time dependence or reversibility of effects was given and no histological findings on the respiratory tract were reported although a histological examination was conducted. Moreover no such findings were reported in a sub-acute study on dogs in which an xylene-based TPP aerosol was tested (M&T Chemicals, 1975) up to 20 mg/m³. Therefore, TPP is not expected to cause respiratory irritation.

The risk arising from TPP's skin sensitising (Category 1B) and eye damaging (Category 1) potential can only be addressed qualitatively due to the lack of suitable quantitative data.

b) Systemic effects after chronic exposure

The most relevant sub-acute and sub-chronic data which need to be considered regarding DNEL derivation for systemic toxicity after long-term exposure to DMAC are summarized in the Table below.

Table: Toxicity data relevant for DNEL (systemic, long-term exposure) derivation

Application route	Study type (reference)	NOAEL/NOAEC
Inhalation	Sub-acute toxicity study in dogs (whole body exposure, 28d, xylene-based aerosol; M&T Chemicals, 1983)	10 mg/m³
Oral	Sub-chronic toxicity study in rats (gavage, water-based vehicle; BASF, 2002)	6 mg/kg bw/day
	Sub-acute toxicity study in dogs (gavage, oil-based vehicle; M&T Chemicals, 1983)	1 mg/kg bw/day

  

The conservative NOAEC of 10 mg/m³ determined in the sub-acute inhalation study in dogs (xylene-based aersosol) was much lower than the NOAEC of 2400 mg/m³ determined in the sub-acute inhalation study in rats (aerosol from molten substance). This lower value was selected as starting point for worker DNEL (inhalation, systemic, long-term) derivation. Since, it is expected that the dog study using a solvent-based vehicle represents the worst-case scenario, the default assessment factor for interspecies factor (remaining differences) of 2.5 was reduced to 1.

 

No experimental data on the dermal route were available as starting point for the derivation of a worker DNEL (dermal, systemic, long-term). Extrapolation of the dog sub-acute oral NOAEL of 1 mg/kg bw/d (M&T Chemicals, 1983) yielded a DNEL of 0.07 mg/kg bw/d applying a factor of 2 for exposure duration, 1.4 for allometric scaling from dog to human and a intraspecies factor of 5 for workers. The same DNEL was calculated when the dog sub-acute inhalation NOAEL of 10 mg/m³ (M&T Chemicals, 1983) was used as starting point considering the 6-h breathing volume of 0.1008 m³/kg bw for the dog and applying the above mentioned assessment factors. Equally, the rat sub-chronic NOAEL of 6 mg/kg bw/d (BASF, 2002) yields a comparable DNEL of 0.08 mg/kg bw/d considering a factor of 7/5 to account for differences in exposure days between rat and worker and applying a assessment factors of 2 for exposure duration, 4 for allometric scaling from rat to human, 2.5 for remaining interspecies differences and a intraspecies factor of 5 for workers. Thus, the selection of the sub-acute oral NOAEL of 1 mg/kg bw/d in the dog (M&T Chemicals, 1983) as starting point for worker DNEL (dermal, long-term) derivation is justified.

General Population - Hazard via inhalation route

Systemic 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

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:

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

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.01 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

28

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.7 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The general population-DNEL long-term for oral route - systemic is derived from the NOAEL of 1 mg/kg bw/d, obtained in the sub-acute oral study in dogs (M&T Chemicals, 1983) in which TPP was administered in oil. The NOAELcorr is calculated as follows: NOAELcorr = 1 mg/kg bw/d*((5 d/wk)/(7 d/wk)) = 0.7 mg/kg bw/d.

AF for dose response relationship:

1

Justification:

The dose response was unremarkable (no additional factor needed).

AF for differences in duration of exposure:

2

Justification:

The most sensitive endpoint was observed in a sub-acute oral study. Of note, neurotoxic effects were already observed after 2 dosages in this study suggesting a non time dependend effect, in which TPP's toxicity doesn't increase gradually with exposure time. Therefore the AF was set at 2. The factor wasn't waived completely in order to account for remaining uncertainties since only 2 animals per dose were used in this study.

AF for interspecies differences (allometric scaling):

1.4

Justification:

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

AF for other interspecies differences:

1

Justification:

The insensitivity of the rat towards neurotoxic effects in a 90-day oral study, in which a water based vehicle was used (BASF, 2002), suggests that the dog study is representing a worst case scenario. Therefore, no additional interspecies factors were considered.

AF for intraspecies differences:

10

Justification:

The default factor for general population was used.

AF for the quality of the whole database:

1

Justification:

Sub-acute and a sub-chronic oral studies on different species using different vehicles revealed comparable NOAELs. Similar DNELs were calculated from all three studies. No additional factor is needed.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is already conservative (no further assessment factor needed).

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 for the eyes

Local effects

Hazard assessment conclusion:

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

Additional information - General Population

No consumer uses were identified. The general population does not get in contact with the substance. Therefore, in accordance with the REACH legislation (regulation (EC) No 1907/2006, Annex I, 1.4.1), no DNEL has to be derived for the general population.