Diphenyl methylphosphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.99 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):

375

Dose descriptor starting point:

LOAEC

Value:

318 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

1 121 mg/m³

Explanation for the modification of the dose descriptor starting point:

LOAEL of 318 mg/kg bw is established for oral route of exposure for DPP based on the experimental data of oral repeated dose toxicity studies in rats conducted with the read-across substances.

AF for dose response relationship:

3

Justification:

extrapolation of LOAEL to NAEL

AF for differences in duration of exposure:

2

Justification:

sub-chronic studies were used

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default AF for other interspecies differences, i.e. in toxicodynamics

AF for intraspecies differences:

5

Justification:

default for workers

AF for the quality of the whole database:

5

Justification:

due to read-across (4 of 5 category members are phosphates while the target chemical is phosphonate)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties are identified

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:

0.21 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):

1 500

Dose descriptor starting point:

LOAEL

Value:

318 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

318 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

LOAEL of 318 mg/kg bw is predicted for oral route of exposure based on the experimental data of oral repeated dose toxicity studies in rats conducted with the read-across substances.

AF for dose response relationship:

3

Justification:

extrapolation of LOAEL to NAEL

AF for differences in duration of exposure:

2

Justification:

sub-chronic studies were used

AF for interspecies differences (allometric scaling):

4

Justification:

default AF in case of interspecies differences

AF for other interspecies differences:

2.5

Justification:

default AF for other interspecies differences, i.e. in toxicodynamics

AF for intraspecies differences:

5

Justification:

default AF for workers

AF for the quality of the whole database:

5

Justification:

due to read-across (4 of 5 category members are phosphates while the target chemical is phosphonate)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

250

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:

Not applicable. Dermal acute toxicity study is used.

AF for dose response relationship:

1

Justification:

clear dose response.

AF for interspecies differences (allometric scaling):

4

Justification:

default AF in case of interspecies differences

AF for other interspecies differences:

2.5

Justification:

default AF for other interspecies differences, i.e. in toxicodynamics

AF for intraspecies differences:

5

Justification:

default AF for workers

AF for the quality of the whole database:

1

Justification:

Study conducted with the target substance.

AF for remaining uncertainties:

5

Justification:

An additional AF due to the use of acute data.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Available dose descriptors:

For Diphenyl Methyl phosphonate (DPP), the following dose descriptors are available:

Long-term exposure – systemic effects (inhalation DNEL)

There are no long-term inhalation studies with the target substance available. The inhalation DNEL can be derived from the oral LOAEL of 318 mg/kg bw predicted by read-across (OECDQSAR Toolbox, v.2.3) by route-to-route extrapolation.

Acute/short-term exposure – systemic effects (inhalation DNEL):

DPP is not expected to bear a significant hazard by inhalation due to its very low vapour pressure (0.0089 Pa at 25 °C). Moreover, the substance is solid at room temperature. Therefore no further testing is needed for inhalation route of exposure and no DNEL is required.

Long-term exposure – local effects (inhalation DNEL)

No long-term inhalation DNEL for local effects is needed since the substance is not irritating or sensitizing to respiratory system. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

Acute/short-term exposure – local effects (inhalation DNEL):

The substance does not bear a significant airborne hazard (and is not irritating or sensitizing to respiratory system). The long-term inhalation DNEL for systemic effects covers sufficiently local effects. Therefore no further testing is needed for inhalation route of exposure and no DNEL is required.

Long-term exposure – systemic effects (dermal DNEL)

Long-term systemic DNEL for the dermal route has been derived from the oral LOAEL of 318 mg/kg bw predicted by read-across (OECD QSAR Toolbox, v.2.3).The starting point has been obtained by conversion of oral LOAEL into dermal LOAEL (route-to-route extrapolation).

Acute/short-term exposure – systemic effects (dermal DNEL):

There is an acute dermal study available for DPP (Bomhard, 1991, Report No. T8039835). The substance was acutely toxic in contact with skin and should be classified as H311 (Cat3). Therefore, DNEL for acute systemic effects needs to be derived. A LD50 of 569 mg/kg bw for females and LD50 of 786 for males have been established in this study. There were no deaths, clinical signs or body weight impairment at 200 mg/kg bw, the lowest dose level tested and therefore this dose is considered to be a NOAEL for acute effects.

Long-term exposure – local effects (dermal DNEL)

No long-term dermal DNEL for local effects is needed since the substance is not irritating or sensitizing to skin. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

Acute/short-term exposure – local effects (dermal DNEL):

The substance is not irritating to the skin (Thyssen, 1979) and predicted as non-sensitizer to skin (OECD QSAR Toolbox, v.2.3). Therefore no DNEL for local effects is necessary. The short-term dermal DNEL for systemic effects covers sufficiently local effects.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No Observed Effect Level could be established from the relevant studies. The controlling of risk of any hazard relevant for these endpoints should be covered qualitatively introducing appropriate RMMs and OCs. Furthermore, local effects are covered sufficiently by the DNELs for systemic effects.

Modification of the starting point:

From all available data on DPP for the different human health endpoints it is clear, that the substances exert its effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance, reflecting the routes, the duration and the frequency of exposure.

Bioavailability (absorption)

There is no substance-specific experimental information on absorption by the oral, dermal and inhalation routes available. The absorption rates are assessed based on the physico-chemical properties and on the effects observed in treated animals in the available studies. Due to the molecular weight of 248.21 g/mol and logPow of 2.8 and the systemic effects observed in the acute oral study in rats, absorption of DPP from the gastro-intestinal tract is considered to be optimal and set to 100 % (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). The oral absorption is considered to be the same in animals and in humans (worst-case). A significant dermal absorption is expected for the substance (molecular weight of 248.21 g/mol, logPow of 2.8 and water solubility of 1560 mg/L point to a well absorption through the skin). According to the TGD, Part I, Appendix VI, 100 % of dermal absorption should be considered in this case. Dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of the target chemical in humans is available. Absorption by inhalation is considered to be negligible (low vapour pressure). Therefore, 50 % absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects.

The following formula was used: corrected dermal NOAEL = oral NOAEL x (ABSoral-rat/ABS dermal-human) where ABS is absorption.

Oral-to-inhalation extrapolation is performed to obtain long-term inhalation NOAEC for systemic effects. The following formula was used: corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 hours (0.38m³/kg bw).

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral predicted LOAEL, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral predicted LOAEL was used for the derivation of inhalation long-term DNEL;

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in both cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers.

Extrapolation of duration:

An assessment factor of 2 was applied for duration of exposure (sub-chronic-to-chronic) since the studies of category members which have been used for the read-across were all sub-chronic.

Quality of whole data base:

The assessment factors for uncertainties to the quality of the data base were used: 5 (due to read-across).

Issues related to dose response:

An assessment factor of 3 was applied to convert predicted LOAEL into NAEL (in case of long-term DNELs).

Remaining uncertainties:

An assessment factor of 5 was used to cover severity of effects (the substance is toxic in contact with skin) in case of derivation of acute dermal DNEL for systemic effects. A default AF of 1 was used in all other cases.

Calculation of DNELs:

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat LOEL of 318 mg/kg bw was converted into the inhalation LOAEC:

Inhalation LOAEC = oral LOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 318 mg/kg bw x (1/0.38 m³/kg/day) x (100 %/50 %) x (6.7/10) = 1121 mg/m³.sRV is standard respiratory volume of rats during 8 h exposure (=0.38 m³/kg bw); ABS - absorption; 6.7 m³ is the standard respiratory volume of workers (sRV human) during 8-hour working day and 10 m³ is worker Respiratory Volume (wRV) by light activity.

DNEL = 1121 mg/m³/(2.5 x 5 x 2 x 3 x 5) = 23.5 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 3 – dose response, 5 – quality of data base (read-across). The total AF amounts to 375.

Long-term exposure – systemic effects (dermal DNEL)

The predicted oral rat LOAEL of 318 mg/kg bw was converted into the dermal LOAEL:
Dermal LOAEL = oral LOAEL x (ABS oral-rat/ABS dermal-human) = 318 mg/kg bw x (100 %/100 %) = 318 mg/kg bw.

DNEL = 318 mg/kg bw/(4 x 2.5 x 5 x 2 x 3 x 5) = 0.21 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic studies), 3 – dose response, 5 – quality of data base (read-across). The total AF amounts to 1500.

Acute/short-term exposure – systemic effects (dermal DNEL):

The acute dermal rat NOAEL of 200 mg/kg bw is the starting point for DNEL derivation. No modification is necessary (dermal study and dermal route of exposure in humans).

DNEL = 200 mg/kg bw/ (4 x 2.5 x 5 x 1 x 1 x 1 x 5) = 0.8 mg/kg bw. Assessment factors are: 4 - interpsecies, 2.5 - remaining interspecies differences, 5 -intraspecies, 1 - study duration (acute study), 1- dose response (clear dose response), 1 - quality of data base (default), 5 - an additional assessment factor to cover uncertainties arisen from the use of acute NOAEL and for the severity of effects. The total AF amounts to 250

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:

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 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 DNELs are required for general population since there is no consumer use for DPP monomer.

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