Reaction Products of Diphosphorus Pentaoxide with n-Alcohols, C8-10 (even), salted with Amines, C12-14, Tert-alkyl

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 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

Modified dose descriptor starting point:

other: NOEC

Value:

264.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

A NOAEL of 150 mg/kg bw /day from the 28-day study in rats (Wragg et al., 1996) was converted into the corrected inhalatory NOEC taking into account the standard daily respiratory volume of 0.38 m³ for rats, the standard respiratory volume in workers during 8 hours: 6.7 m³ under normal conditions and 10 m³ by light activity as well as the absorption rates (oral 100 %, inhalation 100 % (worst-case)).

AF for dose response relationship:

1

Justification:

default (three doses were tested)

AF for differences in duration of exposure:

6

Justification:

sub-acute study

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling should be applied in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans

AF for intraspecies differences:

5

Justification:

default for workers

AF for the quality of the whole database:

1

Justification:

default (GLP guideline study)

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:

1 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

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 150 mg/kg bw /day from the 28-day study in rats (Wragg et al., 1996) was converted into the corrected dermal NOAEL taking into account the rates for absorpion (oral 100 %, dermal 50 %).Thereby the corrected dermal NOAEL is: oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ABS dermal-human) = 300 mg/kg bw.

AF for dose response relationship:

1

Justification:

default (three doses were tested )

AF for differences in duration of exposure:

6

Justification:

sub-acute study

AF for interspecies differences (allometric scaling):

4

Justification:

default for rats in case of oral-to-dermal extrapolation

AF for other interspecies differences:

2.5

Justification:

default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans

AF for intraspecies differences:

5

Justification:

default for workers

AF for the quality of the whole database:

1

Justification:

default (GLP guideline study)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties are identified

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Available dose descriptors:

The substance Reaction Product of Diphosphorus Pentaoxide with Alcohols C8 -C10, salted with Amines, C12 -C14, Tert-alkyl is not acutely toxic by oral and dermal routes of exposure because LD50 values are 5000 and greater than 2000 mg/kg bw for oral and dermal routes of exposure, respectively (Mallory, 1993; Bonnette, 1995, Study No. 3263.85)). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance (0.000005 kPa at 25 °C ) (Tremain and Bartlett, 1995). The substance is non-volatile and therefore no risk of irritation or sensitisation of respiratory tract exists. Therefore, no DNELs for acute/short-term exposures for systemic effects for all routes of exposure need to be derived.

The substance is not irritating to skin in concentrations up to 50 % (Bonnette, 1995; Study No. 3263.116). The data from skin irritation test in rabbits with the diluted test material, in principle, allow to set a NOAEL for local effects. Therefore a DNEL for local effects (skin irritation) can be derived. Besides this, the substance is not sensitizing to skin (Douds, 1995). Thus, no specific DNEL for skin sensitization is needed.

For long-term exposures, DNELs are needed for systemic effects by inhalation and dermal routes. The NOAEL of 15o mg/kg bw established in the 28 -day study in rats (Wragg et al., 1996) is used as the starting point. The DNELs for inhalation and dermal routes can be derived by route-to-route extrapolation applying appropriate assessment factors. No DNELs for local effects for long-term exposures (inhalation and dermal) can be derived since no dose-response information is available for these routes.

Modification of the starting point:

From all available data on the target and read-across substancesit is clear that these substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance and reflecting the routes, the duration and the frequency of exposure. DNELs are derived only for workers since no consumer use is intended.

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.

Oral absorption:

The substances has logPow value of 1.39 and water solubility of 1.72 g/L , parameters which are suggestive to favour absorption via gastrointestinal tract. Furthermore, the salted alkylamine phosphates will dissociate under acidic condition of the stomach releasing alkyl phosphates and alkyl amine. Alkyl phosphates (di and mono) could further be hydrolysed to phosphoric acid and corresponding fatty alcohols which together with alkylamines have probably a deviating pattern of absorption from those of the parent (salted) compound. The absorption of released alkyl phosphate and alkylamine constituents is expected to be easier than that of the original compound. Taken this fact into account together with the effects found at the mid and the highest dose level in the 28 -day study in rats (Wragg et al., 1996) absorption by oral route is considered to be significant. The oral absorption is set to 100 % (worst-case) for the purposes of hazard assessment (DNEL derivation). The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

No significant dermal absorption is expected for the target substance because based on the results of the acute dermal toxicity study in rats the substance is of low toxicity by dermal route of exposure (Bonnette, 1995; Study No. 3263.85). The were no mortalities, animals gained in body weight and had only few clinical signs. However, if the log Pow value of 1.39 and water solubility of 1.72 g/L, dermal uptake is anticipated to be moderate to high (ECHA guidance R7.C, 2012). On the other hand, molecular weight of the UVCB substance is expected to be high, so that dermal uptake will be limited. Moreover, the target substance could dissociate in contact with skin and therefore breakdown products with a deviating absorption pattern are expected. Based on these data, 50 % dermal absorption is considered appropriate. Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of the target substance in humans is available.

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 0.000005 kPa at 25 °C) and not to be higher than absorption by oral route. However, 100 % absorption is assumed for inhalation route (as worst-case in case of the route-to-route extrapolation) and considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain long-term inhalation NOEC for systemic effects. The following formula was used:

Corrected inhalatory NOEC = oral NOEL x (1/sRV_rat) x (ABS_oral-rat/ABS_inh-human) x (6.7 m³/10 m³) where sRV is the 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.

Oral-to-dermal extrapolation is performed to obtain dermal NOAEL for systemic effects. The following formula was used (as described in the Example B.5 of the Appendix R.8 -2, ECHA REACH Guidance R8):

Corrected dermal NOEL = oral NOEL x (ABS_oral-rat/ABS_derm-rat) x (ABS_derm-rat/ABS_derm-human) = oral NOEL x (ABS_oral-rat/ABS_derm-human).

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 h (0.38 m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the oral one-generation reproductive toxicity study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

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 NOAEL from the 28 -day study, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL 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 all cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers for all endpoints and for all exposure routes.

Extrapolation of duration:

An assessment factor of 6 was applied for duration of exposure (sub-acute study).

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 was applied since NOEL is used (a clear dose response).

Calculation of DNELs:

Short-term exposure – local effects (irritation DNEL):

In the primary irritation study in rabbits, the substance was not irritating in concentrations up to 50 %. Taking into account density of 0.94579, 1L of the diluted substance at concentration of 50 % contains 473 g. Then, 0.5 mL of the applied dilution contains 0.237 g (= 237 mg). This corresponds to 86.2 mg/kg bw based on the mean body weight of 2.75 kg for rabbits used in the study (the body weight is reported as 2.0 to 3.5 kg). The value of 86.2 mg/kg bw can be considered as NOAEL for local effects. However, the local effects in this case are not more critical than systemic effects for dermal route since this NOAEL of 86.2 mg/kg bw is higher than the derived NOEL of 30 mg/kg bw for systemic effects for dermal route (see below oral-to-dermal extrapolation). Therefore local effects can be covered by systemic effects and no specific DNEL is needed (Guidance on Risk Characterisation of local effects, EC, JRC, Ispra, 05/03/2010).

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

The oral rat NOAEL of 150 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS_oral-rat/ABS_inhal-human) x (6.7 m³/10 m³) = 150 mg/kg bw x (1/0.38 m³/kg/day) x (100 %/100 %) x (6.7/10) = 264.5 mg/m³

DNEL = 264.5 mg/m³/ (2.5 x 5 x 6 x 1 x 1) = 3.5 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 75.

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

For the oral rat NOAEL of 15 mg/kg bw the following conversion was necessary:

Dermal NOAEL =oral NOAEL x (ABS_oral-rat/ABS_derm-human) = 150 x (100 %/50 %) = 300 mg/kg bw

DNEL = 300 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 1.0 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 300.

Selected DNELs

DNEL systemic inhalation = 3.5 mg/m³

DNEL systemic dermal (long-term) = 1 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information