Phosphoric acid, 2-ethylhexyl ester, ammonium salt

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.47 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

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:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8 h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8 h exposure period).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalatory NOAEC = 1/SRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

= [125 mg/kg bw/day] X  [1/0.38 m3/kg bw/day] X [1/2] X [6.7 m3/10m3].

Thus, the corrected dose descriptor for inhalation is 110.2 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

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:

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:

0.417 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

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For systemic hazard assessment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidanc

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

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:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

For DNEL derivation (long-term systemic for all routes of exposure), the dose descriptor was based on the results of the repeated dose toxicity study where the most sensitive NOAEL of 125 mg/kg bw/day was applied (Dunster et al 2012). Default assessment factors were applied in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (Version 2.1, November 2012).

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 422 under GLP.  The substance was administered twice daily to 10 male and 10 female Wistar Han™:RccHan™: rats by oral gavage at dose levels of 60, 125 and 250 mg/kg bw/day for up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females).  Although there was no recovery phase, this is not a guideline requirement.

The key findings in this study were episodes of increased salivation were evident in animals of either sex treated with 250 mg/kg bw/day and in males treated with 125 mg/kg bw/day during the treatment period. An isolated incident of noisy respiration was also evident in one female treated with 250 mg/kg bw/day on Day 6. No such effects were detected in females treated with 125 mg/kg bw/day or animals of either sex treated with 60 mg/kg bw/day. Males treated with 250 mg/kg bw/day showed a reduction in body weight gain during Weeks 1, 2 and during the final week of treatment. No such effects were detected in females treated with 250 mg/kg bw/day or animals of either sex treated with 125 or 60 mg/kg bw/day.  Males treated with 250 mg/kg bw/day showed a slight reduction in overall food consumption when compared to controls. No such effects were detected in females treated with 250 mg/kg bw/day or in animals of either sex treated with 125 or 60 mg/kg bw/day. Sloughing on the non glandular and/or glandular regions of the stomach were evident in a number of animals treated with 250 and 125 mg/kg bw/day and in one male treated with 60 mg/kg bw/day. No such effects were detected in females treated with 60 mg/kg bw/day. 

Whilst microscopic changes identified in the stomach may be considered to be adverse, however, they are also considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 250 mg/kg bw/day for females and 125 mg/kg bw/day for males.

There was no effects reported for reproductive and developmental toxicology following OECD 422, Dunster J, 2012:

NOAEL (fertility) = 250 mg/kg bw/day

NOAEL (reproduction & development) = 250 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.362 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):

150

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

54.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

Concerning absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalator NOAEC = 1/sRVrat x ABSoral-rat/ABSinh-rat x ABSinh-rat/ABSinh-human

= [125 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2].

Thus, the corrected dose descriptor for inhalation is 54.35 mg/m3 for the general population.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal 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

Route of original study:

Oral

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

Modified dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

An acute dermal study conducted on the substance in accordance with OECD 402 (Anon, 2018) concluded that the substance has a dermal LD50 (females) > 2,000 mg/kg bw. It is therefore concluded that the substance poses no systemic acute dermal hazard.

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)

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

Route of original study:

Oral

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

Modified dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band.

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.

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:

low hazard (no threshold derived)

Additional information - General Population

For DNEL derivation (long-term systemic for all routes of exposure), the dose descriptor was based on the results of the repeated dose toxicity study where the most sensitive NOAEL of 125 mg/kg bw/day was applied (Dunster et al 2012). Default assessment factors were applied in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (Version 2.1, November 2012).

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 422 under GLP.  The substance was administered twice daily to 10 male and 10 female Wistar Han™:RccHan™: rats by oral gavage at dose levels of 60, 125 and 250 mg/kg bw/day for up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females).  Although there was no recovery phase, this is not a guideline requirement.

The key findings in this study were episodes of increased salivation were evident in animals of either sex treated with 250 mg/kg bw/day and in males treated with 125 mg/kg bw/day during the treatment period. An isolated incident of noisy respiration was also evident in one female treated with 250 mg/kg bw/day on Day 6. No such effects were detected in females treated with 125 mg/kg bw/day or animals of either sex treated with 60 mg/kg bw/day. Males treated with 250 mg/kg bw/day showed a reduction in body weight gain during Weeks 1, 2 and during the final week of treatment. No such effects were detected in females treated with 250 mg/kg bw/day or animals of either sex treated with 125 or 60 mg/kg bw/day.  Males treated with 250 mg/kg bw/day showed a slight reduction in overall food consumption when compared to controls. No such effects were detected in females treated with 250 mg/kg bw/day or in animals of either sex treated with 125 or 60 mg/kg bw/day. Sloughing on the non-glandular and/or glandular regions of the stomach were evident in a number of animals treated with 250 and 125 mg/kg bw/day and in one male treated with 60 mg/kg bw/day. No such effects were detected in females treated with 60 mg/kg bw/day. 

Whilst microscopic changes identified in the stomach may be considered to be adverse, however, they are also considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 250 mg/kg bw/day for females and 125 mg/kg bw/day for males.

There was no effects reported for reproductive and developmental toxicology following OECD 422, Dunster J, 2012:

NOAEL (fertility) = 250 mg/kg bw/day

NOAEL (reproduction & development) = 250 mg/kg bw/day