Di(tetraethylammonium)hexahydroxoplatinate(IV)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No. 110, October 2010)

Overall assessment factor (AF):

36

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

25.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

DNEL of HHPA-TEAH.

The DNEL of TEAH is 0.12 mg/m3.

See discussion section (Hazard via inhalation route: systemic effects following long-term exposure).

AF for dose response relationship:

2

Justification:

Value is NOAEL; study has been performed with analogue

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure worker

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand for inhalation; is included in dose descriptor starting point

AF for other interspecies differences:

1

Justification:

No remaining differences

AF for intraspecies differences:

3

Justification:

Difference in sensitivity among workers

AF for the quality of the whole database:

1

Justification:

Reliable studies used

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

other: ECETOC guidance (Technical Report No. 110, October 2010)

Overall assessment factor (AF):

144

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

57.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL of HHPA-TEAH.

The DNEL of TEAH is 0.069 mg/kg bw/day

See discussion section (Hazard via dermal route: systemic effects following long-term exposure).

AF for dose response relationship:

2

Justification:

Value is NOAEL; study has been performed with analogue

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure worker

AF for interspecies differences (allometric scaling):

4

Justification:

Correction for caloric demand from rat to human

AF for other interspecies differences:

1

Justification:

No remaining differences

AF for intraspecies differences:

3

Justification:

Difference in sensitivity among workers

AF for the quality of the whole database:

1

Justification:

Reliable studies used

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Hazard via inhalation route: systemic effects following long-term exposure

As no relevant data on effects of repeated inhalation exposure of humans or laboratory animals to Di(tetraethylammonium)hexahydroxoplatinate(IV) (HHPA-TEAH) or its constituents dihydrogen hexahydroxyplatinate(IV) (HHPA) and tetraethylammonium hydroxide (TEAH) are available, route-to-route extrapolation is considered a suitable alternative method to calculate an inhalation DNEL from available reproductive/developmental toxicity screenings by the oral route.

Detailed information on the read-across approach and the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH Read-Across justification’ document attached in IUCLID section 13.2.

 

Key reproduction/developmental toxicity information from read-across substances:

NOAEL HHPA (repeated dose, oral, rat): 1000 mg HHPA/kg bw/day.

NOAEL TEAH (repeated dose, oral, rat; based on structural analogue TMAH): 5 mg TEAH/kg bw/day.

 

The DNEL calculation for HHPA-TEAH is based on the most sensitive endpoint per route of exposure of HHPA and TEAH and the lowest corresponding DNEL taking into account the maximum HHPA (14.1%) or TEAH (17.4%) content in HHPA-TEAH.

 

HHPA

Dose descriptor starting point (after route-to-route extrapolation):

Corrected inhalatory NOAEL(mg/m³) for workers, 8 h exposure/day

= oral NOAEL*(1/sRV[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV)

= 1000mg/kg bw/day*(1/0.38 m³/kg bw/day)*(0.5/100)*(6.7 m³[8h]/10 m³[8h])

= 8.82mg/m³

It is noted that the standard respiratory rate conversion figure (0.38 m³/kg bw/day) already incorporates a factor of 4 for allometric scaling from rat to human. An assessment factor (AF) for allometric scaling is therefore not considered to be justified in this scenario, given that the metabolism of inorganic metal cations is conventionally assumed not to occur to any relevant extent. Moreover, ECHA guidance notes that “allometric scaling is an empirical approach for interspecies extrapolation of various kinetic processes generally applicable to substances which are renally excreted, but not to substances which are highly extracted by the liver and excreted in the bile. It appears that species differences in biliary excretion and glucuronidation are independent of caloric demand (Walton et al. 2001)” (ECHA, 2012a). Oral toxicokinetic studies have demonstrated that, while gastrointestinal absorption of platinum is very low, the absorbed fraction is excreted predominantly via the faecal route (Moore et al., 1975b). It is therefore considered appropriate to increase the corrected inhalatory NOAEC by a factor of 4:

Dose descriptor starting point (after route to route extrapolation)

= Corrected inhalatory NOAEL(worker, 8 h exposure/day)*4

= 8.82*4

= 35.26 mg/m³

Application of the assessment factors (AF 6 for subacute (28-day) to chronic extrapolation, AF 2.5 for remaining interspecies toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences and AF 5 for intraspecies differences for worker; overall AF 75) to this corrected inhaled NOAEL gives a systemic long-term inhalation DNEL for HHPA of 0.47 mg/m³.

 

TEAH

Dose descriptor starting point (after route-to-route extrapolation):

Corrected inhalatory NOAEL(mg/m³) for worker, 8 h exposure/day

= oral NOAEL*(1/sRV[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV)

= 5mg/kg bw/day*(1/0.38 m³/kg bw/day)*(50/100)*(6.7 m³[8h]/10 m³[8h])

= 4.4mg/m³

Application of the assessment factor (AF 2 for dose response relationship (study has been performed with structural analogue), AF 6 for subacute (28-day) to chronic extrapolation and AF 3 for intraspecies differences in sensitivity for workers; overall AF36) to this corrected inhaled NOAELgives a systemic long-term inhalation DNEL for TEAH of 0.12 mg/m³.

 

HHPA-TEAH

TEAH is the moiety with the lowest DNEL for systemic long-term effects via the inhalation route and the highest concentration within HHPA-TEAH and will therefore be the driver for the toxicological effects of HHPA-TEAH. The systemic long-term DNEL for the inhalation route for HHPA-TEAH is calculated based on the corresponding NOAEL for TEAH and its maximal content in HHPA-TEAH:

Corrected inhalatory NOAEL(mg/m³) for worker, 8 h exposure/day for HHPA-TEAH

= NOAEL TEAH / maximum weight fraction TEAH in HHPA-TEAH

= 4.4 mg/m³/ 0.174

= 25.3 mg/m³

Application of the assessment factor (overall AF36 for TEAH, see above) to this corrected inhaled NOAEL gives a systemic long-term inhalation DNEL for HHPA-TEAH of 0.7 mg/m³.

 

 

 

Hazard via inhalation or dermal route: systemic effects following acute exposure

DNELs for acute toxicity should be calculated if an acute toxicity hazard, leading to classification and labelling (i.e. under EU CLP regulations) has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures).

There are no data in relation to acute inhalation or dermal exposure to di(tetraethylammonium)hexahydroxoplatinate(IV) (HHPA-TEAH) and HHPA-TEAH is not classified for acute toxicity according to CLP. According to the data for HHPA and TEAH, no acute toxicity up to 2000 mg/kg bw is expected for the oral and dermal route for HHPA-TEAH.

 

 

 

Hazard via inhalation route: local effects following long-term or acute exposure

There are no data in relation to respiratory tract irritation or sensitisation of HHPA-TEAH in humans or laboratory animals. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated.

HHPA-TEAH is classified as corrosive to the skin (Category 1B) on the basis of an EpiDerm skin corrosion study (Lacey, 2019). Despite the lack of respiratory tract irritation data, it would appear prudent to assume that this substance would also irritate the respiratory tract if inhaled at sufficient levels/durations. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment, Part E (Risk Characterisation (ECHA, 2016) “substances classified for skin corrosion Category 1B/1C in CLP” or “Serious eye damage Category 1 in CLP “… “which relate to corrosive or severe irritant effects to the eye or irritant effects to the eyes, respiratory tract and skin simultaneously, are allocated to the moderate hazard band on the basis that exposure to such corrosives, eye damaging or irritant substances should be well-controlled”. Therefore, consider recommended Risk Management Measures/Operational Conditions (RMMs/OCs) in Table E.3-1 of ECHA (2016).

 

 

 

Hazard via dermal route: systemic effects following long-term exposure

No relevant data on effects of repeated dermal exposure of humans or laboratory animals to di(tetraethylammonium)hexahydroxoplatinate(IV) (HHPA-TEAH) or its constituent dihydrogen hexahydroxyplatinate (IV) (HHPA) are available. For TEAH, a dermal repeated dose toxicity was conducted with substance analogue TMAH. Data for HHPA from a combined repeated-dose with reproductive/developmental toxicity screening study by the oral route and route-to-route extrapolation to calculate a dermal DNEL can be a suitable alternative method (particularly as first pass effects are not expected to be significant for an inorganic compound).

Detailed information on the read-across approach and the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH Read-Across justification’ document attached in IUCLID section 13.2.

 

Key repeated dose information from read-across substances:

NOAEL HHPA (repeated dose, oral, rat): 1000 mg HHPA/kg bw/day.

NOAEL TEAH (repeated dose, dermal, rat; based on structural analogue TMAH): 10 mg TEAH/kg bw/day.

 

The DNEL calculation for HHPA-TEAH is based on the most sensitive endpoint per route of exposure of HHPA and TEAH and the lowest corresponding DNEL taking into account the maximum HHPA-TEAH HHPA (14.1%) or TEAH(17.4%)content.

 

HHPA

Dose descriptor starting point (after route to route extrapolation):

Corrected dermal NOAEL (mg/kg bw/day)

= oral NOAEL*(ABS[oral-rat]/ABS[derm-human])

= 1000 mg/kg bw/day*(0.5%/10%)

= 50 mg/kg bw/day

Application of the assessment factors (AF 6 for subacute (28-day) to chronic extrapolation, AF 2.5 for remaining interspecies toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences and AF 5 for intraspecies differences for worker; overall AF 75) to this corrected dermal NOAEL gives a systemic long-term dermal DNEL for HHPA of 0.67 mg/kg bw/day.

 

TEAH

Dose descriptor starting point=10 mg/kg bw/day.

Application of the assessment factors (AF 2 for dose response relationship (study has been performed with structural analogue), AF 6 for subacute (28-day) to chronic extrapolation, AF 4 for allometric scaling and AF 3 for intraspecies differences in sensitivity for workers; overall AF144) to this dermal NOAEL gives a systemic long-term dermal DNEL for TEAH of 0.069 mg/kg bw/day.

 

HHPA-TEAH

TEAH is the moiety with the lowest DNEL for systemic long-term effects via the dermal route and the highest concentration within HHPA-TEAH and will therefore be the driver for the toxicological effects of HHPA-TEAH. The systemic long-term DNEL for the dermal route for HHPA-TEAH is calculated based on the corresponding NOAEL for TEAH and its maximal content in HHPA-TEAH:

Dose descriptor starting point for HHPA-TEAH

= dermal NOAEL for TEAH / maximum weight fraction TEAH in HHPA-TEAH

= 10mg/kg bw/day/ 0.174

= 57.5 mg/kg bw/day.

Application of the assessment factor (overall AF144 for TEAH, see above) to this corrected NOAEL gives as ystemic long-term dermal DNEL for HHPA-TEAH of 0.4mg/kg bw/day.

 

 

 

Hazard via dermal route: local effects following long-term or acute exposure

In a guideline EpiDerm skin corrosion study (OECD 431, Lacey 2019) HHPA-TEAH was corrosive to skin and classified as sub-category 1B. Despite the lack of respiratory tract irritation data, it would appear prudent to assume that this substance would also irritate the respiratory tract if inhaled at sufficient levels/durations. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment, Part E (Risk Characterisation (ECHA, 2016) “substances classified for skin corrosion Category 1B/1C in CLP” or “Serious eye damage Category 1 in CLP “… “which relate to corrosive or severe irritant effects to the eye or irritant effects to the eyes, respiratory tract and skin simultaneously, are allocated to the moderate hazard band on the basis that exposure to such corrosives, eye damaging or irritant substances should be well-controlled”. Therefore, consider recommended Risk Management Measures/Operational Conditions (RMMs/OCs) in Table E.3-1 of ECHA (2016).

 

 

 

Hazard for the eyes

As HHPA-TEAH is classified as skin corrosion 1B and is a strong base (pH > 13) it is classified as serious eye damage Cat 1. Accordingly, it is placed in the medium hazard band for effects on the eye, and the appropriate RMMs and OCs in Table E3-1 of ECHA (2016) should be considered.

 

 

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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:

medium hazard (no threshold derived)

Additional information - General Population

DNELs have been derived only for workers, not for consumers/general population. No uses have been identified in which consumers are exposed to di(tetraethylammonium)hexahydroxoplatinate(IV) (HHPA-TEAH). HHPA-TEAH is only used as an intermediate in industrial settings and HHPA-TEAH is chemically transformed into another substance before reaching the consumers.

Regarding the general population, and following the criteria outlined in ECHA guidance R16 (2016), an assessment of indirect exposure of humans via the environment for HHPA-TEAH has not been performed as the registered substance is manufactured/imported/marketed at <100 tpa.