Dihydrogen hexahydroxyplatinate, compound with 2-aminoethanol (1:2)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.023 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:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1.725 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL is expressed in Pt as this is what is being measured in the workplace and used in the exposure assessment.

The DNEL for HHPA-2AE is 0.14 mg/m3.

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

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted combined repeated-dose with reproductive/developmental toxicity screening study, conducted by the oral route; the NOAEL was set at 300 mg HHPA-2AE/kg bw/day.

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required.

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker.

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not requried.

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:

0.016 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):

75

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1.2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The DNEL is expressed in Pt as this is what is being measured in the workplace and used in the exposure assessment.

The DNEL for HHPA-2AE is 0.1 mg/kg bw/day.

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

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL from a well-conducted combined repeated-dose with reproductive/developmental toxicity screening study, conducted by the oral route; the NOAEL was set at 300 mg HHPA-2AE/kg bw/day.

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation.

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required.

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences.

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker.

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high.

AF for remaining uncertainties:

1

Justification:

Not required.

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 HHPA:2AE are available, route-to-route extrapolation to calculate an inhalation DNEL from a reliable combined repeated-dose with reproductive/developmental toxicity screening by the oral route was considered a suitable alternative method (particularly as first pass effects are not expected to be significant for this essentially inorganic compound).

 

In the combined study (OECD Test Guideline [TG] 422), conducted to GLP, HHPA:2AE was administered to rats by gavage for 36 days (in males) and 50-63 days (in females) at doses of 0, 100, 300 or 1000 mg/kg bw/day. Treatment-related adverse effects were observed in the high dose animals (including “slight to pronounced salivation”, slightly reduced motility, and decreased food consumption, body weight and body weight gain). No effects on reproductive parameters, indications of maternal/foetal toxicity, or developmental effects were observed at any dose level. The NOAELs for reproductive (fertility) effects in parental animals and for pre- and post-natal developmental effects in the pups were set at 1000 mg/kg bw/day, the highest dose tested. The NOAEL for general systemic toxicity was set at 300 mg/kg bw/day (Hansen, 2017). These equate to NOAELs of 164.8 and 49.4 mg/kg bw/day, respectively, when expressed as elemental platinum based Pt content of the test substance. T

he tested HHPA:2AE had an elemental platinum content of 16.48%.

 

Laboratory studies provide only very limited insights into the extent of absorption of platinum compounds following inhalation. When two volunteers inhaled mainly diammonium hexachloroplatinate at calculated mean air concentrations of 1.7 and 0.15 µg Pt/m³, respectively, urinary Pt concentrations peaked (15 -100-fold increases were seen) about 10 hr later. The results indicated rapid absorption and urinary excretion, but gave no quantitative insights into the extent of absorption (Schierl et al., 1998). Urinary Pt measurements in rats following an acute inhalation of radiolabelled Pt, PtO₂, PtCl₄or Pt(SO₄)₂(particle diameter around 1 µm) indicated only small fractions of the administered dose were absorbed, even for the two soluble salts. Most of the radiolabel appeared in the faeces, presumably reflecting mucociliary clearance and a lack of significant absorption from the gastrointestinal tract (or lungs) (Moore et al., 1975a).

 

Available data indicate that absorption of soluble Pt compounds is also very low following oral exposure. In rats, less than 0.5% of an oral dose of radiolabelled PtCl₄was absorbed (Moore et al., 1975b,c). Similar results were obtained when Pt(SO₄)₂was administered orally to mice (Lown et al., 1980). The reported maximum plasma 2-AE concentration after oral administration of 0, 100, 300 or 1000 mg 2-AE/kg bw/day (as part of a 2-generation reproduction toxicity study) equated to 81 mg/kg bw in animals administered the highest dose; the overall range of plasma concentrations indicated an absorption of 2.6 – 8.1% (Fiume et al., 2015).

 

Following REACH guidance, the worst-case (and, therefore, most health-precautionary) scenario for DNEL calculation is obtained by considering the minimum absorption by the ‘starting’ route. Therefore, for this oral-to-inhalation extrapolation, a figure of 0.5% oral absorption has been used, based on the laboratory study of Pt salts in rats. In line with the guidance, the worst-case of 100% absorption after inhalation has still been assumed for the ‘end’ route (which is clearly significantly higher than the available, albeit limited, data indicates, and thus almost certainly over-precautionary).

 

Expressed as HHPA:2AE, the corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV) = 300 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(0.5/100)*(6.7 m3 [8h]/10 m3 [8h]) = 2.644 mg/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 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, 2012). 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 NOAEC (worker, 8 h exposure/day)*4 = 2.644*4 = 10.6 mg/m³.

 

Application of the assessment factors (overall AF 75, described above) to this corrected inhaled NOAEC gives a systemic long-term inhalation DNEL for HHPA:2AE of 0.14 mg/m³, which equates to an elemental platinum exposure of 0.023 mg/m³(23.1 μg/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 identifiedandthere 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 HHPA:2AE. In a guideline (OECD TG 423, acute toxic class method) acute oral toxicity study in rats (3/sex/group), no mortality or clinical signs of toxicity were apparent in animals given a single dose of 2000 mg/kg bw and observed for 14 days. Consequently the LD₅₀was determined to be in excess of this limit dose and that HHPA:2AE does not require classification for its acute oral toxicity.

 

“A qualitative risk characterisation for this endpoint could be performed for substances of very high or high acute toxicity classified in Category 1, 2 and 3 according to CLP…. when the data are not sufficiently robust to allow the derivation of a DNEL” (ECHA, 2016a). However, HHPA:2AE is not classified for acute toxicity according to CLP, so a qualitative assessment is not required.

 

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:2AE in humans or laboratory animals. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated.

 

The compound is not considered a significant skin sensitiser based on a local lymph node assay in mice (Haferkorn, 2016) [see ‘Hazard via dermal route: local effects following long-term or acute exposure’ for more detailed discussion of this study].

HHPA:2AE is classified as corrosive to the skin (Category 1B) on the basis of an EpiDerm skin corrosion study (Spruth, 2016a) [see ‘Hazard via dermal route: local effects following long-term or acute exposure’ for more detailed discussion of this study]. 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 (2016a) guidance “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 (2016a).

 

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

As no relevant data on effects of repeated dermal exposure of humans or laboratory animals to HHPA:2AE are available, route-to-route extrapolation to calculate a dermal DNEL from the combined repeated-dose with reproductive/developmental toxicity screening study by the oral route was considered a suitable alternative method (particularly as first pass effects are not expected to be significant for an essentially inorganic compound). This study has been described in detail above [“Hazard via inhalation route: systemic effects following long-term exposure”] (Hansen, 2017).

 

The oral NOAEL of 300 mg/kg bw/day, based on the observation of signs of toxicity (including reduced motility, decreased body weight, decreased body weight gain and food consumption), was taken as the health-precautionary critical point of departure for calculating the long-term systemic dermal DNEL for HHPA:2AE. No adverse effects on reproduction (fertility), or on pre- or post-natal development of pups, were reported. This figure equates to a NOAEL of 49.4 mg/kg bw/day for elemental platinum (based on Pt content in the test substance).

 

This derivation has utilised REACH guidance. In order to make the most health-precautionary derivation, the worst-case scenario is obtained by the minimum absorption by the ‘starting’ route. Therefore, for this oral-to-dermal extrapolation, a figure of 0.5% oral absorption has been used based on experimental data in rats (Moore et al., 1975b,c). The default assumption in the REACH guidance is that dermal absorption will not be higher than by the oral route (ECHA, 2012).

 

However, twoin vitropermeation studies on a related soluble platinum salt, dipotassium tetrachloroplatinate, indicated a greater degree of dermal absorption [about 5-8%] than this default process would assume. Using a K₂PtCl₄solution (0.3 mg Pt/ml in synthetic sweat) and full thickness skin from six donors (three African and three Caucasian), 4.8 and 2.3%, respectively (as mean values), diffused into the skin in 24 hr; the receptor solutions contained a further 3.4 and 0.5%, respectively (Franken et al., 2015). A slightly earlier publication reported mean skin diffusion and receptor solution percentages of 2.2% and 2.3%, respectively, in similar studies on full thickness skin from four Caucasian females (Franken et al., 2014). Apart from these studies, very little information appears to be available regarding dermal absorption of platinum compounds.

 

Inin vitrostudies of 2-AE on skin samples from rats, mice, rabbits and humans, undiluted 2-AE was applied to the skin for 6 hours. The cumulative dose absorbed was reported to be 5.98%, 16.92%, 8.66% and 0.61% in the four respective species. Absorption of aqueous 2-AE was 1.32%, 24.79%, 1.87% and 1.11%, respectively. Human skin was the least permeable of the samples examined (Fiume et al., 2015).

 

In the absence of high-quality data for dermal absorption, default guidance allows for the estimation of dermal absorption based on other relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. HHPA:2AE is prepared and marketed in aqueous solution, and therefore may be able to cross the lipid-rich environment of the stratum corneum to a “low to moderate” extent. Specific expert guidance on the health risk assessment of metals indicates that considerations based on physico-chemical properties do not apply to these substances (“as inorganic compounds require dissolution involving dissociation to metal cations prior to being able to penetrate skin by diffusive mechanisms”) and, as such, dermal absorption might be assumed to be very low (values of 0.1 and 1.0% are suggested for dry and wet media, respectively) (ICMM, 2007).

 

Experimental dermal penetration data (human in vitro studies) for a chloroplatinate substance indicated about 5-8% dermal absorption, with values of 0.61 or 1.11% for similar studies using 2-AE. Therefore, the lower of the two ECHA (2014) default values for dermal absorption, 10%, would seem an appropriate value for the current safety assessment. However, the potential of HHPA:2AE to disrupt skin barrier function, possibly facilitating increased dermal penetration, cannot be excluded, especially considering its known corrosivity to human skin in vitro. A value of 20% dermal absorption is, therefore, proposed.

 

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 300 mg/kg bw/day*(0.5%/20%) = 7.5 mg/kg bw/day.

 

Application of the assessment factors (overall AF 75) described above to this corrected dermal NOAEL gives a systemic long-term dermal DNEL for HHPA:2AE of 0.1 mg/kg bw/day, which equates to a platinum exposure of 0.016 mg/kg bw/day (16.5 μg/kg bw/day).

 

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

Two reliablein vitroEpiDerm studies of HHPA:2AE’s skin corrosion/irritation potential have been carried out. 

 

In the first study, conducted according to OECD TG 439, HHPA:2AE displayed a mean cell viability of less than 50% (17.9%) and was hence considered to be irritant to skin (Spruth, 2016b). In a further study, conducted according to OECD TG 431, the mean cell viability following exposure to HHPA:2AE was calculated to be greater than 50% (51.5%) after a 3-minute exposure and less than 15% (12.8%) after a 1-hour exposure, and it was therefore considered to be corrosive to skin (Spruth, 2016a). On this basis, HHPA:2AE is classified as corrosive to the skin (CLP category 1B).

 

In another guideline (OECD TG 442B) study, HHPA:2AE failed to induce skin sensitisation in the mouse local lymph node assay (LLNA) when tested at concentrations of up to 50% (Haferkorn, 2016). Consequently, the compound is not classified for skin sensitisation under CLP.

 

No dose-response data was available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. On the basis of the observed skin corrosivity (category 1B), the substance would be considered in the moderate hazard band according to ECHA (2016a) guidance. Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2016a).

 

Hazard for the eyes

In a bovine corneal opacity and permeability (BCOP) study (OECD TG 437) the irritancy score was calculated to be 4.6 (a score > 55 represents an ocular corrosive and a score ≤ 3 represents a substance for which classification is not required). Hence no classification conclusion concerning irritant or corrosive potential of the test item can be made (Spruth, 2016c).

According to ECHA guidance on the application of CLP criteria (ECHA, 2017), “if a substance or mixture is classified as Skin corrosive Category 1 then serious damage to eyes is implicit…thus, the corrosive substance or mixture is also classified, but the corresponding hazard statement is not indicated on the label and there is no need to proceed with classification for eye effects”. HHPA:2AE is classified for skin effects as corrosive sub-category 1B. Consequently, the compound is classified for eye effects in Category 1 under EU CLP. No dose-response data was available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. Substances classified for serious eye damage (Category 1 in CLP) should be 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 RMMs/OCs in Table E.3-1 of ECHA (2016a).

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

DNELs have been derived only for workers, not for consumers/general population. No uses have been identified in which consumers are exposed to HHPA:2AE. In all uses with potential consumer exposure due to service life of articles, HHPA:2AE is chemically transformed into another substance before reaching the consumers, and the subsequent lifecycle steps after this transformation are included in the assessment of the newly-formed substance. Regarding the general population, and following the criteria outlined in ECHA guidance R16 (2016), an assessment of indirect exposure of humans via the environment forHHPA:2AE has not been performed as the registered substance is manufactured/imported/marketed at <100 tpa and is not classified as STOT-RE 1 or as CMR.