platinum(IV) nitrate/nitric acid solution

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 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

Dose descriptor starting point:

NOAEC

Value:

37.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

Default ECHA AF; NOAEL of 1000 mg/kg bw/day (highest tested dose) from a well-conducted repeated-dose/reproductive toxicity screening study, conducted by the oral route on another soluble Pt(IV) compound, dihydrogen hexahydroxyplatinate.

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. Due to its corrosivity, no long-term studies on Pt dinitrate have been conducted. This quantitative DNEL has, therefore, been derived Read-across from a combined repeated dose toxicity (oral) and reproductive/developmental toxicity study on the related soluble Pt(IV) salt, dihydrogen hexahydroxyplatinate, was usedto support the risk characterisation and protection of worker safety. the A lack of systemic toxicity is predicted if Pt dinitrate could be tested at high repeated doses in repeated toxicity studies.

AF for remaining uncertainties:

1

Justification:

Not required

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Explanation for the modification of the dose descriptor starting point:

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

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Explanation for the modification of the dose descriptor starting point:

]

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high 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

No relevant repeated dose toxicity data were identified for platinum dinitrate. Good support for the conclusion that a repeated dose toxicity study can be waived comes from two sources. Firstly, a consideration of the known toxicity and physico-chemical properties of this compound. Platinum dinitrate is a strong acid (pH<2.0) and exhibits skin corrosivity in vitro.

Secondly, there are good-quality endpoint-specific data on another platinum (IV) species. As an indication of the general low systemic toxicity of soluble Pt(IV) substances, and as support for the risk characterisation and protection of worker safety, a supporting quantitative inhalation DNEL was calculated by route-to-route extrapolation from a combined repeated-dose with reproductive/developmental toxicity screening by the oral route.

 

In the study, conducted according to OECD Test Guideline (TG) 422 and GLP, rats (12/sex/group) received dihydrogen hexahydroxyplatinate (in corn oil) by gavage at doses of 0, 100, 300 or 1000 mg/kg bw/day. Males were dosed from test days 1-35 (inclusive), while females were dosed from test day 1 (2 weeks prior to mating), throughout mating and gestation, until day 3 post-partum or the day before sacrifice (from test day 41 for the first sacrificed females to test day 58 for the last sacrificed female). There were no reported test-item-related effects on body weight, food/water consumption, haematological and clinical chemistry parameters, or on the organs subjected to gross or histopathological examination. Likewise, there were no differences in the measured reproductive parameters, and no gross pathological changes to the pups that were attributed to treatment. Thus, the NOAEL for systemic, reproductive and developmental toxicity was set at 1000 mg/kg bw/day, the highest dose tested (Hansen, 2015). This equates to NOAELs of 652.14 and 1066.69 mg/kg bw/day when expressed as elemental platinum and platinum dinitrate, respectively based on MWt ratios[1].

 

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, PtCl4 or 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 (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 PtCl4 was absorbed (Moore et al., 1975b,c). Similar results were obtained when Pt(SO4)2 was administered orally to mice (Lown et al., 1980). 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, taken from the laboratory study 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 dihydrogen hexahydroxyplatinate, the corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV) = 1000 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(0.5/100)*(6.7 m3 [8h]/10 m3 [8h]) = 8.82 mg/m3. This equates to exposures of 5.75 mg/m3 and 9.40 mg/m3 in terms of elemental platinum and platinum dinitrate, respectively. [

MWts used for calculations: Pt metal, 195.08 g mol^-1; Dihydrogen hexahydroxyplatinate, 299.14 g mol^-1; Platinum dinitrate (UVCB), 319.09 g mol^-1.]

This supports the hypothesis that, even if testing were possible, platinum dinitrate would not be expected to cause any significant systemic toxicity.

 

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, 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 NOAEC (worker, 8 h exposure/day)*4 = 8.82*4 = 35.26 mg/m3, which is equivalent to a platinum dinitrate NOAEC of 37.61 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 platinum dinitrate of 0.50 mg/m3 [501.5 μg/m3], which equates to a platinum exposure of 0.31 mg/m3[306.6 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 identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures).

 

Testing for acute toxicity by all routes has been waived on account of the extreme low pH of the test substance. Platinum dinitrate is classified as being corrosive to skin (category 1A) and causing eye damage (category 1), but no classification for acute toxicity has been proposed. The acute systemic hazard of this substance is unknown, and a qualitative risk assessment could not be performed. However, the labelling elements associated with skin corrosion should mitigate exposures via all routes.

 

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

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

 

Platinum dinitrate is not classified as a skin sensitiser [see ‘Hazard via dermal route: local effects following long-term or acute exposure’ for more detailed discussion of this study])

 

Platinum dinitrate is considered corrosive to the skin (Lehmeier, 2013a,b, 2014) [see ‘Hazard via dermal route: local effects following long-term or acute exposure’ for more detailed discussion of these studies] and therefore serious damage to eyes is implicit. Despite the lack of respiratory tract irritation data, it would appear prudent to assume that platinum dinitrate would also irritate the respiratory tract if inhaled at sufficient levels/durations. According to ECHA (2012b) guidance “substances classified as Skin corrosive Category 1A according to CLP […], which relates to strong corrosive effects, are allocated to the high hazard band on the basis that exposure to such extreme corrosive substances should be strictly contained.”

 

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

No relevant repeated dose toxicity data were identified for platinum dinitrate. However, good support for the conclusion that a repeated dose toxicity study can be waived comes from two sources. Firstly, a consideration of the known toxicity and physico-chemical properties of this compound. Platinum dinitrate is a strong acid (pH<2.0) and exhibits skin corrosivity in vitro. Secondly, there are good-quality endpoint-specific data on another platinum(IV) species. In a combined repeated-dose and reproductive/developmental toxicity screening test, no adverse effects were observed at daily doses of hexahydroxyplatinic acid up to 1000 mg/kg bw/day. This supports the hypothesis that, even if testing were possible, platinum dinitrate would not be expected to cause any significant systemic toxicity.

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

Platinum dinitrate has been reported to have a pH of -0.7, with a calculated acid reserve of 26.46 g of sodium hydroxide (Umicore, 2011). The substance, in solid and solution forms, has also been tested in in vitro membrane barrier tests (CORROSITEX™ Assays), in accordance with OECD TG 435 and GLP. Solid platinum dinitrate (500 mg) was applied to four “BIOBARRIERS” for up to one hour. The mean breakthrough time from these four applications was 16.88 minutes. This falls into the range of 3-30 minutes which results in a CLP classification as skin corrosive, sub-category 1B (Lehmeier, 2013a).

 

The same method was used to evaluate platinum dinitrate solution ‘type H’; 500 μL of the solution was applied to four ‘BIOBARRIERS’ for up to 4 hours. The mean breakthrough time was 3.94 minutes, again triggering CLP classification for skin corrosion in sub-category 1B (Lehmeier, 2013b). Another study, on platinum dinitrate solution, reported a mean breakthrough time of 3.00 minutes. This solution was classified in skin corrosion sub-category 1A (Lehmeier, 2014).

 

An in vivo Guinea Pig Maximisation Test (GPMT), conducted according to OECD TG 406 and GLP, on platinum dinitrate (as solutions in arachis oil) found no evidence of skin sensitisation reactions in ten animals challenged with 1% and 0.5% solutions (“the highest non-irritant concentration…and one lower concentration”, one on each flank of each test animal), following an intradermal injection induction (1%) and topical induction (5%) (Sanders, 1999).

 

A classification of platinum dinitrate in skin corrosion sub-category 1A represents the most health-precautionary assessment. According to ECHA (2012b) guidance “substances classified as Skin corrosive Category 1A according to CLP […], which relates to strong corrosive effects, are allocated to the high hazard band on the basis that exposure to such extreme corrosive substances should be strictly contained.”

 

Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2012b).

 

Hazard for the eyes

According to ECHA guidance on the application of CLP criteria (ECHA, 2015), “if a substance or mixture is classified as Skin corrosive Category 1 then serious damage to eyes is implicit and there is no need to proceed with classification for eye effects”. Platinum dinitrate is classified for skin effects as corrosive sub-category 1A. Consequently, the compound is also 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 (2012b).

[1]

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 platinum dinitrate. In all uses with potential consumer exposure due to service life of articles, platinum dinitrate 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 for platinum dinitrate 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.