Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.47 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:
NOAEC
Value:
35.26 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 from a well-conducted combined repeated-dose with reproductive/developmental toxicity screening study, conducted by the oral route; the highest dose was set at 1000 mg/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:
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:
0.67 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:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

[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 highest dose was set at 1000 mg/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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low 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 dihydrogen hexahydroxyplatinate are available, route-to-route extrapolation to calculate an inhalation DNEL from a 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 an inorganic compound).

 

In the combined 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 a NOAEL of 652.14 mg/kg bw/day when expressed as elemental platinum 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.

 

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.

 

Application of the assessment factors (overall AF 75, described above) to this corrected inhaled NOAEC gives a systemic long-term inhalation DNEL for dihydrogen hexahydroxyplatinate of 0.47 mg/m3, which equates to an elemental 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).

 

There are no data in relation to acute inhalation or dermal exposure to dihydrogen hexahydroxyplatinate. In a guideline (OECD TG 401) acute oral toxicity study in rats (5/sex/group), an LD50value >2150 mg/kg bw was reported for dihydrogen hexahydroxyplatinate (referred to in the study report as “hexahydroxoplatinum(IV) acid”, with CAS RN 52438-26-3)[2]. There were no deaths or other clinical signs of toxicity within a 14-day observation period (Berthold, 1995a). It was concluded that dihydrogen hexahydroxyplatinate 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, 2012b). However, dihydrogen hexahydroxyplatinate 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 dihydrogen hexahydroxyplatinate in humans or laboratory animals; the compound is not considered a significant skin (or respiratory) sensitiser based on a cytokine fingerprinting assay in mice (Dearman and Kimber, 2011). Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated. Further, dihydrogen hexahydroxyplatinate is not considered a skin irritant.

 

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 dihydrogen hexahydroxyplatinate are available, route-to-route extrapolation to calculate a dermal DNEL from a 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 inorganic compound). This study has been described in detail above [“Hazard via inhalation route: systemic effects following long-term exposure”] (Hansen, 2015).

 

The oral NOAEL of 1000 mg/kg bw/day, based on the lack of adverse general systemic, reproductive or developmental effects, was taken as the health-precautionary critical point of departure for calculating the long-term systemic dermal DNEL for dihydrogen hexahydroxyplatinate. This equates to a NOAEL of 652.14 mg/kg bw/day for elemental platinum (based on MWt ratios).

 

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, 2012a).

 

However, two in vitro permeation 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 K2PtCl4 solution (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.

 

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. Dihydrogen hexahydroxyplatinate is reported to have aqueous solubility of <10 mg/L (Gregory, 2014), and therefore may be able to cross the lipid-rich environment of the stratum corneum to a “low to moderate” extent. 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”) (ICMM, 2007).

 

Experimental dermal penetration data (human in vitro studies) for a chloroplatinate substance indicated about 5-8% dermal absorption. Therefore, an assumption of 100% uptake seems to be unduly conservative. It is deemed suitably health precautionary to take forward the lower of the two ECHA default values for dermal absorption, 10%, for the safety assessment of dihydrogen hexahydroxyplatinate.

 

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 1000 mg/kg bw/day*(0.5%/10%) = 50 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 dihydrogen hexahydroxyplatinate of 0.67 mg/kg bw/day, which equates to a platinum exposure of 0.43 mg/kg bw/day.

 

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

Although hexahydroxyplatinic acid (CAS RN 52438-26-3)3at high concentration demonstrated a mild proliferative response using a conventional Local Lymph Node Assay (LLNA) approach (40% and 80% HHPA in DMF gave a Stimulation Index (SI) of 5.4 and 5.7, respectively), the more sophisticated detailed cytokine fingerprinting assay indicated that it was not a significant skin (or respiratory) sensitiser, demonstrating a cytokine profile similar to that of the recognised non-sensitiser tetraammine platinum dichloride (TPC). While this study was well-conducted and reported, and appears scientifically reliable, it was not conducted according to GLP or OECD Test Guideline 429 (Dearman and Kimber, 2011).

 

Two in vitro EPISKIN studies of dihydrogen hexahydroxyplatinate’s skin corrosion/irritation potential have been carried out. 

 

In the first study, conducted according to OECD Test Guideline 431, 20 mg of the solid test material was applied to the surface of a reconstructed human epidermis, followed by 10 μL sodium chloride solution. Exposure lasted 4 hours, after which time the viability of the exposed cells was determined by the MTT assay to be 82% of the negative control cells. As a mean cell viability of ≤35% of the negative control is required for a test substance to be considered corrosive, dihydrogen hexahydroxyplatinate was considered to be non-corrosive to skin (Kiss, 2012a).

 

In a follow-up study, conducted according to OECD Test Guideline 439, 20 mg of the solid test material was applied to the surface of a reconstructed human epidermis immediately following the application of 10 μL distilled water (to ensure good contact with the epidermis). After 15 minutes’ exposure, the cells were washed and incubated in a “maintenance medium” for 42 hours. The viability of the exposed cells was again determined by the MTT assay, with viability reported to be 82% of the negative control cells. As a mean cell viability of ≤50% of the negative control is required for a test substance to be considered irritating, dihydrogen hexahydroxyplatinate was considered to be non-irritant to skin (Kiss, 2012b).

 

The evidence from studies on dihydrogen hexahydroxyplatinate indicates that classification as a skin irritant or skin sensitiser, according to the CLP regulation, is not required.

 

Hazard for the eyes

Dihydrogen hexahydroxyplatinate (referred to in the study report as “hexahydroxoplatinum(IV) acid, with CAS RN 52438-26-3)3was instilled into the eyes of 3 New Zealand white rabbits in a well-reported study conducted in accordance with OECD Test Guideline 405 and to GLP. Effects on the iris were seen in one animal at 1 hour (slight circumcorneal hyperemia), and in another animal at 24 and 48 hours (moderate circumcorneal hyperemia). Effects on the conjunctiva were seen in all animals. Notably, in one animal, these were moderate/severe, with maximum scores for discharge and redness reported for at least one time point within the observation period. Indeed, the maximum observed score for conjunctival chemosis (swelling) in this animal was 3 (of a maximum of 4 on the Draize scale). All effects on the iris and conjunctivae were, however, fully reversible within 4 days. No corneal effects (opacity) were observed in any animal. The primary irritation index calculated for all animals was 6, indicating that the substance would be "non-irritant" if graded using a modified method according to Gilman et al. (as the study report has done) (Berthold, 1995b).

 

Given the pronounced variability between the scores in the animals tested, and the severity of the effects observed, it is considered health precautionary to adopt a Category 2 classification for dihydrogen hexahydroxyplatinate according to the EU CLP Regulation (EC 1272/2008). Accordingly, it is placed in the low hazard band for effects on the eye, and the appropriate RMMs and OCs in Table E3-1 of ECHA (2012b) should be considered.

[1]MWts: Pt metal, 195.08 g mol-1; Dihydrogen hexahydroxyplatinate, 299.14 g mol-1

[2]According to ChemIDPlus, the CAS in this study report corresponds to "diaquatetrahydroxyplatinum". The name dihydrogen hexahydroxyplatinate (synonyms hexahydroxoplatinum(IV) acid and hexahydroxyplatinic acid) corresponds to CAS 51850-20-5. This apparent discrepancy within the study report between CAS and name is inconsequential as these are equivalent from a toxicological perspective.

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 dihydrogen hexahydroxyplatinate. In all uses with potential consumer exposure due to service life of articles, dihydrogen hexahydroxyplatinate 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 dihydrogen hexahydroxyplatinate 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.