Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.071 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
5.29 mg/m³
Explanation for the modification of the dose descriptor starting point:

As no relevant data on effects of repeated inhalation exposure to tetraammineplatinum(II) diacetate in humans or laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a repeated-dose oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for an inorganic compound).

 

The oral NOAEL for tetraammineplatinum(II) diacetate was 150 mg/kg bw/day, equating to 76.8 mg/kg bw/day for platinum (based on MWt ratio).

 

Laboratory studies provide only limited insights into the extent of absorption of platinum compounds following inhalation. When two volunteers inhaled CHPS (mainly diammonium hexachloroplatinate) at calculated mean air concentrations of 1.7 and 0.15 µg/m3, respectively, urinary Pt concentrations peaked (15-100-fold increases were seen) about 10 hr later. The results indicated rapid absorption, 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 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).

 

Limited data indicate that absorption of soluble Pt compounds is also very low following oral exposure. In rats, less than 1% 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).

 

Corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV)

= 150 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(0.5/100)*(6.7 m3 [8h]/10 m3 [8h]) = 1.32 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 systemically available platinum is excreted predominantly via the biliary/faecal route (EMA, 2008).

 

It is therefore 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 = 1.32*4 = 5.29 mg/m3

AF for dose response relationship:
1
Justification:
Default ECHA AF; NOAEL from a well-conducted repeated-dose oral toxicity study; 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:
The default ECHA AF of 4 for rat for toxicokinetic differences in metabolic rate (allometric scaling) is considered unnecessary as the compound is inorganic and is consequently not metabolised 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”, while systemically available platinum is excreted predominantly via the biliary/faecal route.
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:
0.1 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
7.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As no relevant data on effects of repeated dermal exposure to tetraammineplatinum(II) diacetate in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a repeated-dose oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for an inorganic compound).

 

The oral NOAEL for tetraammineplatinum(II) diacetate was 150 mg/kg bw/day, equating to 76.8 mg/kg bw/day for platinum (based on MWt ratio).

 

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. Tetraammineplatinum(II) diacetate, with a low partition coefficient (<-3.94; Mekelburger, 2004d) and high water solubility (799 g/L; Mekelburger, 2004e), may be unable to cross the lipid-rich environment of the stratum corneum, especially given the lack of skin irritation potential observed in rabbits (Beerens-Heijnen, 2004a). 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 tetraammineplatinum(II) diacetate.

 

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 150 mg/kg bw/day*(0.5%/10%) = 7.5 mg/kg bw/day

AF for dose response relationship:
1
Justification:
Default ECHA AF; NOAEL from a well-conducted repeated-dose oral toxicity study; 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:
The default ECHA AF of 4 for rat for toxicokinetic differences in metabolic rate (allometric scaling) is considered unnecessary as the compound is inorganic and is consequently not metabolised 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”, while systemically available platinum is excreted predominantly via the biliary/faecal route.
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

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. During assessment of the identified uses for tetraammineplatinum(II) diacetate, no uses have been identified in which consumers are exposed to tetraammineplatinum(II) diacetate. In all uses with potential consumer exposure due to service life or articles, tetraammineplatinum(II) diacetate is chemically transformed into another substance before reaching the consumers, and the subsequent lifecycle steps after this transformation of tetraammineplatinum(II) diacetate are appropriately included in the assessment of this 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 tetraammineplatinum(II) diacetate has not been performed as the registered substance is manufactured/imported/marketed <100 tpa and is not classified as STOT-RE 1 or as CMR.