1,3-diethenyl-1,1,3,3- tetramethyldisiloxane and its platinum(0) complexes

Endpoint summary

Description of key information

Karstedt concentrate (KC) is composed of complexes of platinum with 1,1,3,3-tetramethyl-1,3-diethenyldisiloxane (TMDS). It is likely to be poorly absorbed after administration by the oral route; what small proportion of the substance is taken up is likely to be rapidly excreted. Based on experimental rat data on a water-soluble platinum salt, an oral absorption figure of 0.5% is proposed for the chemical safety assessment (CSA).

Exposure by the inhalation route is anticipated to be low and, in any event, significant absorption from inhalation is unlikely given the relatively low water solubility and low molecular weight. Nevertheless, based on ECHA guidance, a conservative default assumption of 100% inhalation absorption will be used for the CSA (when extrapolating from an oral laboratory animal study to a human inhalation exposure).

A high dermal absorption is also unlikely, notably based on experimental dermal penetration data (human in vitro studies) for other Pt salts, and the lack of an expected potential for disrupting skin barrier function (which could otherwise facilitate increased dermal penetration). A value of 10% dermal absorption is proposed for the CSA (when extrapolating from an oral laboratory animal study to a human dermal exposure).

No information is available on whether or not the KC complex breaks down in any way after administration (e.g. whether there is dissociation prior to Pt absorption). The physico-chemical properties of KC suggest that it has a potential for bioaccumulation in the adipose tissues. The potential for bioaccumulation of certain other metals and ions is also recognised.

Key value for chemical safety assessment

Absorption rate - oral (%):

0.5

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Absorption - platinum

Limited insight into the oral absorption of Karstedt concentrate (KC) can be gained from the toxicokinetic evaluation carried out as part of the combined repeated-dose/reproductive and developmental toxicity study (OECD TG 422) on this complex (Hansen, 2017). Plasma, obtained from rats that received KC by oral gavage at doses of 0 (controls) or 500 (high-dose) mg/kg bw, was analysed for platinum (Pt) levels (as an analytical marker for the test compound) using atomic absorption spectroscopy. Samples were taken pre-dosing, and 3, 6, 12 and 24 hours after administration, on test days 1 or 2, and 28 or 29. An peak plasma platinum concentration of approximately 1200 μg/L (average of 5 high-dose females, 6 hours post-administration) was reported; this equates to < 0.02% oral absorption[1] at this specific point in time. However, this study only measured plasma levels of Pt, administered orally as KC. No information is available on whether or not the KC complex breaks down in any way after administration (e.g. whether there is dissociation prior to Pt uptake), tissue distribution, nor any information on the uptake/distribution of the TMDS ligand.

However, the data correlate with other Pt studies, which indicate that absorption, even of water soluble Pt compounds, is generally very low following oral exposure. Seventy-one fasted male rats were administered a dose of radiolabelled 191Pt (as PtCl4) by oral gavage, to provide 25 μCi of radiation. Routes of excretion, levels of whole-body retention and organ distribution were determined. Less than 0.5% of the orally-administered dose was absorbed (Moore et al., 1975b,c). Similarly, mice given a single gavage administration of radiolabelled Pt(SO4)2 were found to have absorbed only a very small fraction of the dose (Lown et al., 1980). [The authors of this study stated that, while they did not quantify the distribution of the radiolabel, their findings were consistent with those of Moore et al.].

No substance-specific data on inhalation uptake of KC were identified. Laboratory studies provide only very limited insights into the extent of absorption of Pt 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 hours 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).

No substance-specific data on dermal uptake of KC were identified. The low water solubility (35 mg/L) suggests that significant dermal absorption through intact skin is unlikely. Furthermore, REACH guidance states that a reasonable default assumption is that dermal absorption will not be greater than by the oral route (ECHA, 2012) [i.e. <1% in this case]. However, two in vitro permeation studies on a related soluble platinum salt, dipotassium tetrachloroplatinate, showed a greater degree of 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 0.0034 and 0.0005%, respectively (Franken et al., 2015). A slightly earlier publication reported mean skin diffusion and receptor solution percentages of 2.2% and 0.00023%, 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 Pt compounds.

Specific expert guidance on the health risk assessment of metals states that “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). KC was found to be non-corrosive and non-irritating in vitro, and thus the potential for disruption of the skin barrier (potentially facilitating a greater degree of dermal uptake) is anticipated to be minimal.

Absorption - TMDS

A single bolus dose of 0 (controls), 500, 1000 or 2000 mg TMDS/kg bw was administered to 8 mice/sex/group by oral gavage. Blood samples were collected 1 or 4 hours after dosing and analysed for TMDS level; the limit of quantification of the method was 24 ng TMDS/g plasma. Reported plasma TMDS levels were greater than the limit of quantification for all treated animals at both time points. The peak reported plasma level was 11.2 μg TMDS/g plasma, in males receiving the highest dose analysed 1 hour after administration (OECD, 2013); this equates to < 0.03% absorption[2].

No substance-specific data on the absorption of TMDS by the inhalation or dermal routes are available.

Absorption – Key values for CSA

The available data suggest that both Pt and TMDS are individually very poorly absorbed after oral administration; it is currently unknown whether their complexation has any effect on their absorption. Nevertheless, following ECHA guidance and aiming to maintain a suitably health-precautionary figure for use in subsequent risk and exposure assessments, a figure of 0.5% oral absorption has been taken forward, based on the findings for Pt in rats and for TMDS in mice.

Due to the molecular weight of KC, and the chemical nature of the TMDS ligand, it is unclear how the available data on other Pt salts correspond to the potential behaviour of this complex. Further, while it is very unlikely that exposure to KC via the lungs will be significant, ECHA guidance notes “that if data on the starting route (oral) are available these should be used, but for the end route (inhalation), the worst case inhalation absorption should still be assumed (i.e. 100%)”. Therefore, the health-precautionary figure of 100% as recommended by ECHA has been taken forward for the CSA, ensuring the most health-precautionary DNEL is derived.

For dermal absorption, the combination of default values and considerations from the data are somewhat conflicting. Absorption in the range indicated by oral studies (i.e. <1%), as suggested by ECHA guidance and ICMM (2007), seems to be too low when considering the in vitro studies on human skin (Franken et al., 2014, 2015). However, assuming 100% absorption would be overestimating the dermal absorption potential considering its lack of corrosivity or irritation potential. A value of 10% dermal absorption for use in CSA is considered appropriate.

Distribution/Metabolism

No information is available on whether or not the KC complex breaks down in any way after administration (e.g. whether there is dissociation prior to Pt uptake). Once absorbed, distribution of Pt and TMDS throughout the body is expected based on a relatively low molecular weight (~381 g/mol) and water solubility of KC, and also Pt levels detected in plasma following oral (gavage) administration (part of a OECD 422 study).

In Moore et al.’s study (1975b), platinum was found in the liver and kidney of rats gavaged with radiolabelled-PtCl4, although levels in other organs were not significantly above background. Other investigators have detected Pt in the liver, kidney, spleen, lung and testis following gavage administration (Lown et al., 1980). A range of other studies, summarised by the US EPA, concur with these findings, with the kidney clearly the most significant site of deposition. A similar pattern was observed following inhalation (US EPA, 2009).

No substance-specific data on the tissue distribution of TMDS are available. However, it is known to cause particular effects on the reproductive system, indicating that TMDS or its metabolites does reach these tissues.

Elimination

In rats given gavage doses of radiolabelled-platinum compounds, absorbed Pt was found to be excreted in the urine and faeces (Moore et al., 1975b). However, given that oral absorption was so low, faecal excretion of unabsorbed Pt during the first 1-2 days after administration contributed substantially to the detected levels (US EPA, 2009).

KC is considered to have a potential for bioaccumulation in the adipose tissues based on its physico-chemical properties (notably its low water solubility of 35 mg/L and high calculated partition co-efficient of 5.96). Further, the toxicokinetic portion of the OECD 422 study on KC showed “a clear accumulation of Pt in the plasma” of animals dosed for 28 days (Leuschner, 2014). No data are available on the elimination/excretion of TMDS.

Conclusion

Experimental data suggest that KC is likely to be poorly absorbed after administration by the oral route. Based on its physico-chemical properties, KC has the potential to bioaccumulate in adipose tissues. Inhalation is not anticipated to be a significant route of exposure and significant inhalation absorption is unlikely given its relatively low water solubility and low molecular weight. However, ECHA guidance notes “that if data on the starting route (oral) are available these should be used, but for the end route (inhalation), the worst case inhalation absorption should still be assumed (i.e. 100%)”. A high dermal absorption is also unlikely.

Absorption values of 0.5%, 100% and 10% for the oral, inhalation and dermal routes, respectively, are proposed for the CSA, and considered health-precautionary for use in the calculation of DNEL values.

 

[1] Based on reported body weights for female rats (approx. 270 g) and an assumed plasma volume of 20 mL for those rats. 1200 μg Pt/L plasma = 24 μg Pt/rat = 89 μg/kg bw∴< 0.02% of a gavage dose of 500 mg/kg bw.

[2] Based on an estimated body weight of 30 g, an assumed plasma volume of 1.5 mL for those mice (50 mL/kg bw). 11.2 μg TMDS/g plasma = 17.24 μg Pt/rat = 575 μg/kg bw,∴< 0.03% of a gavage dose of 2000 mg/kg bw.

References not included elsewhere:

ECHA (2012). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Reference: ECHA-2010-G-19-EN. Version 2.1. November 2012. http://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf

ECHA (2014). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7c: endpoint specific guidance. Version 2.0. November 2014.

Franken A, Eloff FC, du Plessis J, Badenhorst CJ, Jordaan A and Du Plessis JL (2014). In vitro permeation of platinum and rhodium through Caucasian skin. Toxicology in Vitro 28, 1396 1401.

Franken A, Eloff FC du Plessis J, Badenhorst CJ and Du Plessis JL (2015). In vitro permeation of platinum through African and Caucasian skin. Toxicology Letters 232, 566-572.

ICMM (2007). International Council on Mining & Metals. Health risk assessment guidance for metals. September 2007.

Lown BA, Morganti JB, Stineman CH, D’Agostino RB and Massaro EJ (1980). Tissue organ distribution and behavioral effects of platinum following acute and repeated exposure of the mouse to platinum sulfate. Environmental Health Perspectives 34, 203-212. 

Moore W, Jr, Malanchuk M, Crocker W, Hysell D, Cohen A and Stara JF (1975a). Whole body retention in rats of different 191Pt compounds following inhalation exposure. Environmental Health Perspectives 12, 35-39.

Moore W, Hysell D, Hall L, Campbell K and Stara J (1975b). Preliminary studies on the toxicity and metabolism of palladium and platinum. Environmental Health Perspectives 10, 63-71.

Moore W, Jr, Hysell D, Crocker W and Stara J (1975c). Biological fate of a single administration of 191Pt in rats following different routes of exposure. Environmental Research 9, 152-158.

OECD (2013). SIDS Dossier, approved at CoCAM 5 (15 October 2013), for 1,1,3,3-tetramethyl-1,3-divinyl-siloxane. Available via http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=15AB83CB-F675-4C45-95A2-575C40B3CE32, accessed 28 April 2017.

Schierl R, Fries HG, van de Weyer C and Fruhmann G (1998). Urinary excretion of platinum from platinum industry workers. Occupational and Environmental Medicine 55, 138-140.

US EPA (2009). United States Environmental Protection Agency. Toxicological review of halogenated platinum salts and platinum compounds in support of summary information on the Integrated Risk Information System (IRIS). January 2009 Draft. EPA/635/R-08/018. https://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=513625