Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.015 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:
125 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1.09 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 oral combined repeated-dose with reproductive/developmental toxicity screening study.
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:
0.083 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:
125 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
6.25 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 oral combined repeated-dose with reproductive/developmental toxicity screening study.
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:
no hazard identified

Additional information - workers

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

As no relevant data on the effects of repeated inhalation exposure of humans or laboratory animals to Karstedt concentrate are available, route-to-route extrapolation to calculate an inhalation DNEL from a reliable combined repeated-dose with reproductive/developmental toxicity screening study by the oral route was considered a suitable alternative.

 

In a reliable guideline (OECD TG 422) combined repeated dose and reproductive/developmental toxicity screening study, rats received Karstedt concentrate by gavage at doses of 0, 30, 125 or 500 mg/kg bw/day for at least 28 days. Numerous adverse effects were observed at the highest tested dose: in the parental animals these included reduced growth (males), increased adrenal gland weight (absolute and relative; females) and histopathological findings in the lungs, as well as effects on various blood cell parameters; increases in post-implantation loss (3 of 9 dams were outside of the historical control range) and in the number of stillbirths (and an associated decrease in the live birth index) along with reductions in both the viability index and body weight were apparent for the pups. The study no-observed-adverse-effect level (NOAEL) for systemic toxicity was considered to be 125 mg/kg bw/day; NOAELs for fertility/reproductive performance and for effects on pre- and post-natal development were 500 and 125 mg/kg bw/day, respectively (Hansen, 2017). The systemic NOAEL, considered protective of fertility and developmental toxicity, is the most critical, and is taken forward for chemical safety assessment (CSA).

 

The possible limitations of this study, with regards to a thorough assessment of potential reproductive effects, are acknowledged. ECHA (2012a) guidance recommends “application of an additional assessment factor of 2 to 5, decided on a case-by-case basis that should account for the limitations of this study”. Even applying the most conservative of these (i.e. an additional AF of 5) would result in a DNEL higher than that derived for repeated dose effects (as the AF of 6 for differences in duration of exposure would not also be required). 

 

No substance-specific data on inhalation uptake of Karstedt concentrate were identified. 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). No substance-specific data on the absorption of 1,1,3,3-tetramethyl-1,3-diethenyldisiloxane (TMDS) by the inhalation route is available.

 

In the combined OECD 422 study, peak platinum plasma levels of around 1.2 mg/L were measured 6 hours after the first gavage administration of 500 mg Karstedt concentrate/kg bw/day (Hansen, 2017), indicating that oral absorption does occur but is likely (very) low (<0.02%) . The data correlate with other Pt studies, which indicate that absorption, even of water 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 Karstedt concentrate, the corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV) = 125 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(0.5/100)*(6.7 m3 [8h]/10 m3 [8h]) = 1.09 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.

 

Application of the appropriate assessment factors (overall AF 75, described above) to the inhaled NOAEC gives a systemic long-term inhalation DNEL for Karstedt concentrate of 0.015 mg/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 Karstedt concentrate. In a guideline (OECD TG 425) acute oral toxicity study in female rats, the LD50 value was found to exceed 5000 mg/kg bw (Haferkorn, 2016a). The compound is not classified for acute oral toxicity according to CLP criteria.

 

 “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, Karstedt concentrate 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 Karstedt concentrate in humans or laboratory animals. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated. Further, the substance is not classified as a skin irritant or skin sensitiser.

 

 

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

As no relevant data on the effects of repeated dermal exposure of humans or laboratory animals to Karstedt concentrate are available, route-to-route extrapolation to calculate a dermal DNEL from a reliable combined repeated-dose with reproductive/developmental toxicity screening study by the oral route was considered a suitable alternative.

 

This study has already been described above [“Hazard via inhalation route: systemic effects following long-term exposure”] (Hansen, 2017).

 

The oral NOAEL of 125 mg/kg bw/day identified in the combined (OECD TG 422) study, and described above, is considered protective of general systemic effects, fertility and developmental toxicity.

 

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).

 

No substance-specific dermal absorption data are available for Karstedt concentrate, though the low water solubility (35 mg/L; Gregory, 2014) suggests that significant dermal absorption through intact skin is unlikely. However, two in vitro permeation studies on a soluble platinum salt, dipotassium tetrachloroplatinate, indicated a greater degree of dermal absorption [about 5-8%] than the ECHA default assumption [i.e. ≤0.5% on this occasion]. 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 platinum compounds. No substance-specific data on the dermal absorption of TMDS is available.

 

Overall, a high dermal bioavailability is unlikely, notably given the low dermal penetration expected for metals (ICMM, 2007) as well as experimental dermal penetration data (human in vitro study) for a soluble platinum salt [indicating about 2-5% dermal absorption], and considering the observed lack of skin irritation potential (Spruth, 2016a) [which could facilitate a greater degree of dermal uptake] and the physico-chemical properties (low water solubility; estimated log Pow of 5.96 for the organic ligand [US EPA, 2010]) of the substance. As such, it is deemed suitably health precautionary to take forward the lower of the two ECHA (2014) default values for dermal absorption, 10%, for the safety assessment of Karstedt concentrate.

 

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 125 mg/kg bw/day*(0.5%/10%) = 6.25 mg/kg bw/day.

 

Application of the appropriate assessment factors (overall AF 75, described above) to this corrected dermal NOAEL gives a systemic long-term dermal DNEL for Karstedt concentrate of 0.083 mg/kg bw/day.

 

 

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

In a guideline (OECD TG 439) in vitro skin irritation (EpiDerm) study with Karstedt concentrate, the test system skin cell viability was calculated to be greater than 50% and the compound was therefore not classified for skin irritation under CLP (Spruth, 2016a).

 

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

 

 

Hazard for the eyes

In a guideline (OECD TG 437) in vitro bovine corneal opacity and permeability (BCOP) eye irritation study with Karstedt concentrate, the in vitro irritation score was below the cut-off value of 3 and the compound was therefore not classified for eye irritation under EU CLP (Spruth, 2016b).

References (for which a ESR has not been created in IUCLID)

ECHA (2009). European Chemicals Agency. Guidance in a Nutshell: Chemical Safety Assessment. Reference: ECHA-09-B-15-EN. September 2009. http://echa.europa.eu/documents/10162/13632/nutshell_guidance_csa_en.pdf

 

ECHA (2011). European Chemicals Agency. Guidance on information requirements and chemical safety assessment Part B: Hazard assessment. Reference: ECHA-11-G-16-EN. Version 2.1. December 2011. https://echa.europa.eu/documents/10162/13643/information_requirements_part_b_en.pdf

 

ECHA (2012a). 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 (2012b). European Chemicals Agency. Guidance on information requirements and

chemical safety assessment. Part E: Risk Characterisation. ECHA-12-G-16-EN. Version 2.0. November 2012. http://echa.europa.eu/documents/10162/13632/information_requirements_part_e_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. http://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf

 

ECHA (2016). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.16: Environmental exposure assessment. Version 3.0. February 2016. http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

 

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. http://www.icmm.com/document/144

 

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

 

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.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.004 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):
150
Dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
0.543 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 oral combined repeated-dose with reproductive/developmental toxicity screening study
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:
10
Justification:
Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.
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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.042 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):
150
Dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
6.25 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 oral combined repeated-dose with reproductive/developmental toxicity screening study
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:
10
Justification:
Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 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):
150
Dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No extrapolation required

AF for dose response relationship:
1
Justification:
Default ECHA AF; NOAEL from a well-conducted oral combined repeated-dose with reproductive/developmental toxicity screening study
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:
10
Justification:
Default ECHA AF for general population, considered sufficient to protect the larger part of the population (including children, the elderly and pregnant women). In the case of these specific sub-groups, based on the available knowledge, there are no expectations of higher sensitivity for the related endpoint effects, and special exposure circumstances are not envisaged.
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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

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

As no relevant data on the effects of repeated inhalation exposure of humans or laboratory animals to Karstedt concentrate are available, route-to-route extrapolation to calculate an inhalation DNEL from a reliable combined repeated-dose with reproductive/developmental toxicity screening study by the oral route was considered a suitable alternative.

 

In a reliable guideline (OECD TG 422) combined repeated dose and reproductive/developmental toxicity screening study, rats received Karstedt concentrate by gavage at doses of 0, 30, 125 or 500 mg/kg bw/day for at least 28 days. Numerous adverse effects were observed at the highest tested dose: in the parental animals these included reduced growth (males), increased adrenal gland weight (absolute and relative; females) and histopathological findings in the lungs, as well as effects on various blood cell parameters; increases in post-implantation loss (3 of 9 dams were outside of the historical control range) and in the number of stillbirths (and an associated decrease in the live birth index) along with reductions in both the viability index and body weight were apparent for the pups. The study NOAEL for systemic toxicity was considered to be 125 mg/kg bw/day; NOAELs for fertility/reproductive performance and for effects on pre- and post-natal development were 500 and 125 mg/kg bw/day, respectively (Hansen, 2017). The systemic NOAEL, considered protective of fertility and developmental toxicity, is most critical and was taken forward for CSA.

 

The possible limitations of this study, with regards to a thorough assessment of potential reproductive effects, are acknowledged. ECHA (2012a) guidance recommends “application of an additional assessment factor of 2 to 5, decided on a case-by-case basis that should account for the limitations of this study”. Even applying the most conservative of these (i.e. an additional AF of 5) would result in a DNEL higher than that derived for repeated dose effects (as the AF of 6 for differences in duration of exposure would not also be required). 

 

No substance-specific data on inhalation uptake of Karstedt concentrate were identified. 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). No substance-specific data on the absorption of 1,1,3,3-tetramethyl-1,3-diethenyldisiloxane (TMDS) by the inhalation route is available.

 

In the combined OECD 422 study, peak platinum plasma levels of around 1.2 mg/L were measured 6 hours after the first gavage administration of 500 mg Karstedt concentrate/kg bw/day (Hansen, 2017), indicating that oral absorption does occur but is likely (very) low (<0.02%) . The data correlate with other Pt studies, which indicate that absorption, even of water 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 Karstedt concentrate, the corrected inhalatory NOAEC (general population, 24 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) = 125 mg/kg bw/day*(1/1.15 m3/kg bw/day)*(0.5/100) = 0.543 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.

 

Application of the appropriate assessment factors (overall AF 150, described above) to the inhaled NOAEC gives a systemic long-term inhalation DNEL for Karstedt concentrate of 0.0036 mg/m3.

 

 

Hazard via inhalation, dermal or oral 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 Karstedt concentrate. In a guideline (OECD TG 425) acute oral toxicity study in female rats, the LD50 value was found to exceed 5000 mg/kg bw (Haferkorn, 2016a). The compound is not classified for acute oral toxicity according to CLP criteria.

 

 “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, Karstedt concentrate 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 Karstedt concentrate in humans or laboratory animals. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated. Further, the substance is not classified as a skin irritant or skin sensitiser.

 

 

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

As no relevant data on the effects of repeated dermal exposure of humans or laboratory animals to Karstedt concentrate are available, route-to-route extrapolation to calculate a dermal DNEL from a reliable combined repeated-dose with reproductive/developmental toxicity screening study by the oral route was considered a suitable alternative.

 

This study has already been described above [“Hazard via inhalation route: systemic effects following long-term exposure”] (Hansen, 2017).

 

The oral NOAEL of 125 mg/kg bw/day identified in the combined (OECD TG 422) study, and described above, is considered protective of general systemic effects, fertility and developmental toxicity.

 

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).

 

No substance-specific dermal absorption data are available for Karstedt concentrate, though the low water solubility (35 mg/L; Gregory, 2014) suggests that significant dermal absorption through intact skin is unlikely. However, two in vitro permeation studies on a soluble platinum salt, dipotassium tetrachloroplatinate, indicated a greater degree of dermal absorption [about 5-8%] than the ECHA default assumption [i.e. ≤0.5% on this occasion]. 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 platinum compounds. No substance-specific data on the dermal absorption of TMDS is available.

 

Overall, a high dermal bioavailability is unlikely, notably given the low dermal penetration expected for metals (ICMM, 2007) as well as experimental dermal penetration data (human in vitro study) for a soluble platinum salt [indicating about 2-5% dermal absorption], and considering the observed lack of skin irritation potential (Spruth, 2016a) [which could facilitate a greater degree of dermal uptake] and the physico-chemical properties (low water solubility; estimated log Pow of 5.96 for the organic ligand [US EPA, 2010]) of the substance. As such, it is deemed suitably health precautionary to take forward the lower of the two ECHA (2014) default values for dermal absorption, 10%, for the safety assessment of Karstedt concentrate.

 

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 125 mg/kg bw/day*(0.5%/10%) = 6.25 mg/kg bw/day.

 

Application of the appropriate assessment factors (overall AF 150, described above) to this corrected dermal NOAEL gives a systemic long-term dermal DNEL for Karstedt concentrate of 0.042 mg/kg bw/day.

 

 

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

In a guideline (OECD TG 439) in vitro skin irritation (EpiDerm) study with Karstedt concentrate, the test system skin cell viability was calculated to be greater than 50% and the compound was therefore not classified for skin irritation under CLP (Spruth, 2016a).

 

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

 

 

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

A reliable combined repeated-dose with reproductive/developmental toxicity screening study by the oral route was used to calculate a DNEL for this route.

 

This study has already been described above [“Hazard via inhalation route: systemic effects following long-term exposure”] (Hansen, 2017).

 

The oral NOAEL of 125 mg/kg bw/day identified in the combined (OECD TG 422) study, and described above, is considered protective of general systemic effects, fertility and developmental toxicity.

 

Application of the appropriate assessment factors (overall AF 150, described above) to this NOAEL gives a systemic long-term oral DNEL for Karstedt concentrate of 0.83 mg/kg bw/day.

 

 

Hazard for the eyes

In a guideline (OECD TG 437) in vitro bovine corneal opacity and permeability (BCOP) eye irritation study with Karstedt concentrate, the in vitro irritation score was below the cut-off value of 3 and the compound was therefore not classified for eye irritation under EU CLP (Spruth, 2016b).

 

References (for which a ESR has not been created in IUCLID)

ECHA (2009). European Chemicals Agency. Guidance in a Nutshell: Chemical Safety Assessment. Reference: ECHA-09-B-15-EN. September 2009. http://echa.europa.eu/documents/10162/13632/nutshell_guidance_csa_en.pdf

 

ECHA (2011). European Chemicals Agency. Guidance on information requirements and chemical safety assessment Part B: Hazard assessment. Reference: ECHA-11-G-16-EN. Version 2.1. December 2011. https://echa.europa.eu/documents/10162/13643/information_requirements_part_b_en.pdf

 

ECHA (2012a). 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 (2012b). European Chemicals Agency. Guidance on information requirements and

chemical safety assessment. Part E: Risk Characterisation. ECHA-12-G-16-EN. Version 2.0. November 2012. http://echa.europa.eu/documents/10162/13632/information_requirements_part_e_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. http://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf

 

ECHA (2016). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.16: Environmental exposure assessment. Version 3.0. February 2016. http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

 

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. http://www.icmm.com/document/144

 

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

 

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.