Dihydrogen tetrachloropalladate(2-)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.9 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

Value:

814.5 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 and reproductive/developmental toxicity study; the dietary levels were set with the aim of achieving a dose of 1000 mg/kg bw/day in the high dose group, though this was around 786.1 mg/kg bw/day in reality

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation. Male animals were dosed for 28-days in total, while low- and mid-dose females received treatment for a longer period of time (cfr. OECD422 guideline)

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF of 4 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:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.1 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

Value:

231 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 and reproductive/developmental toxicity study; the dietary levels were set with the aim of achieving a dose of 1000 mg/kg bw/day in the high dose group, though this was around 786.1 mg/kg bw/day in reality

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation. Male animals were dosed for 28-days in total, while low- and mid-dose females received treatment for a longer period of time (cfr. OECD422 guideline)

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 palladium 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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

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

Justification for route to route extrapolation

As no relevant data on effects of repeated exposure to dihydrogen tetrachloropalladate in humans or laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a combined repeated dose and reproductive/developmental oral toxicity study on disodium tetrachloropalladate, a substance that was considered to fall in the same category of tetrachloropalladate substances. Data for category member substances are considered equally applicable amongst each other and thus a suitable alternative for category member substances without substance specific data..

A GLP-compliant repeated dose toxicity study combined with reproductive toxicity screening (according to OECD422) with disodium tetrachloropalladate is available (Szaloki, 2022). This study is used as basis for route-to-route extrapolation to calculate an inhalation DNEL.

The oral NOAEL for disodium tetrachloropalladate is 272 mg/kg(bw)/day. This value is protective against systemic effect, reproductive effects and effects on pup development and growth. Via molecular weight conversion, the corresponding value for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/d.

In the absence of data allowing quantitative comparison between absorption following oral and inhalation exposure, this derivation utilised the REACH default assumption that the absorption percentage for the oral route is half that of the inhalation route, and a default factor of 2 is proposed for absorption differences in the case of oral-to-inhalation extrapolation.

 

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

= 231 mg/kg bw/day*(1/0.38 m³/kg bw/day)*(1/2)*(6.7 m³ [8h]/10 m³ [8h]) =203.7 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 palladium is excreted predominantly via the biliary/faecal route.

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 = 203.7*4 = 814.5 mg/m³.

 

 

Justification and comments

No relevant data on effects of repeated exposure to dihydrogen tetrachloropalladate in humans or laboratory animals are available. Disodium tetrachloropalladate is considered to fall in the same category of tetrachloropalladate substances. Data for category member substances are considered equally applicable amongst each other and thus a suitable alternative for category member substances without substance specific data.

A GLP-compliant study according to OECD N°422 was performed to obtain information on the possible effects on toxicity and reproductive performance of disodium tetrachloropalladate following repeated (daily) administration at a constant concentration in pelleted diet to Wistar (Crl:WI) rats at 3 dose levels (1000, 3000 and 10000 ppm test item in diet). A control group received non-treated control diet.

Under the conditions of this study, the dietary administration of disodium tetrachloropalladate to Wistar rats did not result in test item related mortality.

The NOAEL for systemic toxicity of the parental generation was 3000 ppm (corresponding to 272 mg/kg bw/day) based on effects on body weight, body weight gain and food consumption at 10000 ppm. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/day.

The NOAEL for reproductive effects of the parental generation 10000 ppm (corresponding to 786 mg/kg bw/day) based on no test item related adverse reproductive effects. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 668 mg/kg(bw)/day.

The NOAEL for pup development and survival was 3000 ppm (corresponding to 272 mg/kg bw/day). Effects on the mean High dose pup body weight and body weight gain were considered as secondary to maternal toxicity, as High dose females showed body weight loss during gestation and the effect on final body weights exceeded the MTD. Dam intake was >1000 mg/kg bw/day during lactation for High dose females. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/day.

Considering the outcome of this assay, the use of a NOAEL = 272 mg/kg(bw)/d is considered suitably protective of systemic and reproductive effects.
Hence, the NOAEL of 272 mg/kg bw/day was taken as the critical point of departure for calculating the long-term systemic DNELs for disodium tetrachloropalladate and is considered protective. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/day.

 

 

Hazard via inhalation route: systemic effects following acute exposure

Justification and comments

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 exposure to dihydrogen tetrachloropalladate. In a guideline (OECD TG 401) acute oral toxicity study in rats with dihydrogen tetrachloropalladate, the LD50 value was determined to lie between 200 and 2000 mg/kg bw (van Huygevoort, 2003a). The compound is classified in Category 4 according to CLP criteria. An oral N(L)OAEL (for sub-lethal effects) could be modified into an inhalation N(L)OAEC using route-to-route extrapolation. However, ECHA (2012a) guidance on DNEL calculation notes that this “procedure introduces significant uncertainties especially in relation to what inhalation time-frame this extrapolated N(L)OAEC would represent, and the procedure is therefore discouraged”.

As the substance is marketed or used in a non solid or granular form, inhalation is not considered to be a significant route of exposure.

Further, given that the long-term systemic inhalation DNEL is high (above 10 mg/m³), setting acute DNELs is unnecessary, based on the high-level principle referenced in ECHA (2012a). This criterion states that “As a rule of thumb, a DNELacute should be set for acutely toxic substances if actual peak exposure levels significantly exceed the long-term DNEL”. This is typically inferred to mean several fold exceedance for task-based (e.g. 15 minute TWA) situations. The foreseeable industrial situations are highly unlikely to result in airborne peak exposures well above 10 mg/m³ as these would not be tolerated in the workplaces (due to the general standards applicable to control of particulates). Long-term DNELs for systemic effects are expected to be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNEL for acute systemic toxicity has been calculated.

“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 tetrachloropalladate is classified in Category 4, so a qualitative assessment is not required.

 

 

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

Justification and comments

There are no data in relation to respiratory tract irritation or sensitisation in humans or laboratory animals. Consequently, no worker-DNELs for respiratory tract irritation/corrosion or sensitisation have been calculated.

However, according to ECHA (2012b) guidance (Part E), “since sensitisation is essentially systemic in nature, it is important for the purposes of risk management to acknowledge that skin sensitisation may be acquired by other routes of exposure than dermal. There is therefore a need for cautious use of known contact allergens in products to which consumers or workers may be exposed by inhalation”.

Dihydrogen tetrachloropalladate is classified as a strong skin sensitiser (category 1A). Therefore, consider recommended Risk Management Measures/Operational Conditions (RMMs/OCs) in Table E.3-1 of ECHA (2012b).

 

 

 

Hazard via inhalation route: local effects following acute exposure

Justification and comments

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

However, according to ECHA (2012b) guidance “since sensitisation is essentially systemic in nature, it is important for the purposes of risk management to acknowledge that skin sensitisation may be acquired by other routes of exposure than dermal. There is therefore a need for cautious use of known contact allergens in products to which consumers or workers may be exposed by inhalation”.

Dihydrogen tetrachloropalladate is classified as a strong skin sensitiser (category 1A). Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2012b).

 

 

 

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

Justification for route to route extrapolation

As no relevant data on effects of repeated exposure to dihydrogen tetrachloropalladate in humans or laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a combined repeated dose and reproductive/developmental oral toxicity study on disodium tetrachloropalladate, a substance that was considered to fall in the same category of tetrachloropalladate substances. Data for category member substances are considered equally applicable amongst each other and thus a suitable alternative for category member substances without substance specific data..

A GLP-compliant repeated dose toxicity study combined with reproductive toxicity screening (according to OECD422) with disodium tetrachloropalladate is available (Szaloki, 2022). This study is used as basis for route-to-route extrapolation to calculate an inhalation DNEL.

The oral NOAEL for disodium tetrachloropalladate is 272 mg/kg(bw)/day. This value is protective against systemic effect, reproductive effects and effects on pup development and growth. Via molecular weight conversion, the corresponding value for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/d.

Dihydrogen tetrachloropalladate, with water solubility in excess of 10,000 mg/L (Gregory, 2014), may be unable to cross the lipid-rich environment of the stratum corneum. However, based on a mean breakthrough time of about 3 minutes in an in vitro membrane barrier test (BSL Bioservice, 2013), the compound is classified as corrosive sub-category 1A. This corrosive potential may disrupt skin barrier function, facilitating dermal penetration. As such, it is considered health precautionary to take forward the ECHA default dermal absorption value of 100%.

In the absence of data allowing quantitative comparison between absorption following oral and dermal exposure, and noting that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor of 1) is required for oral-to-dermal extrapolation, in line with ECHA (2012a) guidance.

 

Justification and comments

No relevant data on effects of repeated exposure to dihydrogen tetrachloropalladate in humans or laboratory animals are available. Disodium tetrachloropalladate is considered to fall in the same category of tetrachloropalladate substances. Data for category member substances are considered equally applicable amongst each other and thus a suitable alternative for category member substances without substance specific data

A GLP-compliant study according to OECD N°422 was performed to obtain information on the possible effects on toxicity and reproductive performance of disodium tetrachloropalladate following repeated (daily) administration at a constant concentration in pelleted diet to Wistar (Crl:WI) rats at 3 dose levels (1000, 3000 and 10000 ppm test item in diet). A control group received non-treated control diet.

Under the conditions of this study, the dietary administration of disodium tetrachloropalladate to Wistar rats did not result in test item related mortality.

The NOAEL for systemic toxicity of the parental generation was 3000 ppm (corresponding to 272 mg/kg bw/day) based on effects on body weight, body weight gain and food consumption at 10000 ppm. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/day.

The NOAEL for reproductive effects of the parental generation 10000 ppm (corresponding to 786 mg/kg bw/day) based on no test item related adverse reproductive effects. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 668 mg/kg(bw)/day.

The NOAEL for pup development and survival was 3000 ppm (corresponding to 272 mg/kg bw/day). Effects on the mean High dose pup body weight and body weight gain were considered as secondary to maternal toxicity, as High dose females showed body weight loss during gestation and the effect on final body weights exceeded the MTD. Dam intake was >1000 mg/kg bw/day during lactation for High dose females. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/day.

Considering the outcome of this assay, the use of a NOAEL = 272 mg/kg(bw)/d is considered suitably protective of systemic and reproductive effects.
Hence, the NOAEL of 272 mg/kg bw/day was taken as the critical point of departure for calculating the long-term systemic DNELs for disodium tetrachloropalladate and is considered protective. Using molecular weight conversion, the corresponding NOAEL for dihydrogen tetrachloropalladate is 231 mg/kg(bw)/day.

 

 

 

Hazard via dermal route: systemic effects following acute exposure

Justification and comments

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).

No acute dermal toxicity study was conducted. In a guideline (OECD TG 401) acute oral toxicity study in rats with dihydrogen tetrachloropalladate, the LD50 value was determined to lie between 200 and 2000 mg/kg bw (van Huygevoort, 2003a). The compound is classified in Category 4 according to CLP criteria.

The long-term systemic dermal DNEL is 3.1 mg/kg bw/day. Setting acute DNELs is unnecessary, based on the high-level principle referenced in ECHA (2012a). This criterion states that “As a rule of thumb, a DNELacute should be set for acutely toxic substances if actual peak exposure levels significantly exceed the long-term DNEL”.

The foreseeable industrial situations are highly unlikely to result in peak exposures well above 3.1 mg/kg bw/day due to the general standards applicable to control.

Long-term DNELs for systemic effects are expected to be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNEL for acute systemic toxicity has been calculated.

“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 tetrachloropalladate is classified in Category 4, so a qualitative assessment is not required.

 

 

 

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

Justification and comments

In a guideline (OECD TG 435) in vitro membrane barrier test, dihydrogen tetrachloropalladate was classified as corrosive sub-category 1A under GHS, on the basis of a mean breakthrough time of about 3 minutes (Lehmeier, 2013). Further, no dose-response data was available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. At worst this would be considered in the high hazard band according to ECHA (2012b) guidance.

In another guideline (OECD TG 406) study, dihydrogen tetrachloropalladate induced skin sensitisation in the guinea pig maximisation test (GPMT). Evidence of sensitisation was observed in >30% of the treated animals, after induction by intradermal injection (0.05%; a second induction, by topical application at 5%, occurred one week later) and a challenge concentration of 5% applied three weeks later (van Huygevoort, 2003b). The compound is classified for skin sensitisation as Category 1A, under CLP.

According to ECHA (2012b) guidance “strong skin sensitizers (classified in Sub-category 1A in CLP) are allocated to the high hazard band on the basis that exposure to such potent skin sensitising substances should be strictly contained and dermal contact avoided”. Further, “substances classified as Skin corrosive Category 1A according to CLP, which relates to strong corrosive effects, are allocated to the high hazard band on the basis that exposure to such extreme corrosive substances should be strictly contained”.

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

 

 

Hazard via dermal route: local effects following acute exposure

Justification and comments

In a guideline (OECD TG 435) in vitro membrane barrier test, dihydrogen tetrachloropalladate was classified as corrosive sub-category 1A under GHS, on the basis of a mean breakthrough time of about 3 minutes (Lehmeier, 2013). Further, no dose-response data was available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. At worst this would be considered in the high hazard band according to ECHA (2012b) guidance.

In another guideline (OECD TG 406) study, dihydrogen tetrachloropalladate induced skin sensitisation in the GPMT. Evidence of sensitisation was observed in >30% of the treated animals (van Huygevoort, 2003b). The compound is classified for skin sensitisation as Category 1A, under CLP.

According to ECHA (2012b) guidance “strong skin sensitizers (classified in Sub-category 1A in CLP) are allocated to the high hazard band on the basis that exposure to such potent skin sensitising substances should be strictly contained and dermal contact avoided”. Further, “substances classified as Skin corrosive Category 1A according to CLP, which relates to strong corrosive effects, are allocated to the high hazard band on the basis that exposure to such extreme corrosive substances should be strictly contained”.

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

 

 

 

Hazard for the eyes

Justification and comments

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

No dose-response data was available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. Substances classified for serious eye damage (Category 1 in CLP) should be allocated to the “moderate hazard band on the basis that exposure to such corrosives, eye damaging or irritant substances should be well-controlled”. Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2012b).

 

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 dihydrogen tetrachloropalladate, no uses have been identified in which consumers are exposed to dihydrogen tetrachloropalladate. In all uses with potential consumer exposure due to service life of articles, dihydrogen tetrachloropalladate is chemically transformed into another substance before reaching the consumers, and the subsequent lifecycle steps after this transformation of dihydrogen tetrachloropalladate 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 dihydrogen tetrachloropalladate 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.