Disodium tetrachloropalladate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.8 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:

959.1 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 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:

18.1 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:

1 360 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 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 inhalation exposure to disodium tetrachloropalladate in laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a reliable 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).

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.

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)

= 272 mg/kg bw/day*(1/0.38 m³/kg bw/day)*(1/2)*(6.7 m³ [8h]/10 m³ [8h]) =239.8 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 = 239.8*4 = 959.1 mg/m³.

 

 

Justification and comments

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.

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.

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.

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.

 

 

 

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 disodium tetrachloropalladate.

In a guideline (OECD TG 401) acute oral toxicity study in rats with disodium tetrachloropalladate, the LD50 value was determined to be between 500 and 2000 mg/kg bw (Middleton and Husband, 1978). 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”.

Further, high peak exposures are not anticipated. ECHA (2015a,b) guidance on requirements for acute toxicity testing notes that “inhalable particles…are generally smaller than 100 μm in diameter. Particles larger than 100 μm are less likely to be inhalable”. In a guideline (OECD TG 110) granulometry screening test, with the substance as a dry dispersion, the 10th, 50th and 90th percentile average particle sizes for disodium tetrachloropalladate were 115, 597 and 1293 μm, respectively, in the <2 mm fraction (Potthoff, 2015). In addition, dustiness testing (a more energetic particle size distribution measurement) with various other palladium compounds (not including disodium tetrachloropalladate) returned mass median aerodynamic diameter (MMAD) values in the range of 24.1-38.2 μm. An MMAD value <100 μm indicates that a significant proportion of a substance is likely to be inhalable. Respiratory tract deposition modelling with the dustiness data for each of the palladium species yielded output values in the range of 40.0-52.5, 0.12-0.41 and 0.08-0.64% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. Hence, for all of the tested palladium species, very little airborne substance (<1%) is expected to deposit in the lower regions of the human respiratory tract, i.e. the TB or pulmonary regions via oronasal normal augmenter breathing. Similar behaviour is anticipated for disodium tetrachloropalladate. Most of the inhaled fraction is likely to be retained in the head region and therefore would be cleared by ingestion, along with that deposited in the TB region, and oral bioavailability will again predominantly determine systemic uptake. Less than 1% is likely capable of reaching the alveoli. Consequently, inhalation is not anticipated to be a significant route of exposure for disodium tetrachloropalladate.

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). 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, disodium 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”.

Disodium tetrachloropalladate is classified as a skin sensitiser (category 1A), based on substance-specific test data. 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-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”.

Disodium tetrachloropalladate is classified as a skin sensitiser (category 1A), based on substance-specific test data. Therefore, consider recommended Risk Management Measures/Operational Conditions (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 disodium tetrachloropalladate in laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a reliable 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).

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.

 

Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Disodium tetrachloropalladate, with water solubility of 622 g/L (Winde, 2011), may be unable to cross the lipid-rich environment of the stratum corneum, especially given the lack of skin irritation potential (which could, in theory, disrupt skin barrier function). In the light of the limited available experimental data, ECHA guidance indicates a default value of 100% dermal absorption (ECHA, 2014). However, guidance on the health risk assessment of metals indicates that molecular weight and log Pow considerations 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”) and tentatively proposes more conservative dermal absorption figures: 1.0 and 0.1% following exposure to liquid/wet media and dry (dust) respectively (ICMM, 2007). Given the low penetration expected from metals, and the high water solubility (and, thus, low expected lipophilicity), it is suitably health precautionary to take forward the lower of the two ECHA default values for dermal absorption, of 10%, for the safety assessment of disodium tetrachloropalladate.

In the absence of absorption data for the starting route, a pragmatic assumption has to be made (i.e. a limited absorption for the oral route). In line with REACH guidance, it is considered that the absorption percentage for the oral route is 50% (instead of 100%).

Accordingly, use of an oral benchmark to assess a dermal exposure necessitates an increase in the starting point by a corrective factor of 5 to account for the difference in absorption between these two routes.

Dose descriptor starting point (after route to route extrapolation) = NOAEL*(ABS[oral-rat]/ABS[der-human]) = 272 mg/kg bw/day*(50%/10%) = 1360 mg/kg bw/day.

 

Justification and comments

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.

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.

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.

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.

 

 

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 data are available. The existing in vivo skin irritation study on disodium tetrachloropalladate does not include an assessment of systemic effects. No signs of general systemic toxicity were apparent in the skin sensitisation studies on disodium tetrachloropalladate.  Exposure considerations provide good support for the conclusion that an acute dermal toxicity study and hazard classification can be waived. First, disodium tetrachloropalladate is a crystalline solid (Lide, 2008) and skin contact during production and/or use is expected to be very low. Second, disodium tetrachloropalladate is classified for eye irritation and as a skin sensitiser, so appropriate safety labelling, personal protection and RMMs/OCs are required. These will ensure that the potential for skin exposure is minimised. As such, there are sufficient available data for chemical hazard and risk assessment, classification and labelling, and risk mitigation purposes. Further, specific guidance on the health risk assessment of metals (ICMM, 2007) indicates low dermal absorption (up to 1.0%).

As disodium tetrachloropalladate is not classified for acute dermal toxicity, no worker-DNEL for acute systemic toxicity following dermal exposure has been calculated.

 

 

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

Justification and comments

Disodium tetrachloropalladate is classified as a skin sensitiser (category 1A), based on substance-specific test data.

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

Disodium tetrachloropalladate is classified as a skin sensitiser (category 1A), based on substance-specific test data.

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

Disodium tetrachloropalladate is classified for eye effects as Eye damage category 1 under EU CLP on the basis of GLP compliant in vitro test data (OECD437).

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