Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

352.6 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; Systemic NOAEL from a well-conducted 28-day gavage study; the highest dose was set at 100 mg/kg bw/day on the basis of a 14-day dose range finding study (doses of 300 and 600 mg/kg bw/day were considered to be higher than the maximum tolerated)

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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.33 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEL

Value:

100 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; Systemic NOAEL from a well-conducted 28-day gavage study; the highest dose was set at 100 mg/kg bw/day on the basis of a 14-day dose range finding study (doses of 300 and 600 mg/kg bw/day were considered to be higher than the maximum tolerated)

AF for differences in duration of exposure:

6

Justification:

Default ECHA AF for subacute (28-day) to chronic extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

The default ECHA AF of 4 for rat for toxicokinetic differences in metabolic rate (allometric scaling) is considered unnecessary as the compound is inorganic and is consequently not metabolised to any relevant extent. Moreover, ECHA guidance notes that “allometric scaling is an empirical approach for interspecies extrapolation of various kinetic processes generally applicable to substances which are renally excreted”, while systemically available 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

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

medium hazard (no threshold derived)

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

Justification for route to route extrapolation

As no relevant data on the effects of repeated inhalation exposure to diammonium hexachloropalladate in humans or 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).

The oral NOAEL was 100 mg/kg bw/day, equating to 30 mg/kg bw/day as palladium (based on MWt ratio).

In the absence of data allowing quantitative comparison between the extent of absorption following inhalation and oral exposure, this derivation utilises the REACH guidance 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)

= 100 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/2)*(6.7 m3 [8h]/10 m3 [8h]) = 88.2 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 = 88.2*4 = 352.6 mg/m3.

Justification and comments

In a guideline (OECD TG 407) 28-day gavage toxicity study in rats, the systemic NOAEL was the highest tested dose (100 mg/kg bw/day). Although there were some treatment-related effects at this dose (histological inflammation of the glandular stomach mucosa of both sexes and elevated mean white blood cell counts in males), these were considered to reflect a local irritant effect of the test substance rather than systemic toxicity (Matting, 2015).

In another guideline study (OECD TG 421), parental animals displayed similar effects in the glandular stomach mucosa as those seen in the 28-day toxicity study at the top tested dose (100 mg/kg bw/day). No systemic effects were seen in the parenteral animals at this dose (Török-Bathó, 2015).

Further,no reproductive/developmental toxicity was observed in this study(Török-Bathó, 2015) following gavage dosing of rats at the highest tested dose (100 mg/kg bw/day). The possible limitations of this study, as reassurance of an absence of 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) results 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).

Hence, the systemic NOAEL of 100 mg/kg bw/day (equivalent to 30 mg/kg bw/day as palladium) from the repeated dose study was taken as the critical point of departure for calculating the long-term systemic DNELs, and is considered protective of fertility and developmental toxicity.

The DNEL (4.70 mg/m3) equates to a palladium exposure of 1.41 mg/m3.

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 diammonium hexachloropalladate. In a guideline (OECD TG 401) acute oral toxicity study in rats, an LD50 value of 1226 mg/kg bw (males and females combined) was obtained (Dreher, 1989). The compound is classified in Category 4 for acute oral toxicity 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, the proportion of diammonium hexachloropalladate <100 μm, as measured by simple sieving, was 0.1% (Tremain, 2011c). Dustiness testing, a more energetic measurement of particle size distribution, with diammonium hexachloropalladate returned a mass median aerodynamic diameter (MMAD) value of 28.6 μm (Parr, 2011; Selck and Parr, 2011), indicating that a significant proportion of the substance is likely to be inhalable. Nevertheless, respiratory tract deposition modelling with the dustiness data yielded output values of 48.0, 0.11 and 0.062% for the nasopharyngeal (head), tracheobronchial (TB) and pulmonary regions of the respiratory tract, respectively. Hence, very little airborne substance (<1%) will be deposited in the lower regions of the human respiratory tract, i.e. the TB or pulmonary regions via oronasal normal augmenter breathing. 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 0.1% is likely capable of reaching the alveoli. Consequently, inhalation is not considered to be a significant route of exposure.

Further, given that the long-term systemic inhalation DNEL is relatively high (4.70 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 4.70 mg/m3as 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, diammonium hexachloropalladate is only 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-DNEL for respiratory tract irritation/corrosion or sensitisation has 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”. Diammonium hexachloropalladate is classified as a moderate skin sensitiser. 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 (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”. Diammonium hexachloropalladate is classified as a moderate skin sensitiser. 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 the effects of repeated dermal exposure to diammonium hexachloropalladate in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a repeated dose oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for an inorganic compound).

The oral NOAEL was 100 mg/kg bw/day, equating to 30 mg/kg bw/day as palladium (based on MWt ratio).

Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Diammonium hexachloropalladate, with a water solubility in excess of 10,000 mg/L (Gregory, 2014), may be unable to cross the lipid-rich environment of the stratum corneum. In the light of the limited available experimental data, ECHA guidance indicates that a default value of 100% dermal absorption should be used (ECHA, 2014). However, specific 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 dermal absorption figures: 1.0 and 0.1% following exposure to liquid/wet media and dry (dust) respectively (ICMM, 2007). Nevertheless, diammonium hexachloropalladate is classified as a skin irritant. This is based on the observation of moderate skin irritation in a GLP study in rabbits (Guest, 1989a). Such irritant 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

In a guideline (OECD TG 407) 28-day gavage toxicity study in rats, the systemic NOAEL was the highest tested dose (100 mg/kg bw/day). Although there were some treatment-related effects at this dose (histological inflammation of the glandular stomach mucosa of both sexes and elevated mean white blood cell counts in males), these were considered to reflect a local irritant effect of the test substance rather than systemic toxicity (Matting, 2015).

In another guideline study (OECD TG 421), parental animals displayed similar effects in the glandular stomach mucosa as those seen in the 28-day toxicity study at the top tested dose (100 mg/kg bw/day), although no systemic effects were seen in the parenteral animals at this dose (Török-Bathó, 2015).

Further, no reproductive/developmental toxicity was observed in this study(Török-Bathó, 2015) following gavage dosing of rats at the highest tested dose (100 mg/kg bw/day). The possible limitations of this study, as reassurance of an absence of 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) results 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).

Hence, the systemic NOAEL of 100 mg/kg bw/day (equivalent to 30 mg/kg bw/day as palladium) from the repeated dose study was taken as the critical point of departure for calculating the long-term systemic DNELs, and is considered protective of fertility and developmental toxicity.

The DNEL (1.33 mg/kg bw/day) equates to a palladium exposure of 0.40 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, an LD50 value of 1226 mg/kg bw (males and females combined) was obtained (Dreher, 1989). The compound is classified in Category 4 for acute oral toxicity according to CLP criteria.

Skin contact to diammonium hexachloropalladate during production and/or use is expected to be negligible. Given that the long-term systemic dermal DNEL is relatively high (1.33 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”. As consumer exposure is expected to be negligible, such peak exposures are not anticipated. Consequently, no worker-DNEL for acute systemic dermal 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, diammonium hexachloropalladate is only 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 GLP skin irritation study in rabbits, equivalent to guideline (OECD TG 404), diammonium hexachloropalladate produced moderate skin irritation (Guest, 1989a). The compound is classified for skin irritation as Category 2 under CLP. 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 low hazard band according to ECHA (2012b) guidance.

In another guideline (OECD TG 429) study, diammonium hexachloropalladate induced skin sensitisation in the mouse local lymph node assay (LLNA). The calculated Effect Concentration 3 (EC3) value was 11.9% (Valiczko, 2013). The compound is classified for skin sensitisation as Category 1B, under CLP.

According to ECHA (2012b) guidance “moderate skin sensitisers (classified in Sub-category 1B in CLP) are allocated to the moderate hazard category band on the basis that exposure to these moderate skin sensitising substances should be well-controlled”.

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 GLP skin irritation study in rabbits, equivalent to guideline (OECD TG 404), diammonium hexachloropalladate produced moderate skin irritation (Guest, 1989a). The compound is classified for skin irritation as Category 2 under CLP. 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 low hazard band according to ECHA (2012b) guidance.

In another guideline (OECD TG 429) study, diammonium hexachloropalladate induced skin sensitisation in the mouse LLNA. The calculated Effect Concentration 3 (EC3) value was 11.9% (Valiczko, 2013). The compound is classified for skin sensitisation as Category 1B, under CLP.

According to ECHA (2012b) guidance “moderate skin sensitisers (classified in Sub-category 1B in CLP) are allocated to the moderate hazard category band on the basis that exposure to these moderate skin sensitising substances should be well-controlled”.

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

Hazard for the eyes

Justification and comments

In a guideline (OECD TG 405) eye irritation study, diammonium hexachloropalladate produced very severe eye irritation in a single male rabbit (due to signs of distress, the animal was killed 1 hour after treatment and no further animals were tested) (Guest, 1989b). The compound is classified 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).

Hazard assessment conclusion: