Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.19 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:

14.1 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 reproductive/developmental toxicity study; the highest dose was set at 100 mg/kg bw/day on the basis of a 14-day dose range finding study (the aim was to induce toxic effects but no death or suffering at the highest dose and to achieve a NOAEL at the lowest dose)

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 (incorporating the gestation period and proceeding up until postpartum day 4)

AF for interspecies differences (allometric scaling):

1

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not requiredDefault 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. Read-across from the structurally-similar compound, tetraamminepalladium hydrogen carbonate was used to fill the repeated dose toxicity (oral) endpoint. No AF is considered necessary for the use of read-across since the source substance displays a high degree of similarity to the target compound. Notably, the counter ions (chloride or hydrogen carbonate) are not anticipated to differentially influence the toxicity of the palladium (2+) species. Further, the systemic DNEL is based on the results of a reproductive/developmental toxicity study on tetraamminepalladium dichloride

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:

0.27 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:

20 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 reproductive/ developmental toxicity study; the highest dose was set at 100 mg/kg bw/day on the basis of a 14-day dose range finding study (the aim was to induce toxic effects but no death or suffering at the highest dose and to achieve a NOAEL at the lowest dose)

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 (incorporating the gestation period and proceeding up until postpartum day 4)

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. Read-across from the structurally-similar compound, tetraamminepalladium hydrogen carbonate was used to fill the repeated dose toxicity (oral) endpoint. No AF is considered necessary for the use of read-across since the source substance displays a high degree of similarity to the target compound. Notably, the counter ions (chloride or hydrogen carbonate) are not anticipated to differentially influence the toxicity of the palladium (2+) species. Further, the systemic DNEL is based on the results of a reproductive/developmental toxicity study on tetraamminepalladium dichloride

AF for remaining uncertainties:

1

Justification:

Not required

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

low 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 effects of repeated inhalation exposure to tetraamminepalladium dichloride in humans or laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a reproductive/developmental oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for an inorganic compound).

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)

= 4 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/2)*(6.7 m3 [8h]/10 m3 [8h]) = 3.53 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 = 3.53*4 = 14.1 mg/m3.

Justification and comments

In a OECD Test Guideline 421 reproductive/developmental toxicity study, conducted according to GLP, rats (12/sex/group) received a solution of tetraamminepalladium dichloride by gavage at doses of 0, 4, 20, or 100 mg/kg bw/day for at least 28 days (males were dosed for 28-days in total, while females received treatment for a longer period of time [incorporating the gestation period and proceeding up until postpartum day 4, i.e. around 7-8 weeks]).Effects on the glandular stomach were seen in the high-dose animals, and likely reflect a local effect of treatment. These effects in the glandular stomach may have contributed to the significantly reduced body weight gain seen in males at 20 and 100 mg/kg bw/day (growth of females was unaffected).The NOAEL for systemic toxicity was 4 mg/kg/day on the basis of reduced growth in males at 20 and 100 mg/kg/day. No test item-related microscopic changes were noted in the reproductive organs. Moreover, no effects on reproductive parameters or indications of maternal/foetal toxicity were observed at any dose level (Török-Bathó, 2015). The possible limitations of this screening 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.

In a guideline (EU Method B.7) 28-day gavage toxicity study on a member of the "tetraamminepalladium salts" category, tetraamminepalladium hydrogen carbonate, a slightly higher NOAEL of 15 mg/kg bw/day was obtained based on microscopic changes in the spleen in high-dose animals (150 mg/kg bw/day) (Wragg et al., 1997).

Hence, the substance-specific systemic NOAEL of 4 mg/kg bw/day for repeated dose effects 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 (0.19 mg/m3) equates to a palladium exposure of 0.08 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 tetraamminepalladium dichloride. In a guideline (OECD TG 401) acute oral toxicity study in rats, on the structurally-related compound tetraamminepalladium hydrogen carbonate, an LD50 value of 933 mg/kg bw (females) was obtained (Allen, 1995). This compound is classified in Category 4 for acute oral toxicity according to CLP. Accordingly, an identical classification was adopted for tetraamminepalladium dichloride. 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”.

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 tetraamminepalladium dichloride <100 μm, as measured by simple sieving, was 16.2% (Atwal, 2011c). Dustiness testing, a more energetic measurement of particle size distribution, with the compound returned a mass median aerodynamic diameter (MMAD) value of 25.7 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 52.5, 0.17 and 0.15% 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 1% is capable of reaching the alveoli. Consequently, inhalation is not considered to be a significant route of exposure.

Further, 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 0.19 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, tetraamminepalladium dichloride 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-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”. Tetraamminepalladium dichloride 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 (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”. Tetraamminepalladium dichloride 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 dermal exposure to tetraamminepalladium dichloride in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a reproductive/developmental oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for inorganic compounds).

Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Tetraamminepalladium dichloride, with water solubility of 327 g/L (Gregory, 2014), 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 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 tetraamminepalladium dichloride.

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]) = 4 mg/kg bw/day*(50%/10%) = 20 mg/kg bw/day

Justification and comments

In a OECD Test Guideline 421 reproductive/developmental toxicity study, conducted according to GLP, rats (12/sex/group) received a solution of tetraamminepalladium dichloride by gavage at doses of 0, 4, 20, or 100 mg/kg bw/day for at least 28 days (males were dosed for 28-days in total, while females received treatment for a longer period of time [incorporating the gestation period and proceeding up until postpartum day 4, i.e. around 7-8 weeks. Effects on the glandular stomach were seen in the high-dose animals, and likely reflect a local effect of treatment. These effects in the glandular stomach may have contributed to the significantly reduced body weight gain seen in males at 20 and 100 mg/kg bw/day (growth of females was unaffected).The NOAEL for systemic toxicity was 4 mg/kg/day on the basis of reduced growth in males at 20 and 100 mg/kg/dayNo test item-related microscopic changes were noted in the reproductive organs. Moreover, no effects on reproductive parameters or indications of maternal/foetal toxicity were observed at any dose level (Török-Bathó, 2015). The possible limitations of this screening 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.

In another guideline (EU Method B.7) 28-day gavage toxicity study on a member of the "tetraamminepalladium salts" category, tetraamminepalladium hydrogen carbonate, a slightly higher NOAEL of 15 mg/kg bw/day was obtained based on microscopic changes in the spleen in high-dose animals (150 mg/kg bw/day) (Wragg et al., 1997).

Hence, the substance-specific systemic NOAEL of 4 mg/kg bw/day for repeated dose effects 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 (0.27 mg/kg bw/day) equates to a palladium exposure of 0.12 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 on tetraamminepalladium dichloride. In a guideline (OECD TG 402) acute dermal toxicity study in rats, on the structurally-related compound tetraamminepalladium hydrogen carbonate, the LD50 value was found to exceed 2000 mg/kg bw (males and females) (Allen, 1997). This compound is not classified for acute dermal toxicity under CLP. Accordingly, an identical lack of classification was expected for tetraamminepalladium dichloride.

As tetraamminepalladium dichloride 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

In a guideline (OECD TG 404) skin irritation study in rabbits, tetraamminepalladium dichloride produced no evidence of skin irritation (Driscoll, 1981). The compound is not classified for skin irritation under CLP.

In another guideline (OECD TG 406) study, tetraamminepalladium dichloride induced skin sensitisation in the guinea pig maximisation test (GPMT). Evidence of sensitisation was observed in 60% of the treated animals (Allen, 2000). 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”.

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 404) skin irritation study in rabbits, tetraamminepalladium dichloride produced no evidence of skin irritation (Driscoll, 1981). The compound is not classified for skin irritation under CLP.

In another guideline (OECD TG 406) study, tetraamminepalladium dichloride induced skin sensitisation in the guinea pig maximisation test (GPMT). Evidence of sensitisation was observed in 60% of the treated animals (Allen, 2000). 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”.

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, tetraamminepalladium dichloride produced severe eye irritation in rabbits (Driscoll and Collier, 1981). The compound is classified in Category 2 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 irritation (Category 2 in CLP) should be allocated to the “low hazard band on the basis that effects due to such moderately irritant substances are anticipated at higher concentrations when compared to the high and moderate hazard band irritants”. Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2012b).

Hazard assessment conclusion: