Diamminedichloropalladium

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.5 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:

1 315 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 831 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 (incorporating the gestation period and proceeding up until postpartum day 5)

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24.9 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:

1 865 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 831 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 (incorporating the gestation period and proceeding up until postpartum day 5)

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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 the effects of repeated inhalation exposure to diamminedichloropalladium in humans or laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a reliable combined repeated dose and 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).

The oral NOAEL was 373 mg/kg bw/day, equating to an NOAEL of 188 mg/kg bw/day for 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)

= 373 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/2)*(6.7 m3 [8h]/10 m3 [8h]) = 328.8 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 = 328.8*4 = 1315 mg/m3.

Justification and comments

In a guideline (OECD TG 422) combined repeated dose and reproductive/developmental toxicity dietary study in rats with diamminedichloropalladium, the systemic NOAEL was considered to be around 373 mg/kg bw/day. Although some evidence of local toxicity was apparent in the glandular mucosa of the stomach at this dose, this was not associated with any microscopic changes. No test item-related microscopic changes were noted in the reproductive organs at 373 mg/kg bw/day, nor effects on reproductive parameters (including fertility) or indications of maternal/foetal toxicity. The high dose animals – receiving about 831 mg/kg bw/day - displayed a marked body weight loss as a consequence of reduced food consumption, probably due to the local effects in the glandular stomach combined with the palatability of the test item in the diet. As a result of the significant loss of body weight in the high dose animals, the oestrous cycle of females was disrupted and it was not possible to assess the reproductive performance of the animals at this dose level. The high dose females were therefore sacrificed on day 28 (Török-Bathó, 2015). The possible limitations of this study, as reassurance of an absence of reproductive effects, are acknowledged. However, as the marked body weight loss at the top dose precluded an assessment of fertility and developmental effects, and no such effects were seen at the lower dose (systemic NOAEL of 373 mg/kg bw/day), a DNEL based on repeated dose effects is considered suitably protective of reproductive effects.

Hence, the systemic repeated dose NOAEL of 373 mg/kg bw/day 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 substance DNEL (17.5 mg/m3) equates to a palladium exposure of 8.81 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 diamminedichloropalladium. In a guideline (OECD TG 401) acute oral toxicity study in female rats, the LD50 value was determined to lie between 300 and 2000 mg/kg bw (Robertson, 2012).The compound is classified in Category 4 accordingly to CLP. 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 diamminedichloropalladium <100 μm, as measured by simple sieving, was 96.8% (Walker, 2011c). Further, dustiness testing, a more energetic measurement of particle size distribution,with diamminedichloropalladium returned a mass median aerodynamic diameter (MMAD) value of 24.9 μm (Parr, 2011; Selck and Parr, 2011), indicating that a significant proportion of the substance is potentially inhalable. However, respiratory tract deposition modelling with the dustiness data yielded output values of 52.2, 0.29 and 0.44% 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, 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, diamminedichloropalladium is classified in Category 4 accordingly to CLP, 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.

Further, diamminedichloropalladium is not classified as a skin irritant or skin sensitiser.

 

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.

Further, diamminedichloropalladium is not classified as a skin irritant or skin sensitiser. 

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 diamminedichloropalladium in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a combined repeated dose and reproductive/developmental oral toxicity study was considered a suitable alternative (particularly as first pass effects are not expected to be significant for inorganic compounds).

The oral NOAEL was 373 mg/kg bw/day.

Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Diamminedichloropalladium, with water solubility of 630 mg/L (Gregory, 2014), may be able to cross the lipid-rich environment of the stratum corneum to a “moderate to high” extent (ECHA, 2014). The lack of skin irritation potential (which could, in theory, disrupt skin barrier function) is likely to reduce the extent of dermal uptake somewhat. 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 lack of skin irritation potential, 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 diamminedichloropalladium.

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]) = 373 mg/kg bw/day*(50%/10%) = 1865 mg/kg bw/day.

 

Justification and comments

In a guideline (OECD TG 422) combined repeated dose and reproductive/developmental toxicity dietary study in rats with diamminedichloropalladium, the systemic NOAEL was considered to be around 373 mg/kg bw/day. Although some evidence of local toxicity was apparent in the glandular mucosa of the stomach at this dose, this was not associated with any microscopic changes. No test item-related microscopic changes were noted in the reproductive organs at 373 mg/kg bw/day, nor effects on reproductive parameters (including fertility) or indications of maternal/foetal toxicity. The high dose animals – receiving about 831 mg/kg bw/day - displayed a marked body weight loss as a consequence of reduced food consumption, probably due to the local effects in the glandular stomach combined with palatability of the test item in the diet. As a result of the significant loss of body weight in the high dose animals, the oestrous cycle of females was disrupted and it was not possible to assess the reproductive performance of the animals at this dose level. The high dose females were therefore sacrificed on day 28 (Török-Bathó, 2015). The possible limitations of this study, as reassurance of an absence of reproductive effects, are acknowledged. However, as the marked body weight loss at the top dose precluded an assessment of fertility and developmental effects, and no such effects were seen at the lower dose (systemic NOAEL of 373 mg/kg bw/day), a DNEL based on repeated dose effects is considered suitably protective of reproductive effects.

Hence, the systemic repeated dose NOAEL of 373 mg/kg bw/day 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 substance DNEL (24.9 mg/kg bw/day) equates to a palladium exposure of 12.5 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). In a guideline (OECD TG 402) acute dermal toxicity study in rats, the LD50 value was found to exceed 2000 mg/kg bw (males and females) (Kiss, 2012a). The compound is not classified for acute dermal toxicity.

As diamminedichloropalladium 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 439) in vitro skin irritation study, diamminedichloropalladium failed to reduce skin cell viability by more than 50% and was not classified for skin irritation under CLP (Kiss, 2012b).

In another guideline (OECD TG 429) study, diamminedichloropalladium failed to induce skin sensitisation in the mouse local lymph node assay (LLNA) at up to concentrations of 25% (Pooles, 2012). Consequently, the compound is not classified for skin sensitisation under CLP.

Hazard via dermal route: local effects following acute exposure

Justification and comments

In a guideline (OECD TG 439) in vitro skin irritation study, diamminedichloropalladium failed to reduce skin cell viability by more than 50% and was not classified for skin irritation under CLP (Kiss, 2012b).

In another guideline (OECD TG 429) study, diamminedichloropalladium failed to induce skin sensitisation in the mouse LLNA at up to concentrations of 25% (Pooles, 2012). Consequently, the compound is not classified for skin sensitisation under CLP.

Hazard for the eyes

Justification and comments

In a guideline (OECD TG 405) eye irritation study, diamminedichloropalladium produced irreversible effects on the eye in rabbits (Kiss, 2012d). 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 irreversible effects on the eye (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 Risk Management Measures (RMMs)/Operational Conditions (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 diamminedichloropalladium, no uses have been identified in which consumers are exposed to diamminedichloropalladium. In all uses with potential consumer exposure due to service life of articles, diamminedichloropalladium is chemically transformed into another substance before reaching the consumers, and the subsequent lifecycle steps after this transformation of diamminedichloropalladium 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 diamminedichloropalladium 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.