tetraammine palladium (II) hydrogen carbonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.23 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:

17.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

As no relevant data on effects of repeated inhalation exposure to tetraamminepalladium(II) hydrogen carbonate in humans or laboratory animals are available, route-to-route extrapolation to calculate an inhalation DNEL from a reproductive/developmental oral toxicity study on a member of the "tetraamminepalladium salts" category, tetraamminepalladium(II) dichloride, was considered a suitable alternative (particularly as first pass effects are not expected to be significant for an inorganic compound).

 

The oral NOAEL for tetraamminepalladium(II) dichloride was 4 mg/kg bw/day. This equates to NOAELs of 1.76 and 4.91 mg/kg bw/day for palladium and tetraamminepalladium(II) hydrogen carbonate, respectively (based on MWt ratios).

 

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.

 

Expressed as tetraamminepalladium(II) hydrogen carbonate the corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV)

= 4.91 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/2)*(6.7 m3 [8h]/10 m3 [8h]) = 4.33 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 = 4.33*4 = 17.3 mg/m3

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 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(II) dichloride was used to fill the reproductive/developmental toxicity 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 (II) species. Also the systemic NOAEL for the hydrogen carbonate (from a reliable 28-day gavage study) was slightly higher (15 mg/kg bw/day). Moreover, the DNEL was derived on the basis of palladium itself.

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:

0.33 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:

24.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As no relevant data on effects of repeated dermal exposure to tetraamminepalladium(II) hydrogen carbonate in humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from a reproductive/developmental oral toxicity study on a member of the "tetraamminepalladium salts" category, tetraamminepalladium(II) dichloride, was considered a suitable alternative (particularly as first pass effects are not expected to be significant for inorganic compounds).

 

The oral NOAEL for tetraamminepalladium(II) dichloride was 4 mg/kg bw/day. This equates to NOAELs of 1.76 and 4.91 mg/kg bw/day for palladium and tetraamminepalladium(II) hydrogen carbonate, respectively (based on MWt ratios).

 

Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Tetraamminepalladium(II) hydrogen carbonate, with a low partition coefficient (<-2.73) and high water solubility (56.2 g/L) (Lumsden et al., 1997), may be unable to cross the lipid-rich environment of the stratum corneum, especially given the lack of skin irritation potential observed in rabbits (Allen, 1995b). In spite of this, in the light of the relatively low molecular weight, ECHA guidance indicates a default value of 100% dermal absorption (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). Given the low penetration expected from metals, the low log Pow and high water solubility (and, thus, low expected lipophilicity), and the lack of skin irritation potential (which could, in theory, disrupt skin barrier function and facilitate dermal penetration), 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(II) hydrogen carbonate.

 

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]) = 4.91 mg/kg bw/day*(50%/10%) = 24.6 mg/kg bw/day

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(II) dichloride was used to fill the reproductive/developmental toxicity 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 (II) species. Also the systemic NOAEL for the hydrogen carbonate (from a reliable 28-day gavage study) was slightly higher (15 mg/kg bw/day). Moreover, the DNEL was derived on the basis of palladium itself.

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)

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