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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.3 µg/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:
2.64 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
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 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:
50 µg/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):
300
Modified dose descriptor starting point:
NOAEL
Value:
15 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
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):
4
Justification:
Default ECHA AF of 4 for rat for toxicokinetic differences in metabolic rate (allometric scaling)
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

No data on effects of repeated inhalation exposure to palladium di(4-oxopent-2-en-2-oate) in humans or laboratory animals are available. Thus, an inhalation DNEL was derived by route-to-route extrapolation from a reliable combined repeated dose and reproduction/developmental oral toxicity study.

 

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 palladium di(4-oxopent-2-en-2-oate), the corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV)

= 3 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(1/2)*(6.7 m3 [8h]/10 m3 [8h]) = 2.64 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.

Justification and comments

In a guideline (OECD TG 422) combined repeated dose and reproductive/developmental toxicity study in rats, involving the gavage administration of palladium di(4-oxopent-2-en-2-oate), the NOAEL for systemic and developmental effects was the lowest tested dose (3 mg/kg bw/day). The critical effect was hypertrophy of the adrenal cortex, as well as reduced body weights. These were considered likely to be adaptive responses. There were no effects on fertility, reproductive performance or prenatal (conceptus to birth) foetal development, but pup body weights were reduced at the end of the lactation period, considered to be a secondary non-specific consequence of the maternal toxicity (Hansen, 2020).

 

Hence, the systemic repeated dose NOAEL of 3 mg/kg bw/day (equivalent to 1.05 mg/kg bw/day palladium) was taken as the critical point of departure for calculating the long-term systemic DNEL for palladium di(4-oxopent-2-en-2-oate), and is considered protective of fertility.

 

This DNEL (35.3 μg/m3) equates to a palladium exposure of 12.3 μg/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 on acute inhalation exposure to palladium di(4-oxopent-2-en-2-oate). In a guideline (OECD TG 401) acute oral toxicity study in female rats with palladium di(4-oxopent-2-en-2-oate), an LD50 value of 2000 mg/kg bw was predicted (Matting, 2013). The compound is classified in Category 4 according to CLP criteria. Although an oral N(L)OAEL (for sub-lethal effects) could be modified into an inhalation N(L)OAEC using route-to-route extrapolation, 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”. Palladium di(4-oxopent-2-en-2-oate) has a very low predicted vapour pressure (8.2x10E-5 Pa; Nau, 2015), indicating that only a small proportion of the substance may be available for inhalation as a vapour. Further, in a guideline (OECD TG 110) granulometry screening test, the proportion of palladium di(4-oxopent-2-en-2-oate) <100 μm, as measured by simple sieving, was 13.1% (Walker, 2011c). However, in another particle size distribution study, on the substance as a dry dispersion, the 10th, 50th and 90th percentile average particle sizes for palladium di(4‑oxopent-2-en-2-oate) were 0.66, 2.1 and 5.4 μm, respectively (Potthoff, 2012). Moreover, dustiness testing, a more energetic measurement of particle size distribution, with palladium di(4-oxopent-2-en-2-oate) returned a mass median aerodynamic diameter (MMAD) value of 38.2 μm (Parr, 2011; Selck and Parr, 2011), indicating that a significant proportion of the substance is likely to be inhalable. However, respiratory tract deposition modelling with the dustiness data yielded output values of 40.0, 0.14 and 0.26% 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 could be coughed or sneezed out of the body or swallowed, with systemic uptake being determined predominantly by oral bioavailability. Less than 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 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 inhalation toxicity has been calculated.

 

ECHA has indicated that “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, palladium di(4-oxopent-2-en-2-oate) is only classified in Category 4 (for acute oral toxicity), so a qualitative assessment is also 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”. Palladium di(4-oxopent-2-en-2-oate) is classified as a 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) “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”. Palladium di(4-oxopent-2-en-2-oate) is classified as a 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

No data on effects of repeated dermal exposure to palladium di(4-oxopent-2-en-2-oate) in humans or laboratory animals are available. Thus, a dermal DNEL was derived by route-to-route extrapolation from a reliable combined repeated dose and reproductive/developmental oral toxicity study.

 

Estimation of dermal absorption is based on relevant available information (mainly water solubility, molecular weight and log Pow) and expert judgement. Given the slight water solubility of palladium di(4-oxopent-2-en-2-oate) (11.1 mg/L; Gregory, 2014) it is unlikely to be dermally bioavailable to any significant extent, especially given the lack of skin irritation potential (which could, in theory, disrupt skin barrier function). Nevertheless, the compound has an optimal log Pow value (2.6; Winkler, 2015) for absorption through the skin. 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 low water solubility (and, thus, low expected dermal bioavailability), 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 palladium di(4-oxopent-2-en-2-oate).

 

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]) = 3 mg/kg bw/day*(50%/10%) = 15 mg/kg bw/day as palladium di(4-oxopent-2-en-2-oate).

Justification and comments

In a guideline (OECD TG 422) combined repeated dose and reproductive/developmental toxicity study in rats, involving the gavage administration of palladium di(4-oxopent-2-en-2-oate), the NOAEL for systemic and developmental effects was the lowest tested dose (3 mg/kg bw/day). The critical effect was hypertrophy of the adrenal cortex, as well as reduced body weights. These were considered likely to be adaptive responses. There were no effects on fertility, reproductive performance or prenatal (conceptus to birth) foetal development, but pup body weights were reduced at the end of the lactation period, considered to be a secondary non-specific consequence of the maternal toxicity (Hansen, 2020).

 

Hence, the systemic NOAEL of 3 mg/kg bw/day (equivalent to 1.05 mg/kg bw/day as palladium) was taken as the critical point of departure for calculating the long-term systemic repeated dose DNELs for palladium di(4-oxopent-2-en-2-oate), and is considered protective of fertility.

 

This DNEL (50 μg/kg bw/day) equates to a palladium exposure of 17.5 μg/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 with palladium di(4-oxopent-2-en-2-oate), the LD50 value was found to exceed 2000 mg/kg bw (males and females) (Matting, 2014). The compound is not classified for acute dermal toxicity according to CLP criteria.

 

As palladium di(4-oxopent-2-en-2-oate) 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, palladium di(4-oxopent-2-en-2-oate) failed to reduce skin cell viability by more than 50% and was not classified for skin irritation under CLP (Kiss, 2012a). Further, in a bio-elution test with palladium di(4-oxopent-2-en-2-oate), the proportion of metal release (from total metal content) in simulated dermal fluid was nominally insignificant (0.57 and 1.90% after 24 and 168 hours respectively) (Rodriguez, 2012).

 

In the preliminary test for a guideline (OECD TG 429) study, palladium di(4-oxopent-2-en-2-oate) induced effects consistent with those of a strong sensitiser. The main mouse local lymph node assay (LLNA) was not conducted due to animal welfare considerations (Váliczkó, 2014). The compound is classified for skin sensitisation as Category 1A, under CLP. Further, in a bio-elution test with palladium di(4-oxopent-2-en-2-oate), the proportion of metal release (from total metal content) in simulated dermal fluid after 24 and 168 hours (0.57 and 1.90% respectively) (Rodriguez, 2012), although nominally insignificant, are relatively high (in terms of sensitisation potential) given that they are almost three orders of magnitude higher than the corresponding values for palladium metal (which is generally regarded as a non-bioavailable and non‑sensitising substance).

 

According to ECHA (2012b) guidance “strong skin sensitisers (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 439) in vitro skin irritation study, palladium di(4-oxopent-2-en-2-oate) failed to reduce skin cell viability by more than 50% and was not classified for skin irritation under CLP (Kiss, 2012a). Further, in a bio-elution test with palladium di(4-oxopent-2-en-2-oate), the proportion of metal release (from total metal content) in simulated dermal fluid was nominally insignificant (0.57 and 1.90% after 24 and 168 hours respectively) (Rodriguez, 2012).

 

In the preliminary test for a guideline (OECD TG 429) study, palladium di(4-oxopent-2-en-2-oate) induced effects consistent with those of a strong sensitiser. The main mouse LLNA was not conducted due to animal welfare considerations (Váliczkó, 2014). The compound is classified for skin sensitisation as Category 1A, under CLP. Further, in a bio-elution test with palladium di(4-oxopent-2-en-2-oate), the proportion of metal release (from total metal content) in simulated dermal fluid after 24 and 168 hours (0.57 and 1.90% respectively) (Rodriguez, 2012), although nominally insignificant, are relatively high (in terms of sensitisation potential) given that they are almost three orders of magnitude higher than the corresponding values for palladium metal (which is generally regarded as a non-bioavailable and non‑sensitising substance).

 

According to ECHA (2012b) guidance “strong skin sensitisers (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, palladium di(4-oxopent-2-en-2-oate) produced irreversible effects on the eye in rabbits (Kiss, 2012b). 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 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 palladium di(4-oxopent-2-en-2-oate), no uses have been identified in which consumers are exposed to palladium di(4-oxopent-2-en-2-oate). In all uses with potential consumer exposure due to service life of articles, palladium di(4-oxopent-2-en-2-oate) is chemically transformed into another substance before reaching the consumers, and the subsequent lifecycle steps after this transformation of palladium di(4-oxopent-2-en-2-oate) 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 palladium di(4-oxopent-2-en-2-oate) 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.