2-ethylhexanoic acid, zirconium salt

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Species:

rat

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.

 

2-ethylhexanoic, zirconium salt is the zirconium metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding zirconium cation and 2-ethylhexanoate anions. The zirconium cation and the 2-ethylhexanoate anion are considered to represent the overall toxicity of 2-ethylhexanoic, zirconium salt in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Repeated dose toxicity

No repeated dose toxicity study with 2-ethylhexanoic acid, zirconium salt is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products zirconium and 2-ethylhexanoic acid as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of 2-ethylhexanoic acid, zirconium salt and the individual constituents.

	Zirconium	2-ethylhexanoic acid (CAS# 149-57-5)	2-ethylhexanoic acid, zirconium salt (CAS# 22464-99-9)
Repeated dose oral toxicity	NOAEL(sub-acute,oral,rat) ≥ 1000 mg Zr acetate/kg bw/day   NOAEL(sub-acute,oral,rat) ≥ 530 mg Zr/kg bw/day	NOAEL(rat;90d)= 300 mg/kg bw/day   NOAEL(mice;90d)= 200 mg/kg bw/day	No data
Repeated dose inhalation toxicity	NOAEC(60day, cat, dog, guinea pig, rabbit, rat)n > 15.4 mg ZrO2/m³   NOAEC(60day, cat, dog, guinea pig, rabbit, rat) > 11.4 mg Zr/m³	No data	No data

 

 

 

Zirconium

Repeated dose toxicity: oral

Rossiello (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test via oral route in rats with the read-across substance zirconium acetate according to OECD guideline 422 (GLP). A NOAEL of ≥1000 mg/kg bw/day (expressed as zirconium acetate anhydrous, equivalent to ≥530 mg Zr/kg bw/day) was derived. No adverse effects were reported in this study.

No effects were reported after oral administration to rats during 17 weeks of zirconium basic carbonate (hydrated form) in the form of a moist paste containing 20.9% zirconium dioxide equivalent. The total intake of zirconium dioxide during the test period was 0, 0.9, 9 and 103.5 g. The equivalent NOAEL for zirconium dioxide was ≥ 3150-7080 mg/kg bw/day (Harrison et al., 1951).

 

Repeated dose toxicity: dermal

No reliable studies are available for repeated dose toxicity via the dermal route of exposure. Testing is waived based on the following justification: a short-term (30 days) and sub-chronic (60 days) study are available for the inhalation route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2 adaptation, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

 

Repeated dose toxicity: inhalation

Two reliable studies were available for this endpoint (Klimisch 2): a 30 day repeated dose inhalation test in dog, rabbit and rat and a 60 day repeated dose toxicity test in cat, dog, guinea pig, rabbit and rat. No effects were reported in any of the species studied after inhalation of ZrO2 dust (NOAEC > 100.8 mg ZrO2/m3 air in the 30 day study and NOAEC > 15.4 mg ZrO2/m3 air in the 60 day study). These studies are used in a weight of evidence approach and support each other in the fact that no inhalation toxicity was observed after repeated exposure. The 28 days study is covered by the 30 days test. The 60 days study didn't observe effects after repeated inhalation exposure. Therefore the 60 days study is used to cover the 90 days study requirement.

 

2-Ethylhexanoic acid

In a 90-day repeated dose toxicity study in rats and mice with 2-ethylhexanoic acid, a diet containing 0.5% 2-ethylhexanoic acid caused no adverse effect in rats in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%, calculated NOAEL ca. 300 mg/kg bw/day). No adverse effect was observed in mice receiving a diet containing 0.5 % 2-ethylhexanoic acid in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%). The NOAEL was calculated to be 200 mg/kg bw/day. Both NOAELs were based on reduced food consumption and a decreased rate of body weight gain in the high dose groups. For further information on the toxicity of 2-ethylhexanoic acid, please refer to the relevant sections in the IUCLID and CSR.

 

2-ethylhexanoic acid, zirconium salt

Since no repeated dose toxicity study is available specifically for 2-ethylhexanoic acid, zirconium salt, information on the individual constituents zirconium and 2-ethylhexanoic acid will be used for the hazard assessment and when applicable for the risk characterisation of2-ethylhexanoic acid, zirconium salt.

For the purpose of hazard assessment of 2-ethylhexanoic acid, zirconium salt, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of the zirconium cation in 2-ethylhexanoic acid, zirconium salt, the NOAEL of 530 mg Zr/kg bw/day in repeated dose toxicity (sub-acute animal data) will be used for the long-term, systemic DNELs.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Information from read-across substances:
animal data for zirconium: NOAEL(rat) = 530 mg Zr/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(rat) = 300mg/kg bw/day, NOAEL(mice) = 200mg/kg bw/day

Justification for classification or non-classification

Considering the read-across principles as detailed above for 2-ethylhexanoic acid, zirconium salt based on the toxicological assessment of the individual constituents, 2-ethylhexanoic acid, zirconium salt does not need classification for Specific target organ toxicity-repeated exposure.