Neodecanoic acid, zirconium salt

Endpoint summary

Description of key information

No repeated dose toxicity study with neodecanoic acid, zirconium salt is available, thus the repeated dose toxicity will be addressed with existing data on the assessment entities zirconium and neodecanoate.

In relevant and reliable repeated dose toxicity studies as well as supporting studies for both moieties of neodecanoic acid, zirconium salt, there were no toxicological findings reported that would justify a classification.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rabbit

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Zirconium

Repeated dose toxicity: oral

No effects were reported after oral administration to rats during 17 weeks of hydrated basic carbonate in form of moist paste containing 20.9% zirconium dioxide from a reliable study (Klimisch 2). The total intake of ZrO2 during the test period is 0, 0.9, 9 and 103.5 g. The equivalent NOAEL for ZrO2 is > 3150 mg/kg bw/day, corresponding to >2334 mg Zr/kg bw/day.

A similar study was performed on kittens, but the reported information from that study is limited and thus is just submitted as supporting information.

In a combined repeated dose toxicity study with the reproduction and developmental toxicity screening test, Sprague Dawley rats were administered zirconium acetate at 0, 100, 300 and 1000 mg/kg bw/day via gavage. The required amount of zirconium acetate solution (containing 40.7% of zirconium acetate anhydrous) was dissolved in the vehicle (purified water). 10 males per group were treated two weeks prior to pairing, throughout pairing and thereafter through the day before scheduled sacrifice (32 days of dosing). 10 females were treated two weeks prior to pairing, throughout pairing until day 3 post partum or the day before scheduled sacrifice (up to 50 days of dosing). No systemic toxicity could be observed. Therefore, on the basis of the results obtained in the study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity after sub-acute exposure was considered to be >=1000 mg/kg bw/day expressed as zirconium acetate anhydrous, equivalent to >=530 mg Zr/kg bw/day.

 

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.

 

Neodecanoate

Repeated dose toxicity, oral:

Male and female Sprague-Dawley rats (n >= 10 per group) were exposed to neodecanoic acid by diet with target exposures of 0, 100, 300, or 1000/700 mg/kg/d for 13 weeks. The highest dose at study initiation targeted 1000 mg/kg/d, but were reduced to 700 mg/kg/day for animal welfare reasons following the second week of exposure. Body weight gain was significantly reduced in female rats in all exposure groups, but terminal body weights were significantly different from controls only for the 1000/700 mg/kg/day exposure group. Body weight gain and terminal body weight were not significantly affected in male rats. Liver weights were significantly increased in both sexes at target exposures of 300 mg/kg/d and greater. Histopathology indicated 1000/700 mg/kg/day exposure resulted in generalized liver hypertrophy, not hyperplasia. In male rats only there were significant increases in kidney weight in all neodecanoic acid exposed groups, with weights increasing with exposure. Gross pathology findings in male rats were also consistent with a treatment-related effect. Histopathology findings were consistent with alpha2u globulin nephropathy, an effect not relevant to humans. Combined prostate and seminal vesicle weights were decreased in male rats exposed to 1000/700 mg/kg/day neodecanoic acid on an absolute and brain weight-relative basis, but not body weight-relative. This was no correlated with any histopathology findings, thus the effects do not appear treatment-related. The study results indicate a human relevant NOAEL of 700 mg/kg/day.

 

Dermal

In a repeated-dose dermal study, neodecanoic acid was applied repeatedly (once daily for 10 applications with a rest period on days 5 and 6) to the skin of rabbits at doses of 0.5 or 2.5 ml/kg (400 or 2280 mg/kg/day).  All animals survived the exposure.  Wheezing was noted in one animal at the 0.5 ml dose level.  Animals at the lower dose level generally showed an overall body weight gain while those at the high level showed terminal weight losses.  The low level animals generally showed slight erythema and moderate atonia and desquamation following the first or fourth application and during the remainder of the study.  At the high level, moderate erythema and moderate or marked atonia and desquamation were present in all animals.  In addition, slight edema was present following the fifth application and slight fissures or cracks were observed in several animals following the last seven applications.  The exposed skin also became hypersensitive to the touch.  There were no indications of systemic toxicity attributed to exposure.

 

Members of the Neo acid C5 to C28 Category have a low order of toxicity under conditions of repeat exposure by oral and dermal routes. In addition, they display a consistent degree of subchronic toxicity by either oral or dermal route of exposure. No classification for repeated dose toxicity is indicated according to the classification, labelling, and packaging (CLP) regulation (EC) No 1272/2008.

 

Neodecanoic acid, zirconium salt

Since no repeated dose toxicity study is available specifically for neodecanoic acid, zirconium salt, information on the assessment entities zirconium and neodecanoate will be used for the hazard assessment and when applicable for the risk characterisation of neodecanoic acid, zirconium salt. For the purpose of hazard assessment of neodecanoic acid, zirconium salt, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of neodecanoic acid in neodecanoic acid, zirconium salt, the NOAEL of 250 mg/kg bw/day for the developmental toxicity will be used. In case of zirconium the NOAEL of 530 mg Zr/kg bw/day obtained in repeated dose toxicity study with the reproduction and developmental toxicity screening test will be used.

Justification for classification or non-classification

In relevant and reliable repeated dose toxicity studies as well as supporting studies for both assessment entities of neodecanoic acid, zirconium salt, there were no toxicological findings reported that would justify a classification for specific target organ toxicity with repeated exposure. Hence, no classification for neodecanoic acid, zirconium salt is required.