2-ethylhexanoic acid, cerium salt

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

2-ethylhexanoic acid, cerium salt is not expected to show adverse effects on sexual function and fertility, since the two constituents cerium and 2-ethylhexanoic acid have not shown adverse effects on sexual function and fertility in relevant bioassays.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

No toxicity data on adverse effects on sexual function and fertility with 2-ethylhexanoic acid, cerium salt is available, thus the reproductive toxicity will be addressed with existing data on the dissociation products cerium and 2-ethylhexanoic acid.

Cerium

Braun (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats according to OECD guideline 422 (GLP) to cerium trinitrate. A NOEL for reproduction/developmental toxicity of 330 mg/kg bw/day was derived, corresponding to 142 mg Ce/kg bw/day. However it was based on effects that could be secondary to the chemical stress observed in pregnant females (due to high local irritation observed in the stomach after repeated oral gavage of the compound) rather than primary effects of the test item.

2-Ethylhexanoic acid

2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean foetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher zinc levels in the mothers leads to lower developmental toxicity in offspring.

2-ethylhexanoic acid, cerium salt

Since no toxicity data on adverse effects on sexual function and fertility is available for 2-ethylhexanoic acid, cerium salt, information on the individual constituents cerium and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of 2-ethylhexanoic acid, cerium salt. For the purpose of hazard assessment of 2-ethylhexanoic acid, cerium salt, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation:
animal data for cerium: NOAEL(rat) = 142 mg Ce/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(rat, P) = 300 mg/kg bw/day

2-ethylhexanoic acid, cerium salt is not expected to show adverse effects on sexual function and fertility, since the two constituents cerium and 2-ethylhexanoic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, 2-ethylhexanoic acid, cerium salt is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

Effects on developmental toxicity

Description of key information

2-ethylhexanoic acid, cerium salt is expected to be a developmental toxicant, based on studies carried out with 2-ethylhexanoic acid.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Additional information

No toxicity data on adverse effects on development of the offspring with 2-ethylhexanoic acid, cerium salt are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products cerium and 2-ethylhexanoic acid.

Cerium

An OECD 422 study including a reproduction/developmental toxicity screening (Braun, 2013) is available for cerium trinitrate. A NOEL for reproduction/developmental toxicity of 330 mg/kg bw/day was derived, corresponding to 100 mg Ce/kg bw/day. This NOAEL is based on changes at 1000 mg/kg/day that included increased total and mean post-implantation loss, decreased mean litter size, increased mean post-natal loss, increased rate of post-natal loss, increased total post-natal loss and decreased group mean pup weights on day 1 post-partum. These effects could however be secondary to the chemical stress observed in pregnant females (due to high local irritation observed in the stomach after repeated oral gavage of the compound) rather than primary effects of the test item.

2-Ethylhexanoic acid

2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean foetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher calcium levels in the mothers leads to lower developmental toxicity in offspring. Based on the above given information, 2-ethylhexanoic acid was classified as toxic for reproduction, developmental toxicity category 2 (H361d/R62).

2-ethylhexanoic acid, cerium salt

Since no reproductive toxicity study is available for 2-ethylhexanoic acid, cerium salt, information on the individual constituents cerium and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of 2-ethylhexanoic acid, cerium salt. For the purpose of hazard assessment of 2-ethylhexanoic acid, cerium salt, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation:

animal data for cerium: NOAEL(rat) = 142 mg Ce/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(rat, F1) = 100 mg/kg bw/day

In case of 2-ethylhexanoic acid, cerium salt, the NOAEL of 100 mg/kg bw/day for the reproductive toxicity in the F1 offspring will be used.

Considering the read-across principles as detailed above for 2-ethylhexanoic acid, cerium salt based on the toxicological assessment of the individual constituents, it is proposed to also read-across the classification of toxic for reproduction, developmental toxicity category 2 (H361d) of 2-ethylhexanoic acid to 2-ethylhexanoic acid, cerium salt.

Justification for classification or non-classification

2-ethylhexanoic acid, cerium salt is not expected to show adverse effects on sexual function and fertility, since the two constituents cerium and 2-ethylhexanoic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, 2-ethylhexanoic acid, cerium salt is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. Further testing is not required.

Considering the read-across principles as detailed above for 2-ethylhexanoic acid, cerium salt based on the toxicological assessment of the individual constituents, it is proposed to also read-across the classification of toxic for reproduction, developmental toxicity category 2 (H361d) of 2-ethylhexanoic acid to 2-ethylhexanoic acid, cerium salt.