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Effects on fertility

Description of key information

No toxicity data on adverse effects on sexual function and fertility with magnesium 2-ethylhexanoate are available, thus the reproductive toxicity will be addressed with existing data on the individual assessment entites magnesium and 2-ethylhexanoic acid.

Magnesium 2-ethylhexanoate is not expected to impair fertility, since the two assessment entites magnesium and 2-ethylhexanoic acid have not shown adverse effects on fertility.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Magnesium

Magnesium is of great importance in human fertility and development. The scientific evidence was taken into account by the Scientific Committee on Food which concluded that magnesium lacks effects on the reproductive function in humans. Also, magnesium is necessary for DNA replication and bone development during pregnancy, demonstrating the pivotal role of magnesium in human fertility in man and women. It is therefore concluded that magnesium itself does not show any developmental toxicity effects. Additional studies in animals are not believed to contribute to the existing evidence for a lack developmental toxicity of magnesium.

 

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 histologic 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.

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.

Magnesium 2-ethylhexanoate

As the two assessment entites of magnesium 2-ethylhexanoate do not impair sexual function and fertility, one may safely assume that magnesium 2-ethylhexanoate does also not have effects on fertility.

For the purpose of hazard assessment of magnesium 2-ethylhexanoate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of 2‑ethylhexanoic acid in magnesium 2-ethylhexanoate, the NOAEL of 100 mg/kg bw/day for the developmental toxicity will be used.

Effects on developmental toxicity

Description of key information

No toxicity data on adverse effects on development of the offspring with magnesium 2-ethylhexanoate are available, thus the developmental toxicity will be addressed with existing data on the assessment entites magnesium and 2-ethylhexanoic acid.

According to Reach regulation (EC) No. 1907/2006 (ANNEX VIII, 8.7.1) developmental toxicity / teratogenicity is not a standard information requirement. However, findings in developmental toxicity resulted in a legally binding classification for reproductive/developmental toxicity for 2-ethylhexanoic acid (Index No.: 607 622-00-7).

Several studies with rats have demonstrated developmental toxicity in response to oral exposure to 2-ethylhexanoic acid. Adverse foetal effects included reduced body weight, and skeletal malformations and variations. The NOAEL was determined to be 100 mg/kg bw/day. Mechanistic studies indicated that the developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of zinc metabolism and distribution in the mother. Developmental effects in the one-generation reproduction study occurred at the same levels, also with a NOAEL of 100 mg/kg bw/day.

Developmental toxicity of magnesium is not expected due indispensability for development.

Since 2-ethylhexanoic acid has a legally binding classification for reproductive/developmental toxicity (Index No.: 607 622-00-7), magnesium 2-ethylhexanoate is classified accordingly.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Quality of whole database:
key study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No toxicity data on adverse effects on development of the offspring with magnesium 2-ethylhexanoate are available, thus the developmental toxicity will be addressed with existing data on the individual moieties magnesium and 2-ethylhexanoic acid.

Magnesium

Magnesium is of great importance in human fertility and development. The scientific evidence was taken into account by the Scientific Committee on Food which concluded that magnesium lacks effects on the reproductive function in humans. Also, magnesium is necessary for DNA replication and bone development during pregnancy, demonstrating the pivotal role of magnesium in human fertility in man and women. It is therefore concluded that magnesium itself does not show any developmental toxicity effects. Additional studies in animals are not believed to contribute to the existing evidence for a lack developmental toxicity of magnesium.

 

2-ethylhexanoic acid

The developmental toxicity of 2-ethylhexanoic acid has been investigated in a standard study in rabbits [USEPA TSCA Health Effects Testing Guidelines CFR 798.4900 (similar to OECD TG 414)]. 2-Ethylhexanoic acid was administered (15/dose) via gavage at 0, 25, 125, or 250 mg/kg-bw/day on days 6 through 18 of gestation. One mid-dose and one high-dose animal died on test. In addition, one mid-dose animal aborted prior to term. High-dose dams experienced hypoactivity, ataxia, and gasping. Body weights and food consumption of animals in this group were reduced. The NOAEL for maternal animals was 25 mg/kg–bw/day and the NOAEL for offspring was 250 mg/kg-bw/day (the highest dose tested). In a guideline study [OECD TG 414] 2-ethylhexanoic acid was administered via drinking water to an unspecified number of animals at 0, 100, 300, or 600 mg/kg-bw/day, for days 6-19 of gestation. No death was observed. 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. The NOAEL for maternal animals was 300 mg/kg-bw/day; the NOAEL for 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.

Magnesium 2-ethylhexanoate

For the purpose of hazard assessment of magnesium 2-ethylhexanoate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of 2‑ethylhexanoic acid in magnesium 2-ethylhexanoate, the NOAEL of 100 mg/kg bw/day for the developmental toxicity will be used.

Justification for classification or non-classification

Magnesium 2-ethylhexanoate is not expected to impair fertility, since the two assessment entites magnesium and 2-ethylhexanoic acid have not shown adverse effects on fertility. Since the assessment entiy 2-ethylhexanoic acid (Index No.: 607 622-00-7) of magnesium 2-ethylhexanoate has a legally binding classification for reproductive toxicity, magnesium 2‑ethylhexanoate is self-classified for reproductive toxicity.

Classification according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 for Reproduction toxicity is: Hazard Category 2, with the Hazard statement H361d (suspected of damaging the unborn child) (Annex VI).