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Effects on fertility

Description of key information

No toxicity data on adverse effects on reproduction with zinc bis(2-ethylhexanoate) are available. In the assessment of toxicity of zinc bis(2-ethylhexanoate), read-across to the assessment entities zinc and 2-ethylhexanoic acid is applied since the ions of zinc bis(2-ethylhexanoate) determine its toxicity in biological compartments.

Since the the moiety 2-ethylhexanoic acid of zinc bis(2 -ethylhexanoate) is legally classified for reproductive toxicity, zinc bis(2 -ethylhexanoate) is subsequently also self-classified for toxicity to reproduction.

 

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).

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

Toxicity for reproduction– effects on fertility

Existing data on effects on fertility of the two moieties of zinc bis(2-ethylhexanoate) are detailed below.

 

Table: Summary of toxicity data on adverse effects on sexual function and fertility of zinc bis(2-ethylhexanoate) and the assessment entities.

 

(slightly soluble) zinc substances

2-ethylhexanoic acid

(CAS# 149-57-5)

Zinc bis(2-ethylhexanoate)

(CAS# 136-53-8)

Two-generation reproductive toxicity study

NOAEL (human data)
=20 mg/kg bw/day

 

not classified

NOAEL(rat; F1)
= 100 mg/kg bw/day

NOAEL(rat; P)
= 300mg/kg bw/day

 

not classified

no data

 

not classified

 

Zinc

The reproductive toxicity of zinc compounds has been investigated in one- and two-generation reproductive toxicity studies in which rats or mice were dosed by gavage or via diet with soluble zinc compounds (i.e., zinc chloride, zinc sulphate) at exposure levels up to 14 mg Zn/kg bw/day (gavage) or 200 mg Zn/kg bw/day (diet) (Khanet al., 2001, 2003, 2007). Further information on potential effects of zinc compounds on male or female reproductive organs could be retrieved from subchronic toxicity studies as conducted by Maitaet al.(1981) and Edwards and Buckley (1995).

 

The available information suggests that high oral doses of zinc (i.e., exposure levels greater than 20 mg Zn/kg bw/day) may adversely affect spermatogenesis and result in impaired fertility indicated by decreased number of implantation sites and increased number of resorptions (US EPA, 2005). However, these effects were only observed in the presence of maternal toxicity as seen in the one- or two-generation studies conducted by Khanet al. (2001, 2003, 2007) or, in case of the study conducted by Kumaret al. (1976), when other study non-zinc relevant study specificities could have impacted the study outcome. In a large number of controlled trials, dietary supplementation with zinc rate of 20 mg/day and 30 mg/day did not result in any adverse reproductive effects in healthy pregnant women as summarised in WHO (2001) and ATSDR (2005).

 

 

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 fetal 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.

 

Zinc bis(2-ethylhexanoate)

Since no toxicity data on adverse effects on sexual function and fertility is available for zinc bis(2-ethylhexanoate), information on the assessment entities zinc and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of zinc bis(2-ethylhexanoate). For the purpose of hazard assessment of zinc bis(2-ethylhexanoate), the point of departure for the most sensitive endpoint of each assessment entity will be used for the DNEL derivation.

Effects on developmental toxicity

Description of key information

No toxicity data on adverse effects on reproduction with zinc bis(2 -ethylhexanoate) are available. In the assessment of toxicity of zinc bis(2-ethylhexanoate), read-across to the assessment entities zinc and 2-ethylhexanoic acid is applied since the ions of zinc bis(2-ethylhexanoate) determine its toxicity in biological compartments.

Since the moiety 2 -ethylhexanoic acid of zinc bis(2 -ethylhexanoate) is legally classified for reproductive toxicity, zinc bis(2-ethylhexanoate) is self-classified for toxicity to reproduction.

 

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).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
Species:
other: human and animal data
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

Toxicity for reproduction – developmental toxicity

Existing data on the developmental toxicity of the two moieties of zinc bis(2-ethylhexanoate) are detailed below.

 

Table: Summary of toxicity data on adverse effects on development of the offspring of zinc bis(2-ethylhexanoate) and the assessment entities.

 

(slightly soluble) zinc substances

2-ethylhexanoic acid

(CAS# 149-57-5)

Zinc bis(2-ethylhexanoate)

(CAS# 136-53-8)

Pre-natal developmental toxicity study

NOAEL (human data)
=20 mg/kg bw/day

 

not classified

NOAEL(rat; mat.)= 250 mg/kg

 

NOAEL(rat; dev)= 100 mg/kg*

 

Category 2, H361d (CLP)

Category 3, R63 (DSD)

no data

 

self-classified,
Category 2, H361d (CLP)

Category 3, R63 (DSD)

Two-generation reproductive toxicity study

NOAEL(rat; F1)
= 100 mg/kg bw/day*

NOAEL(rat; P)
= 300mg/kg bw/day

 

not classified

* Identified as most sensitive endpoint in the registration dossier for 2-ethylhexanoic acid, i.e. has been used for the DNEL derivation of this substance.

 

 

Zinc

The reproductive toxicity of zinc compounds has been investigated in one- and two-generation reproductive toxicity studies in which rats or mice were dosed by gavage or via diet with soluble zinc compounds (i.e., zinc chloride, zinc sulphate) at exposure levels up to 14 mg Zn/kg bw/day (gavage) or 200 mg Zn/kg bw/day (diet) (Khanet al., 2001, 2003, 2007). Further information on potential effects of zinc compounds on male or female reproductive organs could be retrieved from subchronic toxicity studies as conducted by Maitaet al.(1981) and Edwards and Buckley (1995).

 

The available information suggests that high oral doses of zinc (i.e., exposure levels greater than 20 mg Zn/kg bw/day) may adversely affect spermatogenesis and result in impaired fertility indicated by decreased number of implantation sites and increased number of resorptions (US EPA, 2005). However, these effects were only observed in the presence of maternal toxicity as seen in the one- or two-generation studies conducted by Khanet al. (2001, 2003, 2007) or, in case of the study conducted by Kumaret al. (1976), when other study non-zinc relevant study specificities could have impacted the study outcome. In a large number of controlled trials, dietary supplementation with zinc rate of 20 mg/day and 30 mg/day did not result in any adverse reproductive effects in healthy pregnant women as summarised in WHO (2001) and ATSDR (2005).

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.

 

Zinc bis(2-ethylhexanoate)

Since no toxicity data on adverse effects on development of the offspring is available for zinc bis(2-ethylhexanoate), information on the assessment entities zinc and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of zinc bis(2-ethylhexanoate). For the purpose of hazard assessment of zinc bis(2-ethylhexanoate), the point of departure for the most sensitive endpoint of each assessment entity will be used for the DNEL derivation. 2-ethylhexanoic acid has been identified as the most toxic moiety and, 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 zinc bis(2-ethylhexanoate) based on the toxicological assessment of the assessment entities, the harmonised classification of 2-ethylhexanoic acid for reproductive toxicity is read-across to zinc bis(2-ethylhexanoate). Thus, zinc bis(2-ethylhexanoate is self-classified for reproductive toxicity in category 2 H361d (Suspected of damaging the unborn child).

Justification for classification or non-classification

Since the moiety 2 -ethylhexanoic acid of zinc bis(2 -ethylhexanoate) is legally classified for reproductive toxicity, zinc bis(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).

Additional information