Hexanoic acid, 2-ethyl-, zinc salt, basic

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Species:

other: animal and human data

Additional information

Introduction to read-across matrix

A comprehensive data gap analysis was conducted for the entire substance portfolio of the Metal carboxylates REACH Consortium (MCRC), covering 10 metal carboxylates in total. This literature screening effort included:

 

• all available proprietary studies from the Metal carboxylates REACH Consortium (MCRC)
• detailed literature searches in online databases
• screening of human health review articles
• rigorous quality and reliability screening according to Klimisch criteria, where those criteria apply

 

During the literature search and data gap analysis it became obvious that the overall database on substance-specific human health hazard data for the metal carboxylates is too scant to cover all REACH endpoints. Therefore, the remaining data gaps had to be covered by either experimental testing or read-across from similar substances.

 

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the organic acid counterion and the metal (or one of its readily soluble salts). This way forward is acceptable, since metal carboxylates 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 tests (please refer to the water solubility data in section of the IUCLID and chapter of the CSR). Once the individual constituents 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 the toxicity of the “individual” constituents. Since synergistic effects are not expected for this group of metal carboxylates, the human health hazard assessment consists of an individual assessment of the metal cation and the organic anion.

 

The hazard information of the individual constituents was obtained from existing REACH registration dossiers via a license-to-use obtained by the lead registrant. These registration dossiers were submitted to ECHA in 2010 as full registration dossiers, and are thus considered to contain relevant and reliable information for all human health endpoints. All lead-registrant dossiers were checked for completeness and accepted by ECHA, i.e. a registration number was assigned.

 

Hexanoic acid, 2-ethyl-, zinc salt, basic is the zinc metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent zinc cation and 2-ethylhexanoic acid anions. The zinc cation and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of the hexanoic acid, 2-ethyl-, zinc salt, basic in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). Based on the above information, unrestricted read-across is considered feasible and justified.

Although the term „constituent“ within the REACH context is defined as substance (also being part of a mixture), the term constituent within this hazard assessment is meant to describe either part of the metal carboxylate salt, i.e. anion or cation.

Toxicity for reproduction

No toxicity data on adverse effects on sexual function and fertility with hexanoic acid, 2-ethyl-, zinc salt, basic are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the genetic toxicity of the individual constituents are given below.

 

Table: Summary of toxicity data on adverse effects on sexual function and fertility of hexanoic acid, 2-ethyl-, zinc salt, basic and the individual constituents.

	(slightly soluble) zinc substances	2-ethylhexanoic acid (CAS# 149-57-5)	Hexanoic acid, 2-ethyl-, zinc salt, basic (CAS# 85203-81-2)
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	no data   self-classified, Category 2, H361d
Two-generation reproductive toxicity study		NOAEL(rat; F1) = 100 mg/kg bw/day* NOAEL(rat; P) = 300mg/kg bw/day   not classified	no data   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

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.

 

Hexanoic acid, 2-ethyl-, zinc salt, basic

Since notoxicity data on adverse effects on sexual function and fertilityis available for hexanoic acid, 2-ethyl-, zinc salt, basic, information on the individual constituents zinc and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of hexanoic acid, 2-ethyl-, zinc salt, basic. For the purpose of hazard assessment of hexanoic acid, 2-ethyl-, zinc salt, basic, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.

Short description of key information:

Hexanoic acid, 2-ethyl-, zinc salt, basic is not expected to be toxic for reproduction.

Justification for selection of Effect on fertility via oral route:

Information from read-across substances:

human data for zinc: NOAEL=20mg/kg bw/day

animal data for 2-ethylhexanoic acid: NOAEL(rat, P)=300mg/kg bw/day

Effects on developmental toxicity

Description of key information

Hexanoic acid, 2-ethyl-, zinc salt, basic is expected to be a developmental toxicant.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Species:

other: animal and human data

Additional information

Introduction to read-across matrix

A comprehensive data gap analysis was conducted for the entire substance portfolio of the Metal carboxylates REACH Consortium (MCRC), covering 10 metal carboxylates in total. This literature screening effort included:

 

• all available proprietary studies from the Metal carboxylates REACH Consortium (MCRC)
• detailed literature searches in online databases
• screening of human health review articles
• rigorous quality and reliability screening according to Klimisch criteria, where those criteria apply

 

During the literature search and data gap analysis it became obvious that the overall database on substance-specific human health hazard data for the metal carboxylates is too scant to cover all REACH endpoints. Therefore, the remaining data gaps had to be covered by either experimental testing or read-across from similar substances.

 

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the organic acid counterion and the metal (or one of its readily soluble salts). This way forward is acceptable, since metal carboxylates 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 tests (please refer to the water solubility data in section of the IUCLID and chapter of the CSR). Once the individual constituents 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 the toxicity of the “individual” constituents. Since synergistic effects are not expected for this group of metal carboxylates, the human health hazard assessment consists of an individual assessment of the metal cation and the organic anion.

 

The hazard information of the individual constituents was obtained from existing REACH registration dossiers via a license-to-use obtained by the lead registrant. These registration dossiers were submitted to ECHA in 2010 as full registration dossiers, and are thus considered to contain relevant and reliable information for all human health endpoints. All lead-registrant dossiers were checked for completeness and accepted by ECHA, i.e. a registration number was assigned.

 

Hexanoic acid, 2-ethyl-, zinc salt, basic is the zinc metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent zinc cation and 2-ethylhexanoic acid anions. The zinc cation and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of the hexanoic acid, 2-ethyl-, zinc salt, basic in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). Based on the above information, unrestricted read-across is considered feasible and justified.

Although the term „constituent“ within the REACH context is defined as substance (also being part of a mixture), the term constituent within this hazard assessment is meant to describe either part of the metal carboxylate salt, i.e. anion or cation.

Toxicity for reproduction – developmental toxicity

No toxicity data on adverse effects on development of the offspring with Hexanoic acid, 2-ethyl-, zinc salt, basic are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the reproductive toxicity of the individual constituents are given below.

 

Table: Summary of toxicity data on adverse effects on development of the offspring of Hexanoic acid, 2-ethyl-, zinc salt, basic and the individual constituents.

	(slightly soluble) zinc substances	2-ethylhexanoic acid (CAS# 149-57-5)	Hexanoic acid, 2-ethyl-, zinc salt, basic (CAS# 85203-81-2)
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

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. Based on the above given information, 2-ethylhexanoic acid was classified as toxic for reproduction, developmental toxicity category 2 (H361d, CLP), category 3 (R63, DSD)

 

Hexanoic acid, 2-ethyl-, zinc salt, basic

Since notoxicity data on adverse effects on development of the offspringis available for Hexanoic acid, 2-ethyl-, zinc salt, basic, information on the individual constituents zinc and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of Hexanoic acid, 2-ethyl-, zinc salt, basic. For the purpose of hazard assessment of Hexanoic acid, 2-ethyl-, zinc salt, basic, 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 Hexanoic acid, 2-ethyl-, zinc salt, basic, 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 Hexanoic acid, 2-ethyl-, zinc salt, basic based on the toxicological assessment of the individual constituents, the harmonised legally binding classification of 2-ethylhexanoic acid for reproductive toxicity is read-across to Hexanoic acid, 2-ethyl-, zinc salt, basic. Thus, zinc bis(2-ethylhexanoate is self-classified for reproductive toxicity in category 2 H361d (Suspected of damaging the unborn child) and according to Regulation 67/548/EEC in category 3 R63 (Possible risk of harm to the unborn child). 

Justification for selection of Effect on developmental toxicity: via oral route:

Information from read-across substances:

human data for zinc: NOAEL=20mg/kg bw/day

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

Justification for classification or non-classification

Considering the read-across principles as detailed above for Hexanoic acid, 2-ethyl-, zinc salt, basic based on the toxicological assessment of the individual constituents, the harmonised legally binding classification of 2-ethylhexanoic acid for reproductive toxicity is read-across to Hexanoic acid, 2-ethyl-, zinc salt, basic. Thus, Hexanoic acid, 2-ethyl-, zinc salt, basic is self-classified for reproductive toxicity in category 2 H361d (Suspected of damaging the unborn child) and according to Regulation 67/548/EEC in category 3 R63 (Possible risk of harm to the unborn child).