Registration Dossier

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Species:

other: animal and human data

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.

Potassium 2-ethylhexanoate is the potassium metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding monovalent potassium cation and 2-ethylhexanoic acid anions. The potassium cation and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of the potassium 2-ethylhexanoate 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 – effects on fertility

No toxicity data on adverse effects on sexual function and fertility with potassium 2-ethylhexanoate 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 potassium 2-ethylhexanoate and the individual constituents.

potassium substances

2-ethylhexanoic acid

(CAS# 149-57-5)

Potassium 2-ethylhexanoate

(CAS# 3164-85-0)

Two-generation reproductive toxicity study

not reprotoxic (weight of evidence, human data)

not classified

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

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

not classified

no data

not classified

Potassium

There is no evidence of any reprotoxic for potassium compounds. Potassium is abundantly available in the environment and in food, and is extensively distributed throughout the human body, which is contradictory to allegation of reprotoxic potential.

According to EFSA (2005) "the average dietary intake of potassium according to European food consumption studies is in the range of 3000 to 4000 mg/day." Furthermore, the publication states that [r]ecommended daily intakes in Europe are in the order of 3.1-3.5 g/day (SCF, 1993). The US Food and Nutrition Board have set an intake of 4.7 g potassium per day from food as an adequate intake, mainly based on the beneficial effects on blood pressure (FNB, 2004)" Lastly, EFSA (2005) reports that "the concentration of potassium in plasma is tightly regulated within a narrow range of about 3.5 to 5 mmol/L. The body is able to accommodate a high intake of potassium, without any substantial change in plasma concentration by synchronized alterations in both renal and extra-renal handling, with potassium either being excreted in the urine or taken up into cells. Thus the plasma or extracellular concentration of potassium does not give a clear indication of the body content of potassium (EFSA 2005)." Potential for fertility impairment of the abundantly available essential element potassium can be safely excluded.

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.

Potassium 2-ethylhexanoate

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

Short description of key information:
Potassium 2-ethylhexanoate 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 potassium: not reprotoxic
animal data for 2-ethylhexanoic acid: NOAEL(rat, P)=300mg/kg bw/day

Potassium 2-ethylhexanoate is expected to be a developmental toxicant.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Species:

other: animal and human data

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.

Potassium 2-ethylhexanoate is the potassium metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding monovalent potassium cation and 2-ethylhexanoic acid anions. The potassium cation and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of the potassium 2-ethylhexanoate 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 potassium 2-ethylhexanoate 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 development of the offspring of potassium 2-ethylhexanoate and the individual constituents.

potassium substances

2-ethylhexanoic acid

(CAS# 149-57-5)

Potassium 2-ethylhexanoate

(CAS# 3164-85-0)

Pre-natal developmental toxicity study

not reprotoxic (weight of evidence, human data)

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

not reprotoxic (weight of evidence, human data)

not classified

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.

Potassium

There is no evidence of any reprotoxic for potassium compounds. Potassium is abundantly available in the environment and in food, and is extensively distributed throughout the human body, which is contradictory to allegation of reprotoxic potential.

According to EFSA (2005) "the average dietary intake of potassium according to European food consumption studies is in the range of 3000 to 4000 mg/day." Furthermore, the publication states that [r]ecommended daily intakes in Europe are in the order of 3.1-3.5 g/day (SCF, 1993). The US Food and Nutrition Board have set an intake of 4.7 g potassium per day from food as an adequate intake, mainly based on the beneficial effects on blood pressure (FNB, 2004)" Lastly, EFSA (2005) reports that "the concentration of potassium in plasma is tightly regulated within a narrow range of about 3.5 to 5 mmol/L. The body is able to accommodate a high intake of potassium, without any substantial change in plasma concentration by synchronized alterations in both renal and extra-renal handling, with potassium either being excreted in the urine or taken up into cells. Thus the plasma or extracellular concentration of potassium does not give a clear indication of the body content of potassium (EFSA 2005)." Potential for developmental toxicity of the abundantly available essential element potassium can be safely excluded.

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.

Potassium 2-ethylhexanoate

Since notoxicity data on adverse effects on development of the offspringis available for potassium 2-ethylhexanoate, information on the individual constituents potassium and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of potassium 2-ethylhexanoate. For the purpose of hazard assessment of potassium 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 potassium 2-ethylhexanoate, 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 potassium 2-ethylhexanoate 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 potassium 2-ethylhexanoate. Thus, potassium 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 potassium:not reprotoxic
animal data for 2-ethylhexanoic acid: NOAEL(rat, F1)=100mg/kg bw/day

Considering the read-across principles as detailed above for potassium 2-ethylhexanoate 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 potassium 2-ethylhexanoate. Thus, potassium 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).