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EC number: 205-249-0 | CAS number: 136-51-6
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Calcium bis(2-ethylhexanoate) is not expected to be toxic for reproduction.
Additional information
Read-across approach
Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to 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 and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products 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 a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.
Calcium bis(2-ethylhexanoate) is the calcium salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent calcium cation and monovalent 2-ethylhexanoate anions. The calcium cation and the 2-ethylhexanoate anion are considered to represent the overall toxicity of calcium bis(2-ethylhexanoate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts).
A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.
Toxicity for reproduction - effects on fertility
No toxicity data on adverse effects on sexual function and fertility with Calcium bis(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 Calcium bis(2-ethylhexanoate) and the individual constituents.
| calcium substances | 2-ethylhexanoic acid (CAS# 149-57-5) | Calcium bis(2-ethylhexanoate) (CAS# 136-51-6) |
Two-generation reproductive toxicity study | not reprotoxic (weight of evidence, human data) not classified
| NOAEL(rat; F1)
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.
Calcium
Only limited data are available on effects of calcium compounds on the reproductive performance of male and female mice and rats, respectively. A preliminary NOAEL for calcium effects on reproduction and development of offspring may be derived from a CaCO3 feeding study in mice (Richards and Greig, 1952). The study design was similar to that of a one-generation reproductive toxicity study. The highest dose of 2 % CaCO3 (corresponding to 1.1 % Ca) resulted in reduced numbers and total weight of litters, and increased both the number and proportion of litter deaths, hence being considered as LOAEL for effects on reproductive performance. The dose level of 0.73 % Ca may be established as NOAEL although there were some sporadic effects without statistical significance. However, no daily dose levels could be calculated due to lack of data on daily food intake.
However, with respect to potential hazards of calcium for reproduction the following aspects have to be taken into account:
i) Calcium, released as calcium cations in aqueous media is a physiologically essential element and nutrient for all mammals including humans. Comprehensive evaluations of possible adverse health effects of individual nutrients at intakes in excess of dietary requirements have been presented in the scientific opinions of the Scientific Committee on Food (SCF). Where possible, tolerable upper intake levels (UL) for different human populations have been established. The UL is an estimate of the highest level of intake entailing no appreciable risk of adverse health effects. In the opinion on calcium (EFSA 2006), the sources, properties and effects of calcium on animals as well as on different subgroups of the human population have been re-evaluated and a tolerable upper intake level for calcium has been defined. The SCF decided to base the derivation of an UL for calcium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily calcium intakes of 2500 mg from both the diet and supplements were tolerated without any adverse effects. Based on the findings, a tolerable upper intake level of 2500 mg of calcium per day for calcium intake from all sources is proposed for adults, corresponding to a dose of about 36 mg calcium/kg bw/d taking into account an average body weight of 70 kg/person. The UL is considered to also cover any potential reproductive effects.
ii) Supportive information is available in section 7.12 of the technical dossier (Mortimer, 1988) showing that calcium is essential for the function of human spermatozoa (acrosome reaction), i.e. calcium has a beneficial effect on reproductive performance.
iii) Supportive information is available in section 7.12 of the technical dossier (Han, 2000) showing that calcium has a protective effect against lead accumulation in dams and their offspring, i.e. acts beneficially.
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.
Calcium bis(2-ethylhexanoate)
Since no toxicity data on adverse effects on sexual function and fertility is available for Calcium bis(2-ethylhexanoate), information on the individual constituents calcium and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of Calcium bis(2-ethylhexanoate). For the purpose of hazard assessment of Calcium bis(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 Calcium bis(2-ethylhexanoate), the NOAEL of 100 mg/kg bw/day for the reproductive toxicity in the F1 offspring will be used.
Calcium bis(2-ethylhexanoate) is not expected to show adverse effects on sexual function and fertility, since the two constituents calcium and 2-ethylhexanoic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, calcium bis(2-ethylhexanoate) 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.
Justification for selection of Effect on fertility via oral route:
Information from read-across substances:
human data for calcium: not reprotoxic (weight of evidence)
animal data for 2-ethylhexanoic acid: NOAEL(rat, P)=300mg/kg bw/day
Effects on developmental toxicity
Description of key information
Calcium bis(2-ethylhexanoate) is expected to be a developmental toxicant.
Additional information
Read-across approach
Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to 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 and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products 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 a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.
Calcium bis(2-ethylhexanoate) is the calcium salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent calcium cation and monovalent 2-ethylhexanoate anions. The calcium cation and the 2-ethylhexanoate anion are considered to represent the overall toxicity of calcium bis(2-ethylhexanoate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts).
A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.
Toxicity for reproduction - developmental toxicity
No toxicity data on adverse effects on development of the offspring with Calcium bis(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 Calcium bis(2-ethylhexanoate) and the individual constituents.
| calcium substances | 2-ethylhexanoic acid (CAS# 149-57-5) | Calcium bis(2-ethylhexanoate) (CAS# 136-51-6) |
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 | no data
self-classified, |
Two-generation reproductive toxicity study | NOAEL(rat; F1)
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.
Calcium
Only limited data are available on effects of calcium compounds on the reproductive performance of male and female mice and rats, respectively. A preliminary NOAEL for calcium effects on reproduction and development of offspring may be derived from a CaCO3 feeding study in mice (Richards and Greig, 1952). The study design was similar to that of a one-generation reproductive toxicity study. The highest dose of 2 % CaCO3 (corresponding to 1.1 % Ca) resulted in reduced numbers and total weight of litters, and increased both the number and proportion of litter deaths, hence being considered as LOAEL for effects on reproductive performance. The dose level of 0.73 % Ca may be established as NOAEL although there were some sporadic effects without statistical significance. However, no daily dose levels could be calculated due to lack of data on daily food intake.
However, with respect to potential hazards of calcium for reproduction the following aspects have to be taken
into account:
i) Calcium, released as calcium cations in aqueous media is a physiologically essential element and nutrient for all mammals including humans. Comprehensive evaluations of possible adverse health effects of individual nutrients at intakes in excess of dietary requirements have been presented in the scientific opinions of the Scientific Committee on Food (SCF). Where possible, tolerable upper intake levels (UL) for different human populations have been established. The UL is an estimate of the highest level of intake entailing no appreciable risk of adverse health effects. In the opinion on calcium (EFSA 2006), the sources, properties and effects of calcium on animals as well as on different subgroups of the human population have been re-evaluated and a tolerable upper intake level for calcium has been defined. The SCF decided to base the derivation of an UL for calcium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily calcium intakes of 2500 mg from both the diet and supplements were tolerated without any adverse effects. Based on the findings, a tolerable upper intake level of 2500 mg of calcium per day for calcium intake from all sources is proposed for adults, corresponding to a dose of about 36 mg calcium/kg bw/d taking into account an average body weight of 70 kg/person. The UL is considered to also cover any potential reproductive effects.
ii) Supportive information is available in section 7.12 of the technical dossier (Mortimer, 1988) showing that calcium is essential for the function of human spermatozoa (acrosome reaction), i.e. calcium has a beneficial effect on reproductive performance.
iii) Supportive information is available in section 7.12 of the technical dossier (Han, 2000) showing that calcium has a protective effect against lead accumulation in dams and their offspring, i.e. acts beneficially.
Two pre-natal developmental toxicity studies establishing a dose- response relationship of potential adverse effects of calcium after oral administration of calcium carbonate to rats were identified (Shackelford et al., 1993, 1994). The design of these studies was comparable to the OECD guideline 414. In all studies no adverse developmental, foetotoxic or teratogenic effects were noticed up to and including the highest dose levels tested. These studies allow the derivation of a NOAEL value for developmental effects of calcium.
From the study on rats given CaCO3 in feed (Shackelford et al., 1993) the highest dose of 1.25 % Ca is established as the NOAEL for developmental effects, corresponding to a daily dose of 938 mg Ca/kg bw/d.
However, with respect to potential hazards of calcium for developmental toxicity the following aspects have to be taken into account:
i) Calcium, released as calcium cations in aqueous media is a physiologically essential element and nutrient for all mammals including humans. Comprehensive evaluations of possible adverse health effects of individual nutrients at intakes in excess of dietary requirements have been presented in the scientific opinions of the Scientific Committee on Food (SCF). Where possible, tolerable upper intake levels (UL) for different human populations have been established. The UL is an estimate of the highest level of intake entailing no appreciable risk of adverse health effects. In the opinion on calcium (EFSA 2006), the sources, properties and effects of calcium on animals as well as on different subgroups of the human population have been re-evaluated and a tolerable upper intake level for calcium has been defined. The SCF decided to base the derivation of an UL for calcium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily calcium intakes of 2500 mg from both the diet and supplements were tolerated without any adverse effects. Based on the findings, a tolerable upper intake level of 2500 mg of calcium per day for calcium intake from all sources is proposed for adults, corresponding to a dose of about 36 mg calcium/kg bw/d taking into account an average body weight of 70 kg/person. The UL is considered to also cover any potential developmental effects and will be used further in the risk assessment.
ii) Lack of developmental/teratogenic effects or even beneficial effects of calcium supplementation on foetal development is further supported by human data (Villar, 1990; Levine, 1997; Koo, 1999; Section 7.10.1 of the technical dossier).
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 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).
Calcium bis(2-ethylhexanoate)
Since no reproductive toxicity study is available for Calcium bis(2-ethylhexanoate), information on the individual constituents calcium and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of Calcium bis(2-ethylhexanoate). For the purpose of hazard assessment of Calcium bis(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 Calcium bis(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 Calcium bis(2-ethylhexanoate) based on the toxicological assessment of the individual constituents, it is therefore proposed to also read-across the classification of toxic for reproduction, developmental toxicity category 2 (H361d/R62) of 2-ethylhexanoic acid to Calcium bis(2-ethylhexanoate).
Justification for selection of Effect on developmental toxicity: via oral route:
Information from read-across substances:
human data for calcium: not reprotoxic (weight of evidence)
animal data for 2-ethylhexanoic acid: NOAEL(rat, F1) = 100 mg/kg bw/day
Justification for classification or non-classification
Considering the read-across principles as detailed above for calcium bis(2-ethylhexanoate) based on the toxicological assessment of the individual constituents, it is therefore proposed to also read-across the classification of toxic for reproduction, developmental toxicity category 2 (H361d/R63) of 2-ethylhexanoic acid to calcium bis(2 -ethylhexanoate).
Additional information
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