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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 REACH Metal Carboxylates Consortium (RMC), covering 9 metal carboxylates in total. This literature screening effort included:

 

  • all available proprietary studies from the REACH Metal Carboxylates Consortium (RMC)
  • 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.

 

Fatty acids, C6-19-branched, zinc salts is the zinc metal salt of fatty acids, C6-19-branched, which readily dissociates to the corresponding divalent zinc cation and fatty acids, C6-19-branched anions. The zinc cation and the fatty acids, C6-19-branched anion are considered to represent the overall toxicity of the fatty acids, C6-19-branched, zinc salts 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.

 

Introduction to the neoacids hazard assessment

The carboxylic acids “fatty acids, C6-19-branched”, “fatty acids, C9-13-neo” and “neodecanoic acid” are considered similar in their toxicological profile and are therefore grouped together. All neoacids originate from the same production process in which a branched olefin is reacted with carbon monoxide and water at elevated temperature and pressure in the presence of an acid as catalytic component. The dossiers for fatty acids, C6-19-branched, fatty acid C9 to C13 neo and neodecanoic acid contain human health hazard information on fatty acid C9 to C13 neo and neodecanoic acid, indicating that the toxicological profile is similar. This approach was also used and accepted in the US EPA HPV programme, even for a wider range of neo-acid substances (US EPA, April 2009: http://www.epa.gov/chemrtk/pubs/summaries/neoc528/c13335tc.htm).

 

The registrant is of the opinion that the toxicological data for fatty acid C9 to C13 neo and neodecanoic acid can be read-across to fatty acids, C6-19-branched based on the following arguments:

 

- the metabolism of branched fatty acids follow the same mechanism as the unbranched: “Generally, branched-chain aliphatic alcohols are oxidized to the corresponding aldehydes, which, in turn, are oxidized to the corresponding carboxylic acids (Bosron & Li, 1980; Levi & Hodgson, 1989). The aldehyde may also be reduced to the corresponding alcohol, which is probably a short-lived intermediate in vivo. Like their saturated analogues, unsaturated branched-chain aliphatic alcohols and aldehydes are converted by the pathways cited above to the corresponding acids. The acids may undergo ß-oxidative cleavage and complete metabolism to carbon dioxide (Williams, 1959; Voet & Voet, 1990) in amino acid pathways, the fatty acid pathway, and the tricarboxylic acid cycle. Alternatively, they may undergo a combination of omega-, (omega-1)-, and ß-oxidation and selective dehydrogenation and hydration to yield polar metabolites which are excreted as the glucuronic acid or sulfate conjugates in the urine and, to a lesser extent, in the faeces (Diliberto et al., 1990). The principal metabolic pathways for detoxification of these branched-chain substances are determined primarily by four structural characteristics: carbon chain length and the position, number, and size of the alkyl substituents.” (WHO, 1999)

 

- the linear and branched chain fatty acid are not genotoxic: “These negative results indicate that the substances in this group of linear and branched-chain aliphatic unsaturated and unconjugated alcohols, aldehydes, acids, and related esters that are used as flavouring substances are neither mutagenic nor genotoxic.” (WHO, 1999)

 

- branched chain fatty acids are naturally occurring fatty acids, which are present in various nutritional products such as dairy products, animal fats and certain fish (i.e. phytanic and pristanic acid). (Vetter 2009)

 

- branched chain fatty acids are a relevant part of the fatty acids in the amniotic fluid (Ran-Ressler, RR et al, 2008)

 

- Fatty acids, C16-18 and C18-unsatd., branched and linear is a naturally occurring fatty acid in tall oil fatty acid with a content of approx. 7%

 

- naturally occurring fatty acids from C6 to C24 are exempt for the obligation to register (in accordance with regulation (EC) 1907/2006, Annex V, Section 9), this itself shows that the hazardous properties of branched fatty acid of that chainlength are believed to be of low toxicological concern. Since fatty acids, C6-19-branched, although being a synthetic fatty acid, can be considered as being a part of that group, the toxicity is also of low concern.

 

Based on the above given argumentation, read-across among the members of the neo-acids group, i.e. fatty acid C9 to C13 neo, neodecanoic acid and fatty acids, C6-19-branched is justified without restriction.

 

References:

WHO Food Additives Series: 42 (1999) Linear and branched-chain aliphatic, unsaturated, unconjugated alcohols, aldehydes, acids, and related esters, World Health Organization, Geneva, 1999

 

Rinat R Ran-Ressler, Srisatish Devapatla, Peter Lawrence, J Thomas Brenna (2008) Branched Chain Fatty Acids Are Constituents of the Normal Healthy Newborn Gastrointestinal Tract, Pediatric Research (2008) 64, 605–609

 

European Food Safety Authority (EFSA) (2012) Scientific opinion: Branched-chain aliphatic saturated aldehydes, carboxylic acids and related esters of primary alcohols and branched-chain carboxylic acids from chemical groups 1 and 2, EFSA Journal 2010; 8(11):1843

 

Vetter W und Schröder M: Concentrations of phytanic acid and pristanic acid are higher in organic than in conventional dairy products from the German market. In: Food Chem. 119, Nr. 2, 2009, p 746–752

 

 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 fatty acids, C6-19-branched, zinc salts 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 sexual function and fertility of fatty acids, C6-19-branched, zinc salts and the individual constituents.

 

(slightly soluble) zinc substances

Neoacids group

Fatty acids, C6-19-branched, zinc salts
(CAS# 68551-44-0)

Two-generation reproductive toxicity study

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

 

not classified

NOAEL(3-gen;rat, P, F1 and F2)= 75 mg/kg bw/day* (read-across)

 

no classified

no data

 

not classified

* Identified as most sensitive endpoint in the registration dossier for the neoacids group, thus 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).

 

Neoacids

In a modified three-generation reproductive toxicity study, male and female Sprague-Dawley rats were administered fatty acids, C9-13-neo at 0, 100, 500 and 1500 ppm (approximately 0, 5, 25 and 75 mg/kg-bw/day, respectively) in the diet. No adverse effects were observed on survival, appearance, behaviour, body-weight gain and food consumption in the parental, F1 or F2 generations. The reproductive performance of the parents was not affected. No treatment-related gross or microscopic pathological findings were observed at any of the dietary levels.

 

 

fatty acids, C6-19-branched, zinc salts

Fatty acids, C6-19-branched, zinc salts is not expected to show adverse effects on sexual function and fertility, since the two constituents zinc andneoacidshave not shown repro- or developmental toxicity in a range of test systems. Thus, fatty acids, C6-19-branched, zinc salts is not to be classified according to regulation (EC) 1272/2008 for reproductive toxicity. Further testing is not required. For further information on adverse effects on sexual function and fertility of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

 

Information on the individual constituents zinc and neoacids will be used for the hazard assessment and, when applicable, for the risk characterisation offatty acids, C6-19-branched, zinc salts. For the purpose of hazard assessment offatty acids, C6-19-branched, zinc salts, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of neoacids infatty acids, C6-19-branched, zinc salts, the NOAEL of 75 mg/kg bw/day for the reproductive toxicity will be used.


Short description of key information:
Fatty acids, C6-19-branched, zinc salts is not expected to show adverse effects on sexual function and fertility.

Justification for selection of Effect on fertility via oral route:
Information from read-across substances:
human data for zinc: NOAEL= 20 mg/kg bw/d
animal data for neoacids group: NOAEL(rat, P, F1, F2)=75mg/kg bw/day

Effects on developmental toxicity

Description of key information
Fatty acids, C6-19-branched, zinc salts is not expected to show adverse effects on development of the offspring.
Effect on developmental toxicity: 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 REACH Metal Carboxylates Consortium (RMC), covering 9 metal carboxylates in total. This literature screening effort included:

 

  • all available proprietary studies from the REACH Metal Carboxylates Consortium (RMC)
  • 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.

 

Fatty acids, C6-19-branched, zinc salts is the zinc metal salt of fatty acids, C6-19-branched, which readily dissociates to the corresponding divalent zinc cation and fatty acids, C6-19-branched anions. The zinc cation and the fatty acids, C6-19-branched anion are considered to represent the overall toxicity of the fatty acids, C6-19-branched, zinc salts 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.

 

Introduction to the neoacids hazard assessment

The carboxylic acids “fatty acids, C6-19-branched”, “fatty acids, C9-13-neo” and “neodecanoic acid” are considered similar in their toxicological profile and are therefore grouped together. All neoacids originate from the same production process in which a branched olefin is reacted with carbon monoxide and water at elevated temperature and pressure in the presence of an acid as catalytic component. The dossiers for fatty acids, C6-19-branched, fatty acid C9 to C13 neo and neodecanoic acid contain human health hazard information on fatty acid C9 to C13 neo and neodecanoic acid, indicating that the toxicological profile is similar. This approach was also used and accepted in the US EPA HPV programme, even for a wider range of neo-acid substances (US EPA, April 2009: http://www.epa.gov/chemrtk/pubs/summaries/neoc528/c13335tc.htm).

 

The registrant is of the opinion that the toxicological data for fatty acid C9 to C13 neo and neodecanoic acid can be read-across to fatty acids, C6-19-branched based on the following arguments:

 

- the metabolism of branched fatty acids follow the same mechanism as the unbranched: “Generally, branched-chain aliphatic alcohols are oxidized to the corresponding aldehydes, which, in turn, are oxidized to the corresponding carboxylic acids (Bosron & Li, 1980; Levi & Hodgson, 1989). The aldehyde may also be reduced to the corresponding alcohol, which is probably a short-lived intermediate in vivo. Like their saturated analogues, unsaturated branched-chain aliphatic alcohols and aldehydes are converted by the pathways cited above to the corresponding acids. The acids may undergo ß-oxidative cleavage and complete metabolism to carbon dioxide (Williams, 1959; Voet & Voet, 1990) in amino acid pathways, the fatty acid pathway, and the tricarboxylic acid cycle. Alternatively, they may undergo a combination of omega-, (omega-1)-, and ß-oxidation and selective dehydrogenation and hydration to yield polar metabolites which are excreted as the glucuronic acid or sulfate conjugates in the urine and, to a lesser extent, in the faeces (Diliberto et al., 1990). The principal metabolic pathways for detoxification of these branched-chain substances are determined primarily by four structural characteristics: carbon chain length and the position, number, and size of the alkyl substituents.” (WHO, 1999)

 

- the linear and branched chain fatty acid are not genotoxic: “These negative results indicate that the substances in this group of linear and branched-chain aliphatic unsaturated and unconjugated alcohols, aldehydes, acids, and related esters that are used as flavouring substances are neither mutagenic nor genotoxic.” (WHO, 1999)

 

- branched chain fatty acids are naturally occurring fatty acids, which are present in various nutritional products such as dairy products, animal fats and certain fish (i.e. phytanic and pristanic acid). (Vetter 2009)

 

- branched chain fatty acids are a relevant part of the fatty acids in the amniotic fluid (Ran-Ressler, RR et al, 2008)

 

- Fatty acids, C16-18 and C18-unsatd., branched and linear is a naturally occurring fatty acid in tall oil fatty acid with a content of approx. 7%

 

- naturally occurring fatty acids from C6 to C24 are exempt for the obligation to register (in accordance with regulation (EC) 1907/2006, Annex V, Section 9), this itself shows that the hazardous properties of branched fatty acid of that chainlength are believed to be of low toxicological concern. Since fatty acids, C6-19-branched, although being a synthetic fatty acid, can be considered as being a part of that group, the toxicity is also of low concern.

 

Based on the above given argumentation, read-across among the members of the neo-acids group, i.e. fatty acid C9 to C13 neo, neodecanoic acid and fatty acids, C6-19-branched is justified without restriction.

 

References:

WHO Food Additives Series: 42 (1999) Linear and branched-chain aliphatic, unsaturated, unconjugated alcohols, aldehydes, acids, and related esters, World Health Organization, Geneva, 1999

 

Rinat R Ran-Ressler, Srisatish Devapatla, Peter Lawrence, J Thomas Brenna (2008) Branched Chain Fatty Acids Are Constituents of the Normal Healthy Newborn Gastrointestinal Tract, Pediatric Research (2008) 64, 605–609

 

European Food Safety Authority (EFSA) (2012) Scientific opinion: Branched-chain aliphatic saturated aldehydes, carboxylic acids and related esters of primary alcohols and branched-chain carboxylic acids from chemical groups 1 and 2, EFSA Journal 2010; 8(11):1843

 

Vetter W und Schröder M: Concentrations of phytanic acid and pristanic acid are higher in organic than in conventional dairy products from the German market. In: Food Chem. 119, Nr. 2, 2009, p 746–752

 

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 fatty acids, C6-19-branched, zinc salts 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 fatty acids, C6-19-branched, zinc salts and the individual constituents.

 

(slightly soluble) zinc substances

Neoacids group

Fatty acids, C6-19-branched, zinc salts
(CAS# 68551-44-0)

Pre-natal developmental toxicity study

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

 

not classified

NOAEL(rat)=250mg/kg bw/day

 

not classified

no data

 

no classified

Two-generation reproductive toxicity study

NOAEL(3-gen;rat, P, F1 and F2)= 75 mg/kg bw/day (read-across)

 

no classified

no data

 

not classified

* Identified as most sensitive endpoint in the registration dossier for neoacids, thus 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).

 

Neoacids

In a modified three-generation reproductive toxicity study, male and female Sprague-Dawley rats were administered fatty acids, C9-13-neo at 0, 100, 500 and 1500 ppm (approximately 0, 5, 25 and 75 mg/kg-bw/day, respectively) in the diet. No adverse effects were observed on survival, appearance, behaviour, body-weight gain and food consumption in the parental, F1 or F2 generations. The reproductive performance of the parents was not affected. No treatment-related gross or microscopic pathological findings were observed at any of the dietary levels.

 

In developmental toxicity study, pregnant rats, n=22 per dose, were treated by oral gavage to 50, 250, 600 or 800 mg/kg/day neoheptanoic acid, a substance similar in structure to fatty acids, C9-13-neo, during gestation days 6-15. On gestation day 21, the dams were euthanized and the pups were examined for signs of developmental toxicity. Under the conditions of the experimental methods, the test material produced maternal toxicity at dose levels of 600 and 800 mg/kg with maternal lethality at 800 mg/kg. The test material was severely embryotoxic at 800 mg/kg with less than 20% of embryos surviving. Offspring of the 800 mg/kg group had reduced body weight, reduced crown-rump distance, displayed variations signifying delayed development, and a significant percentage (25%) were malformed. In the 600 mg/kg group, there was an increase number of dams with 3 or more resorptions. Offspring of the 600 mg/kg group displayed significant incidences of major (hydrocephalus) and minor (knobby or angular ribs, extra lumbar vertebrae) malformations but showed few signs of delayed development and were not runted. There was no statistically significant evidence of maternal toxicity at dose levels of 50 or 250 mg/kg. There was a slight, but not statistically significant, increase in embryonic resorption noted for the 250 mg/kg group. There was no statistically significant evidence of developmental toxicity at doses for 50 or 250 mg/kg. The NOAEL for maternal toxicity is 250 mg/kg and the NOAEL for developmental toxicity is 250 mg/kg. 

 

fatty acids, C6-19-branched, zinc salts

Fatty acids, C6-19-branched, zinc salts is not expected to show adverse effects on development of the offspring, since the two constituents zinc andneoacidshave not shown developmental toxicity in a range of test systems. Thus, fatty acids, C6-19-branched, zinc salts is not to be classified according to regulation (EC) 1272/2008 for adverse effects on development of the offspring. Further testing is not required. For further information on adverse effects on development of the offspring is available of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

 

Information on the individual constituents zinc and neoacids will be used for the hazard assessment and, when applicable, for the risk characterisation offatty acids, C6-19-branched, zinc salts. For the purpose of hazard assessment offatty acids, C6-19-branched, zinc salts, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.


Justification for selection of Effect on developmental toxicity: via oral route:
Information from read-across substances:
human data for zinc: NOAEL= 20 mg/kg bw/d
animal data for neoacids group: NOAEL(rat, P, F1, F2)=75mg/kg bw/day

Justification for classification or non-classification

Fatty acids, C6-19-branched, zinc salts is not expected to show adverse effects on sexual function and fertility, since the two constituents zinc andneoacidshave not shown repro- or developmental toxicity in a range of test systems. Thus, fatty acids, C6-19-branched, zinc salts is not to be classified according to regulation (EC) 1272/2008 and Directive 67/548 EC for reproductive toxicity.

Fatty acids, C6-19-branched, zinc salts is not expected to show adverse effects on development of the offspring, since the two constituents zinc andneoacidshave not shown developmental toxicity in a range of test systems. Thus, fatty acids, C6-19-branched, zinc salts is not to be classified according to regulation (EC) 1272/2008 and Directive 67/548 EC for adverse effects on development of the offspring.

Additional information

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