Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
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.

 

Fatty acids, C9-13-neo-, zinc salts is the zinc metal salt of fatty acids, C9-13-neo, which readily dissociates to the corresponding divalent zinc cation and fatty acids, C9-13-neo anions. The zinc cation and the fatty acids, C9-13-neo anion are considered to represent the overall toxicity of the Fatty acids, C9-13-neo-, 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 neo acids hazard assessment

The carboxylic acids “fatty acids, C9-13-neo” and “neodecanoic acid” are considered similar in their toxicological profile and are therefore grouped together. Both neo acids 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, C9-13-neo and neodecanoic acid contain human health hazard information on both substances 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).

Based on the above information “fatty acids, C9-13-neo” and “neodecanoic acid” will be assessed for their hazardous properties, using the same dataset for both substances.

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.

Repeated dose toxicity

No repeated dose toxicity study with Fatty acids, C9-13-neo-, zinc salts is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products zinc and fatty acids, C9-13-neo as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of the Fatty acids, C9-13-neo-, zinc salts and the individual constituents.

 

(slightly soluble) zinc substances

Fatty acids, C9-13-neo
(CAS# 68938-07-8)

Fatty acids, C9-13-neo-, zinc salts
(CAS# 92044-84-3)

Repeated dose
oral toxicity

NOAEL(human data)= 0.83 mg Zn/kg bw/day*

NOAEL(rat;28d)= 300 mg/kg bw/day

no data

Repeated dose
inhalation toxicity

NOAEC(guinea pig;5d)=2.7 mg ZnO/m³

no data

no data

Repeated dose
dermal toxicity

no data

NOAEL(rabbit; 10d)= 2,280 mg/kg bw/day n(read-across from neodecanoic acid)

no data

* Identified as most sensitive endpoint in the registration dossier for zinc, thus has been used for the DNEL derivation of this substance.

 

Zinc

From studies in which humans were supplemented with zinc (as zinc gluconate)it was concludedthat women are more sensitive to the effects of high zinc intake and that a dose of 50 mg Zn/day is the human NOAEL. This corresponds to a daily exposure of 0.83 mg Zn/kg bw. At the LOAEL of 150 mg Zn/day, clinical signs and indications for disturbance of copper homeostasis have been observed. Studies conducted on animals are not discussed here, since information on human experience are considered of higher relevance for risk assessment purposes and should take precedence over animal studies.For further information on the toxicity of zinc, please refer to the relevant sections in the IUCLID and CSR.

 

Fatty acids, C9-13-neo

Five male and five female rats were exposed to 0; 10; 55; or 300 mg/kg/day fatty acids, C9-C13 neo by oral gavage for 28 consecutive days. There were no mortalities. Increased salivation was observed after dosing in rats receiving 300 mg/kg. No treatment related changes were observed in body weight, food consumption, haematology, or clinical chemistry. In males receiving 300 mg/kg, kidney weight increased and necropsy revealed an abnormal appearance of the kidney. A dose-related hyaline droplet was noted in males at all treatment levels. The findings in the kidney of the treated males are species and sex specific and not considered relevant to humans. The NOAEL in this study was 300 mg/kg

 

In a repeated-dose dermal study, neodecanoic acid was applied repeatedly (once daily for 10 applications with a rest period on days 5 and 6) to the skin of rabbits at doses of 0.5 or 2.5 ml/kg (400 or 2280 mg/kg/day).  All animals survived the exposure.  Wheezing was noted in one animal at the 0.5 ml dose level.  Animals at the lower dose level generally showed an overall body weight gain while those at the high level showed terminal weight losses.  The low level animals generally showed slight erythema and moderate atonia and desquamation following the first or fourth application and during the remainder of the study.  At the high level, moderate erythema and moderate or marked atonia and desquamation were present in all animals.  In addition, slight oedema was present following the fifth application and slight fissures or cracks were observed in several animals following the last seven applications.  The exposed skin also became hypersensitive to the touch.  There were no indications of systemic toxicity attributed to exposure.

 

Members of the neoacids category have a low order of toxicity under conditions of repeat exposure by oral and dermal routes. In addition, they display a consistent degree of subchronic toxicity by either oral or dermal route of exposure.

 

Fatty acids, C9-13-neo-, zinc salts

Since no repeated dose toxicity study is available specifically for Fatty acids, C9-13-neo-, zinc salts, information on the individual constituents zinc and fatty acids, C9-13-neo will be used for the hazard assessment and when applicable for the risk characterisation of Fatty acids, C9-13-neo-, zinc salts. For the purpose of hazard assessment of Fatty acids, C9-13-neo-, zinc salts, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of zinc in Fatty acids, C9-13-neo-, zinc salts, the NOAEL of 0.83 mg/kg bw/day in repeated dose toxicity (human data) will be used.

 

In relevant and reliable repeated dose toxicity studies for both constituents of Fatty acids, C9-13-neo-, zinc salts, there were no toxicological findings reported that would justify a classification for specific target organ toxicity with repeated exposure. Hence, no classification for Fatty acids, C9-13-neo-, zinc salts as STOT, RE is required.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Information from read-across substances:
human data for zinc: NOAEL=0.83mg/kg bw/day
animal data for neodecanoic acid: NOAEL(rat)=300mg/kg bw/day

Justification for classification or non-classification

Substance Fatty acids, C9-13-neo-, zinc salts is not expected to induce specific target organ toxicity by repeated exposure, since its two moieties zinc and Fatty acids, C9-13-neo-, zinc salts have not shown respective (severe) adverse effects and are not classified as specific target organ toxicant (STOT) - repeated. Thus, substance Fatty acids, C9-13-neo-, zinc salts is not to be classified according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) - repeated. Furthermore, substance Fatty acids, C9-13-neo-, zinc salts is not to be classified according to Directive 67/548/EEC for repeated dose toxicity.