Calcium di(octanoate)

Endpoint summary

Description of key information

The acute oral toxicity of the test item is read-across from dilithium adipate. The acute oral toxicity of dilithium adipate was determined to be in the range 300 mg/kg bw - 2000 mg/kg bw dilithium adipate.

Source and target substances are likely to dissociate after administration into metals ions and fatty acids due to the ionic bond between the metal cation and fatty acid ion being disrupted by polar aqueous media. The fatty acid component is not expected to be hazardous as it is potentially exempt from REACH under Annex V.

 

Fatty acids are an endogenous part of every living cell and are absorbed, digested and transported in animals and humans. When taken up by tissues, they can either be stored as triglycerides or can be oxidised via the ß-oxidation and tricarboxylic acid pathways. Alternative minor oxidation pathways can be found in the liver and kidney (ω-oxidation and ω-1 oxidation) and in peroxisomes for ß-methyl branched fatty acids (α-oxidation). The metabolic products can then be incorporated for example into membrane phospholipids. The fatty acid moieties of the lithium and calcium salts of fatty acids are natural constituents of the human body and essential components of a balanced human nutrition. Fatty acids, through their inclusion in REACH Annex V, are excluded from REACH registration requirements provided they are obtained from natural sources and not chemically modified, are not PBT or vPvB or give rise to an equivalent level of concern, and do not meet the criteria for classification as dangerous, except those classified only as flammable or skin or eye irritants. Therefore, they are considered not to be hazardous to humans.

The main difference between source and target substances is the cation and therefore test organisms would be exposed to either calcium from the target substance or lithium from the source substance. For acute oral toxicity the source substance is considered to be a more toxic compared to the target, as lithium is classified for acute toxicity. The Science Committee for Food (SCF) have issued an opinion on the tolerable daily intake for calcium (2003), in which the upper tolerable daily intake of calcium from all sources for adults is 2500 mg/kg b.w/day; this is significantly higher than acute oral toxicity LD50 value reported for the source substance (300 – 2000 mg/kg). A published LD50 value for octanoic acid, the organic component of the target substance, is reported as 10080 mg/kg with a 95 % confidence interval of 8190 to 12370 mg/kg (Jenner et al. 1964). Therefore, calcium dioctanoate is likely to be less toxic than dilithium adipate and the toxicity seen in studies with lithium adipate is considered to be related to the lithium cation, not the fatty acid component. Read across from this substance for acute oral toxicity needs to be assessed taking into account that lithium is driving the toxicity, and therefore although data for this endpoint is read across from dilithium adipate it is used in combination with published information on calcium and fatty acids and the acute oral classification (Category 4) that is assigned to lithium adipate is not considered to be relevant for calcium dioctanoate.

 

References:

Jenner PM, Hagan EC, Taylor JM, Cook EL and Fitzhugh OG. 1964. Food Flavourings and Compounds of Related Structure I. Acute Oral Toxicity. Fd Cosmet. Toxicol. Vol. 2, pp. 327-343

SCF (Scientific Committee on Food). 2003. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Calcium (expressed on 4 April 2003). SCF/CS/NUT/UPPLEV/64 Final. http://ec.europa.eu/food/fs/sc/scf/out194_en.pdf

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

16 April to 21 May 2015

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP-compliant, guideline study, available as an unpublished report.

Justification for type of information:

Source and target substances are likely to dissociate after administration into metals ions and fatty acids due to the ionic bond between the metal cation and fatty acid ion being disrupted by polar aqueous media. The fatty acid component is not expected to be hazardous as it is potentially exempt from REACH under Annex V. The main difference between source and target substances is the cation and therefore test organisms would be exposed to either calcium from the target substance or lithium from the source substance. For acute oral toxicity the source substance is considered to be more toxic compared to the target, as lithium is classified for acute toxicity. The Science Committee for Food (SCF) have issued an opinion on the tolerable daily intake for calcium (2003), in which the upper tolerable daily intake of calcium from all sources for adults is 2500 mg/kg b.w/day; this is significantly higher than acute oral toxicity LD50 value reported for the source substance (300 – 2000 mg/kg). A published LD50 value for octanoic acid, the organic component of the target substance, is reported as 10080 mg/kg with a 95 % confidence interval of 8190 to 12370 mg/kg (Jenner et al. 1964). Therefore, calcium dioctanoate is likely to be less toxic than dilithium adipate and the toxicity seen in studies with lithium adipate is considered to be related to the lithium cation, not the fatty acid component. Read across from this substance for acute oral toxicity needs to be assessed taking into account that lithium is driving the toxicity, and therefore although data for this endpoint is read across from dilithium adipate it is used in combination with published information on calcium and fatty acids and the acute oral classification (Category 4) that is assigned to lithium adipate is not considered to be relevant for calcium dioctanoate. Further information is included in the read-across justification attached to Section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

- Source: Charles River Deutschland, Sulzfeld, Germany. Animals were 8 to 10 weeks old and nulliparous and non-pregnant.
- Acclimatisation: The acclimatization period was at least 5 days before the start of treatment under laboratory conditions and animals were group housed.
- Housing: Individual housing of animals in the pilot study and group housing of four animals per cage in the main study in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment. The rats had free access to pelleted rodent diet and tap water.
- Environmental conditions: Temperature and relative humidity were set to achieve limits of 18 to 24 deg C, and 40 to 70% humidity. Rate of air exchange was at least 10 changes per hour and there was a 12 hour light/12 hour dark cycle.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

- Preparation: The preparations (w/w) were kept at room temperature protected from light and were dosed within 4 hours after adding the vehicle to the test substance. Homogeneity was obtained to visually acceptable levels.
- Dosing: Oral gavage, using plastic feeding tubes. The test item preparations were stirred on a magnetic stirrer during dosing. The concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.

Doses:

In the absence of any other toxicity information a "Pilot study" was conducted in which single female rats were orally dosed with the test substance at 2000 or 300 mg/kg body weight. Based on the Pilot results, a fixed dose level was selected for the main study and four further females were dosed at 300 mg/kg body weight.

No. of animals per sex per dose:

For the main study a total of five female rats (including the pilot study rat) were treated at a single dose concentration.

Control animals:

no

Details on study design:

- Observations: Clinical observations were made on the day of dosing and then once daily until Day 15. Morbidity and viability checks were made twice daily and individual body weights were recorded on days 0, 8 and 15. At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

The Fixed Dose Procedure does not require any statistical analyses of the data.

Preliminary study:

In the preliminary study at 2000 mg/kg bw with a single animal, the animal was found dead on Day 2. At 300 mg/kg bw no mortality of the single animal occured. Hunched posture and piloerection were noted at both treatment levels, up to day 6 at 300 mg/kg bw.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 mg/kg bw

Based on:

test mat.

Mortality:

During the definitive study, there were no deaths.

Clinical signs:

other: Hunched posture and piloerection were noted for all animals on Day 1.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The highest dose level of Dilithium adipate that did not produce mortality in Wistar rats was established as 300 mg/kg body weight and the estimated minimum lethal dose level was 2000 mg/kg body weight. Based on the mortality rate at 2000 mg/kg body weight, it was concluded that the oral LD50 value of Dilithium adipate was within the range of 300-2000 mg/kg body weight. Based on these results Dilithium adipate should be classified as Category 4.

Executive summary:

The acute oral toxicity of Dilithium adipate to female Wistar rats was determined in a GLP-compliant, fixed-dose method study following OECD guideline 420 (Latour 2015). A preliminary study indicated mortality of a single rat at 2000 mg/kg bw Dilithium adipate but no mortality of a single rat at 300 mg/kg bw Dilithium adipate. For the definitive test four further rats were treated once with 300 mg/kg bw Dilithium adipate by oral gavage and observed for the following 15 days for mortality, systemic toxicity and bodyweight gain. No deaths or significant signs of toxicity were seen. The LD50 value is within the ranges 300 -2000 mg/kg bw Dilthium adipate. Based on these results Dilithium adipate should be classified as Category 4. The study is considered to be relevant and reliable for use for this endpoint.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Column 2 of Annex VIII 8.5 states: "In addition to the oral route (Annex VII, 8.5.1.), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route needs to be provided."   Furthermore Column 2 of Annex VIII 8.5.2 states: "Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size."  The vapour pressure of the substance if very low and the possibility of exposure to aerosols, particles or droplets of an inhalable size is not expected as the substance is formed during the manufacturing process. In conclusion there is no expected exposure via the inhalation route and therefore an acute toxicity inhalation study is not considered to be necessary.

There is no exposure via the dermal route and therefore an acute toxicity dermal study is not considered to be necessary. Furthermore, published results of studies used to assess the dermal toxicity of a number of read-across substances have indicated that there is no toxicity via the dermal route. Based on similarities in structure and properties it can be concluded that exposure via the dermal route is unlikely to result in toxic affects.

Justification for classification or non-classification

The acute oral toxicity of the test item is read-across from dilithium adipate. The acute oral toxicity of dilithium adipate was determined to be in the range 300 mg/kg bw - 2000 mg/kg bw dilithium adipate.

Source and target substances are likely to dissociate after administration into metals ions and fatty acids due to the ionic bond between the metal cation and fatty acid ion being disrupted by polar aqueous media. The fatty acid component is not expected to be hazardous as it is potentially exempt from REACH under Annex V. 

The main difference between source and target substances is the cation and therefore test organisms would be exposed to either calcium from the target substance or lithium from the source substance. For acute oral toxicity the source substance is considered to be more toxic compared to the target, as lithium is classified for acute toxicity. The Science Committee for Food (SCF) have issued an opinion on the tolerable daily intake for calcium (2003), in which the upper tolerable daily intake of calcium from all sources for adults is 2500 mg/kg b.w/day; this is significantly higher than acute oral toxicity LD50 value reported for the source substance (300 – 2000 mg/kg). A published LD50 value for octanoic acid, the organic component of the target substance, is reported as 10080 mg/kg with a 95 % confidence interval of 8190 to 12370 mg/kg (Jenner et al. 1964). Therefore, calcium dioctanoate is likely to be less toxic than dilithium adipate and the toxicity seen in studies with lithium adipate is considered to be related to the lithium cation, not the fatty acid component. Read across from this substance for acute oral toxicity needs to be assessed taking into account that lithium is driving the toxicity, and therefore although data for this endpoint is read across from dilithium adipate it is used in combination with published information on calcium and fatty acids and the acute oral classification (Category 4) that is assigned to lithium adipate is not considered to be relevant for calcium dioctanoate.