Calcium neodecanoate

Endpoint summary

Description of key information

No acute toxicity studies with calcium neodecanoate are available, thus the acute toxicity will be addressed with existing data on the dissociation products calcium and neodecanoate.

Signs of acute oral or acute dermal toxicity are not expected for calcium neodecanoate, since the two moieties calcium and neodecanoic acid have not shown signs of acute oral or acute dermal toxicity in experimental testing (both LD50 > 2000mg/kg).

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Calcium

Acute oral toxicity

 

The normal adult diet contains about 25 mmol of calcium per day. Only about 5 mmol of this is absorbed into the body per day across the intestinal epithelial cells brush border membrane and immediately bound to calbindin, which is a vitamin D-dependent calcium-binding protein. Calbindin transfers the calcium directly through the basal membrane on the opposite side of the cell, where it is actively transported into the body by TRPV6 and calcium pumps (PMCA1) (Balesaria et al., 2009). The plasma total calcium concentration is in the range of 2.2-2.6 mmol/l, whereas the normal ionized calcium is 1.3-1.5 mmol/L. Depending on the plasma albumin concentration, the main carrier of protein-bound calcium in the blood, the total calcium concentration in the blood varies. That is the reason why the biological effect of calcium is determined by the amount of ionized calcium in the blood. The plasma ionized calcium level is tightly regulated to remain within very narrow limits by a set of negative feedback systems. The chief cells in the parathyroid glands sense the calcium level by specialized calcium receptors. In response to a fall in plasma ionized calcium concentration they secrete parathyroid hormone (PTH), while calcitonin is secreted in response to a rise in plasma ionized calcium level. The main effector organs are the skeleton and the kidney.

Beside this negative regulation system of ionized calcium in the plasma, the absorption of calcium in the intestine after oral ingestion is also regulated. Calbindin, the vitamin D-dependent calcium-binding protein, is rate-limiting and down regulated when exposed to high concentrations of calcium (Bronner, 2003). “Fractional calcium absorption is inversely related to the concentration of calcium present in the gut lumen (Ireland and Fordtran, 1973) and dietary load (Heaney et al., 1990). For example, absorption from a meal containing 15 or 500 mg of calcium was 64 and 28 %, respectively (Heaney et al., 1990). In women adapted to a high (2000 mg/day) calcium diet, whole-body retention of calcium increased from 27 to 37 % when they were given a low (300 mg/day) calcium diet for two weeks (Dawson-Hughes et al., 1993)” (EFSA Scientific Opinion on Dietary Reference Values for calcium, 2015).

Calcium absorption is also affected by vitamin D status. The active metabolite of vitamin D-1,25 dihydroxyvitamin D, enhances the intestinal absorption of calcium. Inadequate vitamin D levels lead to a reduction in gastrointestinal calcium absorption of up to 50 %, resulting in only 10 % to 15 % of dietary intestinal calcium being absorbed (Holick, 2007)” (Fong & Khan, 2012).

Therefore, the dietary calcium absorption is strongly regulated by different pathways. Excess calcium intake from foods alone is difficult if not impossible to achieve. Rather, excess intakes are more likely to be associated with the use of calcium or vitamin D supplements. The abuse of these supplements can cause hypercalcemia, which is defined as a high calcium level (>2.6 mmol/L) in the blood serum. The symptoms of a single, acute overdose from accidentally or intentionally taking too many calcium or vitamin D supplements or calcium-containing antacids at one time include stomachache, constipation or diarrhea, headache, nausea and vomiting.

An example for an accidental vitamin D supplement overdose, which increases the calcium absorption, was published by Barrueto et al. (2005). A 2-year-old boy suffered from hypercalcemia and hypertension with colic and constipation resulting from an unintentional overdose with an imported vitamin D supplement (Raquiferol). The patient received a total of 2 400 000 IU of vitamin D over 4 days (estimated average requirements: 400 IU). The patient´s hypercalcemia persisted for 14 days and was complicated by persistent hypertension. However, the boy made a complete clinical recovery, which demonstrates that acute hypercalcemia, induced by vitamin D supplements, has no adverse long-term effects on human health.

One of the main undesirable side-effects of acute excessive calcium supplementation is constipation. “In fact approximately 1 of every 10 participants in the WHI calcium–vitamin D supplementation trial (Jackson et al., 2006) reported moderate to severe constipation. Usually the constipation is alleviated by increasing intakes of water or fiber-rich foods, or by trying another form of supplement (calcium citrate may be less constipating than calcium carbonate, for example)” (Ross et al. 2011).

 

For reference list please refer to endpoint summary of the moieties.

 

 

Acute dermal toxicity

 

In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10 % or 100 % default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals yields substantially lower figures, which can be summarised briefly as follows:

Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn) and current metal risk assessments under REACH, which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.

The following default dermal absorption factors for metal cations are therefore proposed (reflective of full-shift exposure, i.e. 8 hours):

From exposure to liquid/wet media: 1.0 %

From dry (dust) exposure: 0.1 %

This approach is consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007).

 

For reference list please refer to endpoint summary of the moieties.

 

Neodecanoate

 

Neodecanoic acid has a low potential for toxicity via the oral and dermal routes. 

 

Oral

Male and female rats were gavaged with neodecanoic acid at concentrations of 1, 1.5, 2, 3, or 4 ml/kg to assess acute oral toxicity.  All animals that died during the study did so within 3 days of exposure. Signs of toxicity included lethargy, hypothermia, piloerection, dyspnea, and ataxia. Based on these results, it is concluded that the LD50 is approximately 2.27 ml/kg (2066 mg/kg). 

 

Dermal

In a study that assessed acute dermal toxicity, male and female rats were exposed to 4 ml/kg (3640 mg/kg) neodecanoic acid via an occluded dermal patch for 24 hours. After 24 hours, the patch was removed and clinical observations were made once daily for 9 days. There were no deaths observed in this study and there were no signs of a toxicity response.  It is concluded that the LD50 is greater than 3640 mg/kg. 

 

Calcium neodecanoate

Signs of acute oral or acute dermal toxicity are not expected for calcium neodecanoate, since the two moieties calcium and neodecanoic acid have not shown signs of acute oral or acute dermal toxicity in experimental testing (both LD50 > 2000mg/kg). Under the assumption that the moieties of calcium neodecanoate show their toxicological profile individually upon dissolution, the acute oral and dermal (systemic) toxicity of calcium neodecanoate can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1.

A study for acute toxicity via inhalation was not conducted with calcium neodecanoate, since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

 

The calculated oral and dermal LD50 for calcium neodecanoate is > 2000mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

 

Justification for classification or non-classification

Based on in vivo oral and dermal LD50 data on the moieties, acute toxicity estimates for calcium neodecanoate have been calculated resulting in LD50 values > 2000 mg/kg bw.

According to the criteria of REGULATION (EC) No 1272/2008 and its subsequent adaptions, calcium neodecanoate does neither have to be classified and has no obligatory labelling requirement for acute oral or dermal toxicity.