Calcium dibenzoate

Endpoint summary

Description of key information

No acute toxicity studies with Calcium dibenzoate are available, thus the acute toxicity will be addressed with existing data on the dissociation products.

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 dibenzoate

Signs of acute oral or acute dermal toxicity are not expected for Calcium dibenzoate, since the two moieties calcium and benzoic acid have not shown signs of acute oral or acute dermal toxicity in in vivo testing (both LD50 > 2000 mg/kg bw). Under the assumption that the moieties of Calcium dibenzoate show their toxicological profile individually upon dissolution, an acute toxicity estimate (ATE) for the acute oral and dermal (systemic) toxicity of Calcium dibenzoate 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 dibenzoate, 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.

 

Calcium

Oral

Systemic toxicity of calcium is unlikely under normal physiological conditions, considering the biochemical and structural role of calcium in the human body, the normal daily requirement and the regulatory processes to maintain physiological requirements.

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).

Overall, the recommended calcium intake is about 1000-1300 mg/day, whereas the tolerable upper intake level for calcium is about 2500 mg per day for healthy adults with adjustment for age, sex and nutritional status. The calcium absorption is dependent on different factors and the serum level is tightly controlled by a negative feedback system. However, not calcium containing food but abuse of calcium and/or vitamin D supplements lead to hypercalcemia with mild but reversible effects on human health, depending on the dosage and frequency. This clearly demonstrates that oral intake of even large amounts of calcium does not cause adverse or particularly lethal effects in humans. Consequently, further acute toxicity testing is considered scientifically unjustified and further experiments in animals are therefore waived using the rules laid down in Annex XI, Section 1.1.2, 1.1.3 and 1.2.

 

Dermal

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).

 

Based on the above information, one may safely assume an absence of acute dermal toxicity of inorganic calcium substances. Overall, it is known that calcium is essential for epidermal differentiation.

 

Benzoic acid

Oral

2 studies are referenced in the dossier that were qualified as Klimisch 2, because the method used was similar to OECD 401, but were not performed under GLP. These are as follows:

1) Mouse: LD50 = 2250 mg/kg bw (Bier, 1979)

2) Rat: LD50 (M/F) = 2565 mg/kg bw, LD50 (M) = 2742 mg/kg bw, LD50 (F) = 2360 mg/kg bw (Goldenthal, 1974)

For the other studies no actual report or article was available. The results are as follows:

3) Mouse: 1940 <= LD50 <= 2263 mg/kg bw (Abe, 1984)

4) Mouse: 1940 <= LD50 <= 2263 mg/kg bw (McCormick, 1974)

5) Rat: 2000 <= LD50 <= 2500 mg/kg bw (Ignatev, 1965)

6) Mouse: LD50 = 1996 mg/kg bw (Sado, 1973)

7) Mouse (non SPF): LD50 = 1250 mg/kg bw (Schafer, 1985)

8) Cat, dog, rabbit: LD50 = 2000 mg/kg bw (Ellinger, 1923)

9) Rat: LD50 = 2530 mg/kg bw (Marhold, 1977)

10) Mouse: LD50 = 2370 mg/kg bw (Mc Cormick, 1973)

 

Based on the outcome of the key studies the LD50 is >2000 mg/kg bw.

 

Dermal

3 studies are referenced in the dossier. Only one was available for review and showed an LD50 in rabbit of > 2000 mg/kg bw (Goldenthal, 1974). The two other studies also in rabbits seem to confirm this finding ( LD50 >= 2000 mg/kg bw (Opdyke, 1973),

LD50 >= 5000 mg/kg bw (Bio-Fax, 1973)).

 

 

References

Balesaria S, Sangha S, Walters JR (Dec 2009). "Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption". American Journal of Physiology. Gastrointestinal and Liver Physiology. 297 (6): G1193–7. PMC 2850091 Freely accessible. PMID 19779013. doi:10.1152/ajpgi.00237.2009

Barrueto, F.; Wang-Flores, H. H.; Howland, M.A.; Hoffman, R. S.; Nelson, L. S., Acute Vitamin D Intoxication in a Child, Pediatrics Vol. 116, No. 3 September 2005

Bronner F, 2003. Mechanisms of intestinal calcium absorption. Journal of Cellular Biochemistry, 88, 387-393.

Dawson-Hughes B, Harris S, Kramich C, Dallal G and Rasmussen HM, 1993. Calcium retention and hormone levels in black and white women on high- and low-calcium diets. Journal of Bone and Mineral Research, 8, 779-787.

EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2015. Scientific Opinion on Dietary Reference Values for calcium. EFSA Journal 2015; 13(5):4101, 82 pp. doi:10.2903/j.efsa.2015.4101

Flynn A, Moreiras O, Stehle P, Fletcher RJ, Müller DJG, Rolland V. Vitamins and minerals: a model for safe addition to foods. Eur. J. Nutr. 2003, 42, 118-130.

Fong, J.; Khan, A.; Hypocalcemia- Updates in diagnosis and management for primary care- Clinical Review; Can Fam Physician 2012; 58: 158-62

Heaney RP, Weaver CM and Fitzsimmons ML, 1990. Influence of calcium load on absorption fraction. Journal of Bone and Mineral Research, 5, 1135-1138.

Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3):266-81.

Ireland P and Fordtran JS, 1973. Effect of dietary calcium and age on jejunal calcium absorption in humans studied by intestinal perfusion. Journal of Clinical Investigation, 52, 2672-2681.

Jackson, R. D., A. Z. LaCroix, M. Gass, R. B. Wallace, J. Robbins, C. E. Lewis, T. Bassford, S. A. Beresford, H. R. Black, P. Blanchette, D. E. Bonds, R. L. Brunner, R. G. Brzyski, B. Caan, J. A. Cauley, R. T. Chlebowski, S. R. Cummings, I. Granek, J. Hays, G. Heiss, S. L. Hendrix, B. V. Howard, J. Hsia, F. A. Hubbell, K. C. Johnson, H. Judd, J. M. Kotchen, L. H. Kuller, R. D. Langer, N. L. Lasser, M. C. Limacher, S. Ludlam, J. E. Manson, K. L. Margolis, J. McGowan, J. K. Ockene, M. J. O’Sullivan, L. Phillips, R. L. Prentice, G. E. Sarto, M. L. Stefanick, L. Van Horn, J. Wactawski-Wende, E. Whitlock, G. L. Anderson, A. R. Assaf and D. Barad. 2006. Calcium plus vitamin D supplementation and the risk of fractures. New England Journal of Medicine 354(7): 669-83.

Oates T. Lime and limestone. In: Elvers B, Hawkins S, Schulz G (eds.), Ulmann’s Encyclopedia of Industrial Chemistry, 5th ed. VCH, Weinheim, 1990, A15, 317-345.

Ross, A., C.; Taylor,C. L.; Yaktine, A. L.; Del Valle, H. B., Committee to Review Dietary Reference Intakes for Vitamin D and Calcium Food and Nutrition Board DRIDIETARY REFERENCE INTAKES- Calcium Vitamin D, The National Academies Press, Washington, 2011

SCOEL- Recommendation from the Scientific Committee on Occupational Exposure Limits for Calcium oxide (CaO) and calcium hydroxide (Ca(OH)₂)- SCOEL/SUM/137- February 2008

Justification for classification or non-classification

Based on the information available on the acute oral and dermal toxicity on the moieties of Calcium dibenzoate, i.e. calcium and benzoic acid, acute toxicity estimates for Calcium dibenzoate result in LD50 values > 2000 mg/kg bw. There are no indications on narcotic effects or respiratory irritation.

 

According to the criteria of Regulation (EC) No 1272/2008 and its subsequent amendments, Calcium dibenzoate does neither have to be classified and has no obligatory labelling requirement for acute oral or dermal toxicity nor for specific target organ toxicity after single exposure (STOT SE).

 

A substance specific study for acute toxicity via inhalation is not available, since Calcium dibenzoate 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. Calcium dibenzoate is not classified for acute inhalation toxicity because of lacking data.