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Administrative data

Link to relevant study record(s)

Description of key information

Nitrites are essentially completely absorbed after oral exposure, with rapid removal from the circulation predominantly via conversion to nitrate and subsequent urinary excretion; calcium is also appreciably absorbed by this route. As such, an oral absorption figure of 100% is proposed for chemical safety assessment (CSA) and DNEL calculation for calcium nitrite.

Based on a high water solubility, any calcium nitrite reaching the lungs is likely to be absorbed. In line with ECHA guidance, a conservative default assumption of 100% inhalation absorption will be used for CSA and DNEL calculation (when extrapolating from an oral laboratory animal study to a human inhalation exposure).

The highly water-soluble nature of calcium nitrite is suggestive of a low potential for dermal uptake. As such a default value of 10% dermal absorption is proposed for CSA and DNEL calculation (when extrapolating from an oral laboratory animal study to a human dermal exposure).

Once absorbed, distribution and excretion are expected to be rapid, with little or no bioaccumulation anticipated.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

No specific toxicokinetic studies on calcium nitrite are available. However, the nitrite ion in general has been well studied by Expert Groups [often in tandem with the related nitrate ion, since these species are known to interconvert] (EFSA, 2017a; Health Canada, 2013; IARC, 2010; OECD, 2005; WHO, 2011).

An EFSA Panel evaluation regarding the use of sodium and potassium nitrites as food additives considered that these cations “are expected to enter normal homeostatic processes, and are not expected to impact on the toxicity of the salts, which is determined by the nitrite ion; thus the properties of the cations are not discussed further” (EFSA, 2017a). As with the sodium and potassium cations, the calcium ion is ubiquitous in the human body and would therefore behave in a similar manner. As such, it is expected that EFSA would have had a similar conclusion on calcium nitrite if it had also considered it concurrently with the sodium and potassium nitrites. Given that the nitrite anion is clearly the toxicologically-active species in all of these salts, the current toxicokinetic assessment focuses on this species.

 

Absorption - nitrite

In humans, the systemic availability of (sodium) nitrite when given in solution is approximately 100% (EFSA, 2017a). Similarly, ingested nitrite (and nitrate) is “rapidly and almost completely absorbed” (Health Canada, 2013), though nitrite may react with gastric contents prior to absorption (WHO, 2011). In animals, nitrite is rapidly removed from the bloodstream or the intestinal tract by conversion to nitrate, likely due to “intestinal microflora activity”. Plasma nitrite concentrations peaked within 30 minutes of a single gavage dose in rats and mice (EFSA, 2017a).

No information is available on dermal absorption of nitrate or nitrite (Health Canada, 2013). Similarly, no data on the absorption of nitrites following inhalation were identified.

 

Absorption - calcium

Intestinal calcium is well-absorbed through both active [hormonally controlled], saturable, transcellular, and passive, non-saturable, paracellular processes (EFSA, 2017b). Absorption varies considerably throughout the human lifespan, being higher during periods of rapid growth (up to 60% during infancy) and lower in old age (EFSA, 2015).

 

Absorption – Key values for CSA

The available data suggest that oral absorption of nitrite is essentially complete, while calcium is also appreciably absorbed. Moreover, the relatively low molecular weight (MWt; ~132 g/mol) and, more critically, the high water solubility (>500 g/L; Sydney, 2018) are indicative of a high bioavailability of calcium nitrite, as ions, by the oral route. As such, predicted oral absorption of calcium nitrite is set at 100%.

As a highly water-soluble substance with a low MWt, ECHA (2017) guidance indicates that any calcium nitrite reaching the lungs is likely to be absorbed through aqueous pores. ECHA (2012) guidance notes “that if data on the starting route (oral) are available these should be used, but for the end route (inhalation), the worst-case inhalation absorption should still be assumed (i.e. 100%)”. Therefore, the health-precautionary figure of 100% as recommended by ECHA has been taken forward for the CSA, so as to result in the most health-precautionary DNEL.

Given the high water solubility of calcium nitrite, it is unlikely to be able to cross the lipid-rich environment of the stratum corneum to any great extent (i.e. dermal uptake is “low”) (ECHA, 2017). As such, the lower of the two ECHA (2017) default values for dermal absorption, 10%, would seem the more appropriate value for the current CSA.

 

Distribution/Metabolism - nitrite

Toxicokinetic studies in laboratory animals and humans demonstrated that sodium nitrite does not undergo first pass metabolism following oral exposure (EFSA, 2017a). Nitrite is converted to a variety of metabolites, predominantly nitrate via oxidation (EFSA, 2017a; WHO, 2011). Indeed, nitrite appears in a dynamic equilibrium with nitrate, with the latter being the normal state (Health Canada, 2013). In the blood, nitrite is highly reactive with [oxy]haemoglobin, resulting in the formation of methaemoglobin (associated with methaemoglobinaemia) (OECD, 2005), with concomitant production of nitrate (IARC, 2010). Nitric oxide and ammonia are minor nitrite metabolites (Health Canada, 2013).

Nitrite and nitrate are widely distributed in the body, with nitrate the predominant species (IARC, 2010). Parenteral administration of radiolabelled nitrite to mice and rabbits showed an even distribution throughout the soft tissues and organs within 5 minutes, mainly in the form of nitrate. In humans, the volume of distribution was larger than the body water, indicating that nitrites were distributed at higher concentrations in some tissues compared with the blood (EFSA, 2017a).

Nitrite has been shown to cross the placenta (possibly leading to foetal methaemoglobinaemia) in rodents (Health Canada, 2013; WHO, 2011).

Distribution/Metabolism - calcium

The total body burden of calcium in adults is in excess of 1 kg. Nearly all (99%) of total body calcium is located in the skeleton, the remaining 1% being equally distributed between the teeth and soft tissues, with only 0.1% in the extracellular fluid (WHO, 2004).

Calcium nitrite’s physico-chemical properties (low MWt and high water solubility) are supportive of an extensive distribution (of both calcium and nitrite ions).

 

Elimination (and Bioaccumulation) - nitrite

Nitrite is essentially completely converted to nitrate, which is subsequently excreted in the urine; faecal and urinary excretion of nitrite itself is negligible (EFSA, 2017a; WHO, 2011).

Nitrite is not normally detected in body tissues and fluids after oral administration. Elimination from the stomach occurs through two competing pathways: absorption, and reaction with amines [or other nitrosatable compounds] causing formation of nitroso compounds (Health Canada, 2013).

Accordingly, nitrite is considered to have only a low potential for bioaccumulation. This conclusion is supported by its highly water-soluble nature.

Elimination (and Bioaccumulation) - calcium

Unabsorbed dietary calcium is lost in the faeces. The main routes of obligatory (endogenous) calcium loss are urine, faeces, and skin and sweat (dermal losses) (EFSA, 2017b). Serum concentrations of calcium are homeostatically regulated to remain within a narrow range of 2.25–2.6 mmol/L (ionised calcium 1.1–1.4 mmol/L); concentrations of soft tissue calcium are maintained at the expense of bone (EFSA, 2015).

 

Conclusion

Experimental data on calcium and nitrite ions suggest that calcium nitrite would be well absorbed after oral exposure. Based on the limited available data, it is assumed that absorption following inhalation exposure could also be extensive. A low dermal bioavailability is anticipated.

Absorption values of 100%, 10% and 100% for the oral, dermal and inhalation routes, respectively, are proposed for the CSA, and considered health-precautionary for use in the calculation of DNEL values.

 

References (not including IUCLID ESRs):

ECHA (2012). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Reference: ECHA-2010-G-19-EN. Version 2.1. November 2012.http://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf

ECHA (2017). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.7c: endpoint specific guidance. Version 3.0. June 2017.https://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf/e2e23a98-adb2-4573-b450-cc0dfa7988e5

EFSA (2015). European Food Safety Authority. Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on Dietary Reference Values for calcium. EFSA Journal 2015;13(5):4101.https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2015.4101

EFSA (2017a). European Food Safety Authority. Panel on Food Additives and Nutrient Sources Added to Food. Re-evaluation of potassium nitrite (E 249) and sodium nitrite (E 250) as food additives. EFSA Journal 2017, 15(6), 4786.http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2017.4786/epdf

EFSA (2017b). European Food Safety Authority. Dietary Reference Values for nutrients. Summary report. EFSA Supporting publication 2017:e15121.http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2017.e15121/epdf

Health Canada (2013). Guidelines for Canadian Drinking Water Quality: Guideline Technical Document – Nitrate and Nitrite. Catalogue No H144 -13/2-2013E-PDF.http://healthycanadians.gc.ca/publications/healthy-living-vie-saine/water-nitrate-nitrite-eau/alt/water-nitrate-nitrite-eau-eng.pdf?_ga=2.222634333.774105563.1517223052-337288668.1517223052

IARC (2010). International Agency for Research on Cancer. Ingested nitrate and nitrite and cyanobacterial peptide toxins. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. Volume 94, 14-21 June 2006.http://monographs.iarc.fr/ENG/Monographs/vol94/mono94.pdf

OECD (2005). Organization for Economic Co-operation and Development. SIDS Initial Assessment Report (SIAR) for SIAM 20. Sodium nitrite, CAS No: 7632-00-0.https://hpvchemicals.oecd.org/ui/handler.axd?id=5d2b8a51-1de5-4fc9-b7f1-09b3f8725ef5

WHO (2004). World Health Organization. Vitamin and mineral requirements in human nutrition. Second edition.http://apps.who.int/iris/bitstream/handle/10665/42716/9241546123.pdf

WHO (2011). World Health Organization. Nitrate and nitrite in drinking water. Background document for development of WHO guidelines for drinking-water quality. WHO/SDE/WSH/07.01/16/Rev/1.http://www.who.int/water_sanitation_health/dwq/chemicals/nitratenitrite2ndadd.pdf