Phosphorus (P) is most commonly found in nature in its pentavalent form in combination with oxygen, as phosphate (PO₄³⁻). Phosphorus is an essential constituent of all living organisms, and its content is quite uniform across most plant and animal tissues. Orthophosphate (anionic salts of H₃PO₄) is the basic unit for all phosphates. Condensed (pyro-, meta-, and other polyphosphates) are formed when two or more orthophosphate molecules condense into a single molecule. Pyrophosphates refer to compounds with two condensed orthophosphates, and higher number polymers are termed polyphosphates, sometimes preceded by a prefix indicating the number (e.g., tri- and tetrapolyphosphates have three and four condensed phosphates, respectively). The term “metaphosphates” is used when phosphoric acid moieties form a cyclic (ring) structure. Inorganic phosphates (both ortho- and condensed phosphate anions) can be grouped into four classes based on their cations: monovalent cations (sodium, potassium, and hydrogen), divalent (calcium and magnesium), ammonium, and aluminum. The phosphoric acids have been grouped with the other monovalent cations based on valence state.

This document addresses the available data on the toxicity of ammonium phosphate salts (monoammonium phosphate [MAP], diammonium phosphate [DAP], and ammonium polyphosphate [APP]). Monovalent, divalent, and aluminum phosphates are not included in this assessment because they are expected to have differing toxicity, chemistry, and/or toxicokinetics than the ammonium phosphates. Specifically, ammonium phosphate salts are relatively unstable, because ammonium hydroxide is a weaker base than metal hydroxides, and ammonia can escape as a gas (Gard, 2005). The reader is referred to the PPRTV assessments for monovalent, divalent, and aluminum phosphates for assessments of these inorganic phosphate salts.

Ammonium phosphate salts are inorganic salts composed of a phosphate anion and an ammonium cation. These water-soluble salts will dissociate in aqueous environments. Phosphate is the conjugate base of phosphoric acid. Phosphoric acid is a polyprotic acid composed of three dissociable protons with different pKa constants (pK₁ = 2.16, pK₂ = 7.21, pK₃ = 12.32) resulting in successive deprotonation as pH increases. At very low pH values (<2) fully protonated, neutral, phosphoric acid will predominate. In aqueous environments, at pH values between 6.5 and 8.5, phosphoric acid, and mono-, di-, and triphosphates (deprotonated anions) will all exist in equilibrium depending on the specific pH of the system. An aqueous solution of phosphoric acid will therefore contain some proportion of each species. Monovalent and divalent phosphate are found in the body as inorganic anions and as functional groups on many important biomolecules. Ammonium is the conjugate acid of ammonia. Based on its pKa of 9.25, the cation will predominate at pH values below 9, with higher concentrations of the cation as the pH decreases (up to 99% at physiological pH).

Commercial inorganic phosphate salts are used in many applications. The ammonium salts of phosphoric acid addressed in this document are MAP, DAP, and APP. MAP (monovalent: H₂PO₄⁻) and DAP (divalent: HPO₄²⁻) are both discrete chemicals, while APP is a polymeric substance classified by Toxic Substances Control Act (TSCA) guidelines as “chemical substances of unknown or variable composition, complex reaction products and biological materials (UVCB).” Because of the variable molecular weight of APP polymers and variable water solubility, these polymeric salts will likely behave slightly differently than the discrete salts under both biological and environmental conditions. In general, as molecular weight increases and water solubility decreases, bioavailability tends to decrease. However, APP polymers are susceptible to hydrolysis and will break down into smaller molecular weight components over time.

MAP and DAP are used as fertilizers and plant nutrients, flame retardants, in fire-extinguishers and fire-proofing agents, oral care agents, in cosmetics as buffering agents and corrosion inhibitors, and in fermentations for yeast cultures (NLM, 2019a, b, c; CIR Expert Panel, 2016; OECD, 2007a, b, e). MAP and DAP are direct food additives classified by the U.S. Food and Drug Administration (FDA) as generally recognized as safe (GRAS) (CIR Expert Panel, 2016). APP salts are generally used in flame retardants for commercial furniture, automotive fabrics, and draperies; in addition, lower molecular weight, water-soluble APP polymers are used in foods (NRC, 2000).

In general, these salts are soluble in water; however, higher molecular weight APP polymers tend to have lower water solubility. Ammonium phosphate salts will persist in natural waters. In aqueous environments, both the anion (phosphates) and cation (ammonium) are nutrients for algae, other plants, and microbes (ECHA, 2019a, b, c; CIR Expert Panel, 2016; OECD, 2007a). In air, MAP is stable; however, DAP gradually loses up to 8% NH₃ upon exposure to air (CIR Expert Panel, 2016). In aqueous systems and in soils under both aerobic and anaerobic conditions, polyphosphate salts are susceptible to hydrolysis, with reported half-lives ranging between 1 and 18 days (OECD, 2007b, d). In soil, ammonia is rapidly converted to nitrate and nitrite by Nitrosomonas and Nitrobacter bacteria, respectively (OECD, 2007a). Human exposure to ammonium phosphate salts may occur via dermal contact through their use in cosmetics, flame retardants, and fertilizers, or via ingestion through their use as food additives and plant nutrients.

The empirical formulas for and physicochemical properties of the ammonium phosphate salts are shown in Table 1.

Table 1

Identity, Molecular Weight, and Physicochemical Properties of Ammonium Phosphate Salts^, .

A summary of available toxicity values for ammonium phosphate salts (multiple CASRNs) from U.S. EPA and other agencies/organizations is provided in Table 2.

Table 2

Summary of Available Toxicity Values for Ammonium Phosphate Salts (MAP, CASRN 7722-76-1; DAP, CASRN 7783-28-0; and APP, CASRN 68333-79-9).

Literature searches were conducted in April 2019 and updated in October 2020 and July 2021 for studies relevant to the derivation of provisional toxicity values for ammonium phosphate salts (CASRNs 7722-76-1, 7783-28-0, and 68333-79-9). Searches were conducted using U.S. EPA’s Health and Environmental Research Online (HERO) database of scientific literature. HERO searches the following databases: PubMed, TOXLINE¹ (including TSCATS1), and Web of Science. The following resources were searched outside of HERO for health-related values: American Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease Registry (ATSDR), California Environmental Protection Agency (CalEPA), Defense Technical Information Center (DTIC), European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), European Chemicals Agency (ECHA), U.S. EPA Chemical Data Access Tool (CDAT), U.S. EPA ChemView, U.S. EPA Health Effects Assessment Summary Tables (HEAST), U.S. EPA Integrated Risk Information System (IRIS), U.S. EPA Office of Water (OW), International Agency for Research on Cancer (IARC), Japan Existing Chemical Data Base (JECDB), National Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP), Organisation for Economic Co-operation and Development (OECD) Existing Chemicals Database, OECD Screening Information Data Set (SIDS) High Production Volume (HPV) Chemicals via IPCS INCHEM, Occupational Safety and Health Administration (OSHA), and World Health Organization (WHO).

A screening subchronic p-RfD for DAP has been derived in this assessment based on compound- (DAP-) specific data, and it is expected to be protective for MAP as well, given the physicochemical similarities between DAP and MAP (e.g., MAP possesses one less ammonium ion). However, it should not be applied to the risk assessment of APP, which is expected to have a much wider range of potential and variable structures, physicochemical properties, and ammonium content (see Table 1), and for which relevant toxicity data are not available to derive a p-RfD.

Footnotes

1

Note that this version of TOXLINE is no longer updated (https://www​.nlm.nih.gov​/databases/download/toxlinesubset​.html); therefore, it was not included in the literature search updates from October 2020 and July 2021.