Polyphosphoric acids

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

2 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Derivation of long-term exposure DNEL (local effects):

Mastalki et al (1972) reported a NOAEL value of 322 mg/kg bw/d for a repeated dose toxicity test (oral exposure) performed on purebred beagle dogs at dietary levels of 0.3, 1.0 and 3.0% (90-day subacute oral toxicity) of sodium aluminium phosphate. This NOAEL for oral exposure in rats should be extrapolated to a NOAEL for inhalation exposure in human (i.e. workers population). The starting point dose descriptor is calculated as following: (322 mg/kg bw x 70 kg)/ (10 m³) = 2254 mg/m³ where 70 kg is the standard human body weight and 10 m³ is the respiration factor for the worker. In order to cover possible differences in bioavailability between routes this starting dose value should be multiplied by a factor 0.5 (assuming 100% absorption by inhalation exposure and 50% absorption by oral exposure): 2254 mg/m3 x 0.5 = 1127 mg/m³.

Following assessment factors should be applied:

- allometric scale, factor 1.4

- interspecies differences, factor 2.5;

- intraspecies differences, factor 5;

- exposure duration, factor 2 (sub-chronic to chronic exposure duration);

-> The overall assessment factor is: 1.4 x 2.5 x 5 x 2 = 35

The resulting DNEL for long term inhalation, workers is (1127 mg/m³)/35 = 32.2 mg/m³

However, an European Long term Occupational exposure limit (OEL) recommended by the Scientific Expert Group (SCOEL and HSE) is available for phosphoric acid: 8 hour TWA: 1 mg/m3. This value is based on the Rushing observation on phosphorus pentoxide to the ACGIH TLV committee. Nevertheless as this value is more conservative it will be used in the exposure assessment and determination of the risk characterization ratio for polyphosphoric acid as explained below.

Justification for the read-across from phoshoric acid to polyphosphoric acid and choice of the DNELs

Polyphosphoric acid is a mixture of the corresponding acids to phosphate anion and its condensed phosphates as follows:

- orthophosphoric acid or phosphoric acid (17 -76%),

- pyrophosphoric acid (23 -50%),

- triphosphoric acid (1.5 -25%),

- tetraphosphoric acid (0 -12%)

- and pentaphosphoric acid (0 -7%).

 

A condensed phosphate anion M(n+2)PnO(3n+1)has one or several P-O-P bonds and has been obtained by heating (dehydration). When the substance polyphosphoric acid is in contact of excess of water, a rapid hydrolysis is observed with the longer chains (tri, tetra or penta) while a very slow hydrolysis is observed for the dimer form to ortho phosphate. The pyrophosphate ion is the simplest form of a condensed phosphate group. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependant upon the associated cations (if there are) and the ambient pH (if in solution).

No partition coefficient value was determined for these substances as they are inorganic phosphates that are highly ionic (depending on ambient pH). Because of this ionic nature the passive passage across biological membranes will be negligible. Pyrophosphate is an anion that occurs in all living cells and is formed mainly by the synthesis of DNA from Nucleotide triphosphates (DNAn + Deoxyribonucleotide triphosphate → DNAn+1 + pyrophosphate). Usually it is cleaved rapidly into two orthophosphate molecules by one of the different members of the alkaline phosphatase family which are present in all tissues. Pyrophosphate nevertheless is generally relatively stable against uncatalyzed hydrolysis (half life = 10 d in autoclaved Flat branch sediment (Blanchar RW and Riego DC, 1975, Tripolyphosphate and diphosphate hydrolysis in sediments, Soil sci. soc.Am. J 40: 225-229)).

Orthophosphoric acid, the final degradation product of polyphosphoric acid, is a triprotic acid and can dissociate up to 3 times giving a H+ and a phosphate anion (H2PO4- / HPO42- /PO43- ). The phosphate anion is an essential component of the body and is highly regulated metabolically and should be considered as an individual moiety for the purpose of assessing its toxicological impact. It is a natural component of the diet and levels normally ingested are 1-2g, measured as total phosphorus, per person per day (1). Exposure to phosphoric acid at the levels likely to be encountered in the occupational setting would not make a significant contribution to the total phosphate via the oral route.

The hazards associated with occupational exposure to phosphoric acid are likely, therefore, to depend primarily on its acidic nature. Concentrated phosphoric acid is corrosive to living tissues and lower concentrations are irritating to the skin, eyes and mucous membranes of the oral cavity, respiratory and gastro-intestinal tracts. Consequently, toxicity is more intimately related to concentration than to dose. Systemic effects (metabolic acidosis) in man apparently related to phosphoric acid exposure have only been reported on one occasion which involved the ingestion of a large single dose (1) and it would not be reasonable to perform repeated dose toxicity studies at this level.

An assessment of the repeated dose oral toxicity of the phosphate ion can be made based on test data from inorganic phosphates where the cation is not considered to contribute to the overall toxicity of the material. As such a number of sub-acute and sub-chronic studies conducted on the food additive sodium aluminium phosphate and other inorganic phosphates are included in Section 7.5 of this dossier.

The toxicological effects noted in these studies relate only to the phosphate; nephrocalcinosis occurs when high doses of phosphate are administered due to the precipitation of the phosphate moiety as insoluble calcium phosphates in the kidneys. As no effects related to the sodium or aluminium cations were noted it is considered appropriate to consider this data for use in risk assessment.  

General discussion:

Phosphoric acid is used as a food additive and as such a review of the toxicity of phosphoric acid (as well as a number of other inorganic phosphate substances) has been undertaken by a number of regulatory authorities.

In particular the Joint FAO/WHO Expert Committee on Food Additives (JEFCA) (which assesses and evaluates the biological data and toxicological data available for substances that are used as food additives) has published a monograph in which phosphoric acid has been evaluated for acceptable daily intake on the basis of the available toxicity data (2) An estimate of the maximum tolerable daily intake (MTDI) intake for man has been derived to be 70 mg/kg bw of phosphorus. This figure applies to the sum of phosphorus naturally present in the diet and from other sources, such as food additives. As the uses of phosphoric acid that fall under the scope of REACH are not considered to contribute a significant amount of oral phosphorus to the daily intake, it is not considered to be necessary or scientifically justified to conduct further testing for repeated dose oral toxicity or in fact to derive a DNEL from the existing data. MTDI represents a highly reliable and valid figure for use as the long-term exposure oral DNEL in risk assessment.

The phosphate moiety is not considered to differ from that of any other inorganic orthophosphate from a toxicological point of view for the purpose of risk assessment for the inhalation route and the derivation of appropriate DNELs it is considered to be appropriate to use the most reliable data available for orthophosphates (see endpoint records and summary) and no further data should be generated particularly due to the corrosive nature of phosphoric acid, however when using this value concentration limits relating to the corrosive/irritating nature of phosphoric acid should be observed.

Specific occupational risks from phosphoric acid are as a result of inhalation due to the corrosive nature of the material and as such occupational OELs are available to adequately protect against this risk. The values are as follows (1):

- Acute, inhalation: 15 min STEL: 2 mg/m3

- Chronic, inhalation: 8 hr TWG OEL: 1mg/m3

In a risk assessment scenario it is considered appropriate to use these values and as such no testing for the inhalation route would be considered necessary.

 (1)Occupational Exposure Limits, Criteria document for phosphoric acid. Commission of the European Communities, 1992, Report No. EUR 14178 EN

 

(2) Evaluation of certain food additives and contaminants. Twenty-sixth report of the joint

FAO/WHO expert committee of food additives. World Health Organisation. Technical Report

Series 683. 1982. ISBN92 4 120683 7

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.05 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

210

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

No specific concerns; starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1.4

Justification:

from dog to human

AF for other interspecies differences:

2.5

Justification:

remaining differences

AF for intraspecies differences:

10

Justification:

for general population

AF for the quality of the whole database:

1

Justification:

numerous studies available to support this data

AF for remaining uncertainties:

1

Justification:

none

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Derivation of Long term exposure general population – local effects - inhalation DNEL in mg/m³:

The DNEL for inhalation exposure can be derived from the oral NOAEL. This NOAEL for oral exposure in dogs should be extrapolated to a NOAEL for inhalation exposure in human (i.e. general population). The starting point dose descriptor is calculated as following:

(322 mg/kg bw x 70 kg)/ (20 m³) = 1127 mg/m3 where 70 kg is the standard human body weight and 20 m3 is the respiration factor for the general population. In order to cover possible differences in bioavailability between routes this starting dose value should be multiplied by a factor 0.5 (assuming 100% absorption by inhalation exposure and 50% absorption by oral exposure): 1127 mg/m³ x 0.5 = 563.5 mg/m³.

Following assessment factors should be applied:

- allometric scale, factor 1.4;

- interspecies differences, factor 2.5;

- intraspecies differences, factor 10;

- exposure duration, factor 2 (sub-acute to chronic exposure duration);

-> The overall assessment factor is: 1.4 x 2.5 x 10 x 2 = 70

The resulting DNEL for long-term exposure - local effects - inhalation, general population is (563.5 mg/m³)/70 = 8.05 mg/m³