Registration Dossier

Administrative data

Description of key information

There are currently no reliable experimental data available to assess repeated dose toxicity for magnesium hydrogenorthophosphate.

A data waiver is set in place to justify that no further repeated dose toxicity testing is required.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are currently no reliable experimental data available to assess repeated dose toxicity for magnesium hydrogenorthophosphate.

Subacute

For the structural similar substance calcium hydrogenorthophosphate (CAS 7757 -93 -9) one short-term toxicity study is available. This study is not adequate for the risk assessment for the following reason:

A non-guideline repeated dose toxicity study was performed in 1970. Calcium hydrogenorthophosphate was administered at a limit dose of 214 mg/kg bw/day to male rats by means of a stomach tube daily for 14 days. 24 hours after the final dose animals were autopsied and observed for pathological changes. No adverse effects were noted at that dose level under the conditions of this study. Since the treatment lasted only for 14 days and only the limit dose of 214 mg/kg bw was used this study is not reliable to fullfil the endpoint because the treatment duration should have been at least 28 days and the limit dose 1000 mg/kg bw.

A combined repeated dose and reproductive/developmental (OECD 422) study was conducted on potassium dihydrogenorthophosphate (CAS 7758 -11 -4) in the rat on behalf of the National Institute of Environmental

Research, and reported publicly in the OECD SIDS (1). Since the phosphorus is considered to be the critical part in calcium phosphates (see discussion below) this study is reliable to be used as read across. No effects were observed at the highest dose resulting in a NOAEL of 1000 mg/kg bw/day. The lead registrant has sought to access this data however it has not been possible to agree data sharing terms for all co-registrants. As soon as this data is available it will be integrated in the dossier. Nonetheless, the lack of effects on repeated dose toxicity at dose levels well in excess of normal human exposure suggests that magnesium and potassium orthophosphates are not a significant risk to repeated exposure in males and females. Further studies are unlikely to show any significant effects on repeated dose toxicity.

Magnesium and calcium, the firth most abundant elements, are essential nutrients for humans and naturally occurring essential mineral that is highly regulated by homeostatic mechanisms. Mg2+and Ca2+is a major electrolyte present in all biological materials; toxic effects are not likely to arise provided the contributions from food intake do not disturb the homeostatic mechanisms controlling the electrolyte balance of the body. Magnesium and calcium phosphates are used in the following human food and pharmaceutical applications: Magnesium hydrogenorthophosphate: used as laxative; calcium bis(dihydrogenorthophosphate) is used as acidulant and mineral supplement. Trimagnesium bis(orthophosphate) and tricalcium bis(orthophosphate): used as a gastric antacid in doses of 1 g orally. Calcium hydrogenorthophosphate is used as a dietary supplement in doses of 1g orally. In addition other food additive uses also exist. The relatively high pharmaceutical doses taken orally by humans support the low toxicity of these salts. As a consequence of their use patterns extensive review of the potential toxicity of magnesium and calcium phosphates (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 the aforementioned magnesium orthophosphates and calcium phosphates have 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 (2). 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 magnesium and calcium phosphates that fall under the scope of REACH are not considered to contribute a significant amount of phosphorus to the daily intake, it is not considered to be necessary or scientifically justified to conduct further testing for repeated dose oral toxicity. Reference values for the intake of magnesium and calcium are considerably higher than that for phosphorus: Adequate intake (AI) value for calcium in male and female 19-30 years old is 1000 mg/dayand the Estimated Average Requirement (EAR) for magnesium in males aged 19-30 is 330 mg/day and for females aged 19-30 is 255 mg/day(3). It is also not considered to be appropriate to take into account the toxicity of calcium ions as these are indispensable nutrients that are very highly metabolically regulated systemically as well as intra-cellular. As such, the MTDI for phosphorus is considered to be the most appropriate and conservative value for risk assessment. In addition, as the phosphate moiety is not considered to differ from that of any other inorganic phosphate 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 phosphates and no further data was generated on magnesium and calcium phosphates.

It is considered that the regulatory endpoint for repeated dose toxicity is fulfilled on the basis that the available information is both sufficient for characterisation of the hazard profile and the dose response of a substance upon repeated dose exposure and for the performance of a chemical safety assessment for repeated dose toxicity. It is not considered to be scientifically justified to conduct further in vivo testing for this endpoint and as such no testing is proposed. Furthermore, as body phosphate homeostasis in animals enables them to tolerate a wide range of dietary phosphate intakes providing an appropriate phosphate to calcium balance is maintained. Phosphate toxicity may be associated with metabolic disorders of calcium absorption and function and interactions of phosphate with other physiological cations such as calcium, magnesium and manganese (4). Therefore, animal studies to evaluate the safety of high levels of phosphate in the diets of animals are complicated by the need to separate the effect of the phosphate itself from the imbalance in the ratios of phosphate and other essential cations and therefore it is not appropriate to conduct a standard OECD 408 study (90 day repeated dose oral study in rodents) as this would not yield any meaningful data and as such would be an unnecessary in vivo study. It is therefore considered that the safety evaluation of inorganic phosphates as a class, including the various ionic forms, has been thoroughly completed by the use of animal studies and regulatory reviews. No additional animal studies are necessary to understand the calcium phosphate salts in this group. The effects of inorganic phosphate exposure are well known, as are those of calcium, all biological nutrients for life.

(1)http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=545E2F43-CF57-4AED-8784-

C0391BCCC562

(2) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board,of. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride., Press, 1997.

(3) 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

(4) NRC, Mineral Tolerance of Animals. Second revised edition, 2005. The National Academies Press.www.nap.edu

Justification for classification or non-classification

The available data on repeated dose toxicity with the test substance do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for classification.