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Administrative data

Description of key information

Oral (OECD 408, silicon dioxide), subchronic, rat: NOAEL (systemic), males/females = ≥4000-4500 mg/kg bw/day
Oral (dipotassium hydrogenorthophosphate), subchronic, dog: LOAEL (systemic), males/females = 800 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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

Silicon orthophosphate is highly water soluble (1085 mg/L at 20°C). It completely dissociates into silicon and phosphate ions after systemic uptake (relevant pH ranges 2 -7). The tetravalent silicon ion and the phosphate ion will then react with the media to form different silicon and phosphate species depending on the pH and redox potential of the media. The dissociated silicon ion exists in water predominantly as H4SiO4/Si(OH)4, which is also the main species when silicon dioxide is dissolved in water. Therefore the silicon component of silicon orthophosphate can be covered by data from the read-across substance silicon dioxide, whereas the phosphate component will be covered by a read-across from dipotassium hydrogenorthophosphate, sodium dihydrogenorthophosphate and disodium hydrogenorthophosphate. No data for oral repeated dose toxicity is available for the target substance silicon orthophosphate.

Silicon dioxide data

In a subchronic study, similarly performed to OECD guideline No. 408 under GLP conditions, a precipitated SAS Sipernat 22, was administered to 10 male and female rats each at dietary levels of 0.5, 2, and 6.7% (analytical value) for 13 weeks, corresponding to 300-330, 1200-1400, 4000-4500 mg/kg bw/day (Til et al. 1981). No adverse effects based on clinical, haematological, blood-chemical, urinary and (histo-)pathological examinations were observed. Therefore, the NOAEL for male and female rats was determined to be ≥ 4000-4500 mg/kg bw/day.

 

Phosphate data

In the publications of Schneider at al. (1980a+b), groups of 5 Beagle dogs/sex were treated with 800 mg dipotassium hydrogenorthophosphate/kg bw/day by fed for 38 and 14 weeks, respectively. Limited clinical and biochemical investigations were performed and some biopsies were taken. In addition, detailed kidney pathology by light and electron microscpy was done as well as immunohistochemistry. The exposure induced vomiting in animals of both experiments, the dogs became kachetic and one animal died. In all animals, a decrease in body weight and food consumption was observed. Elevated creatinine and blood urea nitrogen was observed in the 38 -week experiment as well as calcification of the kidneys and aorta. Glomerula selective and unselective proteinuria was observed in animals of the 14 -week experiment until day 85. Tubular atrophy (usually of the proximal tubules), focal scar tissue and nephrocalcinosis was observed at the end of the experiment of the dogs in the 14-week experiment as well as slight glomerular changes in the biopsy material taken at 4 week as sequelae of retention of glomerular filtrate. Furthermore, dilation of Bowman´s space, followed by compression and shrinkage of the glomerular tufts and inflammatory processes within the gomerulus was observed. Histochemically, acid phosphatase and beta-glucuronidase were found in cryostat sections. Ultrahistochemically, acid phosphatase was demonstrated. No NOAEL could be established and the LOAEL for dipotassium hydrogenorthophosphate was set at 800 mg/kg bw/day.

In the publication of Schneider et al. (1981), groups of 5 male Beagle dogs were given equimolar amounts of dipotassium hydrogenorthophosphate (1000 -2000 mg/kg bw/day) or disodium hydrogenorthophosphate (800 -1600 mg/kg bw/day) by gavage for up to 22 weeks. The test substance concentrations for both test groups varied over the hole study period (see study entry). Animals of the control group received water. After terminal sacrifice, the kidneys were investigated by light and electron microscopy. The subchronic application of high doses of dipotassium hydrogenorthophosphate or disodium hydrogenorthophosphate had comparable effects. It induces nephropathy in the form of proximal tubular atrophy with negative protein findings and absence of epithelial cells and casts in urine in all animals of the dipotassium hydrogenorthophosphate and in 4/5 of the disodium hydrogenorthophosphate dose group. Therefore, no NOAEL could be identified. The LOAEL for dipotassium hydrogenorthophosphate was determined to be 1000 -2000 mg/kg bw/day and 800 -1600 mg/kg bw/day for disodium hydrogenorthophosphate.

Haut et al. (1980) evaluated the mechanism by which phosphate induces renal injury. Therefore, uninephrectomised, partially nephrectomised, and intact rats were placed on dietary phosphorus intakes of 0.5, 1.0, and 2.0% (equivalent to 50, 100, and 200 g phosphours/day, consisting of 80 % sodium dihydrogenorthophosphate and 20% disodium hydrogenorthophosphate) corresponding to 167, 333, 667 mg/kg bw/day for 18 weeks. Clinical investigations were limited to the measurement of creatinine, calcium and phosphorus in blood plasma and urinalysis consisted of determinations of volume as well as creatinine, calcium and phosphorus levels. Only kidneys were considered at gross pathology and histopathology. None of the animals on a normal phosphorus intake (0.5%) showed any abnormalities. Four out of six intact animals on a 1% phosphorus diet had kidney calcium concentrations within the normal range, and only one showed a histologic change. In contrast, all but one partial and uninephrectomised animals on a 1% phosphorus diet had increased kidney calcium content concentration, and 5/6 animals had histologic changes. The degree of calcification and histologic changes in the uninephrectomised animals on a 1% phosphours diet was similar to that found in the intact animals on a 2% phosphorus diet. It was concluded that renal toxicity of phosphate is enhanced as renal functional mass is reduced. Toxicity of phosphate appears to be largely mediated through kidney calcification. Since this there was no control group included into the study design, this study was not further taken into consideration for NOAEL and DNEL derivation.

In addition, a combined repeated dose study with reproduction /developmental toxicity screening test (OECD 422) was performed on dipotassium hydrogenorthophosphate. The publically available summary states that there were no abnormalities observed which were considered to be dose or treatment related in the parental animals. No adverse effects on development and viability of the offspring was observed. Therefore, the NOAEL of dipotassium hydrogenorthophosphate for systemic toxicity in male and female rats was determined to be ≥1000 mg/kg bw/day. As this study was performed in Korea suitable access was not granted for REACH registration and as such no robust summary for this study is included in the dossier.

Taken all the data on phosphorus compounds into consideration, nephrocalcinosis was the main effect observed in the renal tubes of dogs and rats, the latter ones generally known to be susceptible to nephrocalcinosis when administered high doses of phosphates. The lowest level of phosphorus that produced nephrocalcinosis in the rat (i.e. 1% P in the diet) was used as the basis to set a maximum tolerable daily intake (MTDI) of 70 mg/kg bw/day for phosphoric acid and phosphate salts (Joint FAO/WHO Expert Committee on Food Additives (JECFA)). This value can be applied to all phosphorus compounds discussed as the toxicity effects noted via the oral route are not attributable to the cation but as a result of high doses of phosphates, that are mainly excreted via kidney. 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from dipotassium hydrogenorthophosphate, sodium dihydrogenorthophosphate, disodium hydrogenorthophosphate and silicon dioxide.

Justification for classification or non-classification

The available data on repeated dose toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.