Reaction products of phosphoric acid, rock phosphate and humic acids, potassium salts

Endpoint summary

Description of key information

The submission substance consists of naturally occuring components of generally low toxicity. Evaluation of oral exposure to phosphorous compounds by various international bodies (JECFA, EFSA) yielded a maximum tolerable daily intake) of 70 mg P/kg bw/day. 
A  combined repeated dose - reproductive / developmental toxicity screening test according to OECD 422 with the related substance triple superphosphate (TSP) resulted in a NOAEL of 250 mg/kg bw/day. A similar study with Ca sulfate dihydrate revealed a NOAEL of 79 mg/kg bw/day. 
Contributions of of the ligand humate to the overall toxicity of the submission substance are considered to be small due to the small contribution (<1% on w/w basis).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

good

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

Phosphate:

In a combined repeated dose - reproductive / developmental toxicity screening test according to OECD 422 (Dent 2002) (GLP, RL1) triple superphosphate (TSP) was administered to Sprague-Dawley rats orally (gavage). Animals were either exposed for 6 weeks (males and females of toxicity subgroup) or 2 weeks before mating, during mating and gestation until postnatal day 3 at doses of 0, 250, 750 or 1500 mg/kg bw/day (doses are calculated as TSP added to feed, natural phosphate in feed not counted). Several haematological and clinical chemistry parameters were changed at the two highest dose levels and neurobehavioural changes were observed at the highest dose. Minimal kidney and stomach effects observed at the lowest dose administered were not considered adverse or caused by a locally irritating effect, respectively.

No effects on reproductive parameters or developmental toxicity were observed other than slight reductions in pup body weights at the highest dose level. Therefore, a NOAEL of 250 mg/kg bw/day for repeated dose toxicity was derived from this study performed with TSP.

In an older, but reliable (RL2) published study (Dymsza et al., 1959) normal and high levels of phosphorous (0.43 and 1.3% P) in the form of ortho- (dibasic potassium phosphate) or metaphosphate (Na hexamethphosphate) were fed to male rats over 150 days. Neither the types nor the levels of phosphates impaired growth conclusively as measured by weight geined and femur length. No adverse physiological effects were observed from autopsy, histological and clinical studies. There appeared to be adequate absorption and utilization of calcium, phosphorous and iron with any of the tested diets. The study is not as detailed and comprise fewer investigations compared to current guideline studies, but focuses on potential deleterious effects of phosphate, and includes histopathological examination of the target organ kidney (examination of nephrocalcinosis). Therefore it is considered reliable with respect to the evaluation of phosphates. The NOAEL from this subchronic feeding study is 1.3% P in food, which translates to (ECHA Guidance on IR and CSA, R.8) to 520 mg/kg day for male rats.

Several reviews are available which summarise the results of various older (years 1950 to 1975) feeding studies with various phosphate compounds (JECFA 1982, Weiner et al. 2001; Lang 1959). Very high levels of phosphate in feed may cause an increase of plasma phosphorus and a decrease in serum calcium. In consequence, hypocalcaemia, bone resorption and loss and calcification of soft tissues may occur, especially in the kidney. In rats nephrocalcinosis was observed at high phosphate concentrations in the diet. A LOAEL of 10000 mg P/kg diet was derived by JECFA from studies with rats, which are - according to JECFA - especially susceptible to tissue calcification. A MTDI (maximum tolerable daily intake) of 70 mg P/kg bw/day was established for the intake by humans of phosphates from food.

Humic acid potassium salt:

The substance was tested for subacute toxicity using the EU method B.7.Repeated Dose (28-days) Toxicity (Oral), study with Wistar rats. The test substance was administered as solution in water by stomach tube; oral application of rats was made daily. The study includes four main groups and two satellite groups of animals. Each main group consisted of 5 males and 5 females; each satellite group consisted of 5 males and 5 females.Main groups contained 3 treated groups (doses 250, 500, 1000 mg/kg of body weight /day) and one control group (vehicle only). The satellite groups contained one control group (vehicle only) and one treated group (1000 mg/kg/day). The administration period lasted 28 days.  

Based on slightly reduced body weights and changes in values of haematological and biochemical parameters detected at the hightest dose level a NOAEL of 500 mg/kg bw/day was derived.

Several published studies on the repeated dose toxicity of humic acids or humate salts are available. Two subchronic oral studies did not observe advese effects up to levels of 1000 mg/L drinking water (Daniel 1991; Condie 1985). One study of low reliability reported slight effects on the thyroid gland (Seffner 1985).

Calcium sulfate:

Calcium and sulfate are natural constituents of food and essential food components. It is of limited water solubility.

Calcium sulfate as an food addtive has been evaluated by the EU Commission's Scientific Committee on Food (SCF) and the FAO/WHO Joint Expert Committee on Food Additives (JECFA). These committees allocated an Acceptable Daily Intake (ADI) not specified for the respective calcium and sulfate ions, due to its non-toxicity after oral exposure. It is generally permitted in the EU and the USA as an approved food additive (EU: E516). The European Food Safety Agency EFSA (2008) evaluated the use of Calcium sulfate in food supplements as a source of calcium based on the tolerable upper intake level of 2500 mg calcium/day as established by SCF. EFSA concluded that calcium sulfate as a source of calcium in food supplements is of no safety concern. Similarly, in 2004 EFSA concluded that its use as a mineral substance in food is of no safety concern. Any contribution to the overall exposure from handling the submission substance is considered to be low compared to exposure from food.

Calcium sulfate dihydrate was tested in a combined repeated dose/reproductive toxicity screening test according to OECD Guideline 422. The test material was administered to male and female Sprague Dawley rats by gavage at daily doses of 0, 100, 300 and 1000 mg/kg bw/day. The NOAEL for calcium sulfate anhydrous was 79 mg/kg/day for males based on a significant decrease in TP (Total Protein), ALB (Albumin), BUN (Blood Urea Nitrogen), and CREA (Creatinine) at the 300 mg/kg b.w./day and 1,000 mg/kg b.w./day groups. No effects were observed in females.

Justification for classification or non-classification

The main components of the submission substance are naturally occuring substances of generally low toxicity. LOAELs from repeated dose toxicity studies are well above the classification criterion of 10 mg/kg bw/day for oral studies. No classification is required.