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EC number: 701-238-4 | CAS number: -
A NOAEL for HEDP-2Na of 41 mg/kg bw/d was derived based on anaemia effects described in the interim report of a combined chronic toxicity / carcinogenicity study with disodium etidronate. The NOAEL takes into consideration the most susceptible life span (juvenile animals).
Two key studies are available for repeated dose toxicity by the oral route (dietary) in rats, a 90 day (OECD 408) (HRC, 1977) and a combined chronic toxicity and carcinogenicity study (OECD 453) (HRC, 1979).
In order to reduce the number of animals used, a combined dietary chronic toxicity and carcinogenicity study in rats was carried out (Huntingdon Research Centre, 1979) with HEDP-2Na. With the main exception of the number of animals (40 instead of 50 rats of each sex per dose group) the study meets the criteria of the OECD guideline No. 453. Sprague-Dawley rats were fed diets containing 0-10000 ppm disodium etidronate for 104 weeks. The mean doses for the whole two-year study are equivalent to 0, 19, 78 and 384 mg/kg in males and 0, 24, 96 and 493 mg/kg in females. During the study, animals were observed for clinical signs of toxicity and mortality. Observations included body weight, food and water consumption, ophthalmoscopic examination, hematology, clinical chemistry and urine analysis. During the study and at study terminations all animals underwent necropsies and histopathological examinations. No mortality or treatment-related effects were observed on ophthalmoscopy, clinical chemistry or gross pathology. No histopathological changes were found at study termination. A pale colour of the spleen was seen in the mid and high dose group at 26 weeks, indicating a lack of iron. Concordantly, haematological disturbances associated with anaemia were observed in the high and mid-dose groups at the earlier analysis times. All haematological effects had resolved by the study termination, thus indicating reversibility of the effect. There were no treatment related changes in incidence or types of neoplastic change observed.
As part of the combined dietary chronic toxicity and carcinogenicity study, additional four satellite groups of ten animals of each sex (dose and control groups) were included for evaluation of toxicity and non-neoplastic pathology at 6 months. The results obtained in the first twelve weeks (haematology, biochemistry, urinalysis) were reported separately in a 90 day interim report (Huntingdon Research Centre, 1977). In general, the protocol was similar to the OECD guideline No. 408 (Repeated Dose 90-Day Oral Toxicity in Rodents).
Though the disodium etidronate content of the diet was identical (0-10.000 ppm), the
doses in mg/kg bodyweight/day quoted in the 90 day interim report are higher than those in the chronic study report. (top dose of 817 mg/kg in males and 1000 mg/kg in females c.f. 384 and 493 mg/kg for the 2 year study). This can be explained by the higher feed intake as a function of bodyweight. The doses corresponded to 0, 41, 169, 817 mg/kg bw/d for males and 0, 50, 195 and 1000 mg/kg bw/d for females.
A decrease in red blood cell parameters was seen in the top dose group for both sexes, and for males at 2000 ppm by week 12. There was evidence of prolonged anaemia in both sexes at 10000 ppm. Severe pallor of the skin of the top dose group animals and slight pallor in rats receiving 2000 ppm was seen. These observations are consistent with perturbation of iron homeostasis.
The effects are consistent with the chelating properties of HEDP and its salts causing a reduction in bioavailability of iron. In principle, two NOAEL values – one for adult (78 mg/kg bw/d), one for juvenile animals during their growth phase (41 mg/kg bw/d) – can be derived on the basis of the results (anaemia) of the two key studies. A NOAEL of 41 mg/kg bw/d already takes into account the most susceptible subgroup (adolescent animals).
The NOAEL value can then be adjusted for the molecular weight of the active acid resulting in 34 mg active acid/kg/day.
Acute and short-term inhalation studies of questionable reliability in rats indicate local irritating effects in the nasopharyngeal zone after exposure to aerosols of unknown particle range containing unknown compositions of HEDP and its salts. The pH values were not stated in the reports. As an example, the pH values of aqueous solutions at around 1% can vary between < 2 for the parent polyprotic etidronic acid and 11-12 for the tetrasodium etidronate salt (see pKa values in the chapter “dissociation constant”). Acidic or basic pH conditions significantly determine the induction of local effects and thus could explain the observed irritation.
Justification for grouping:
See CSR Annex I or IUCLID section 13.
Based on the available data, adverse effects on iron homeostasis were not considered to be severe enough to trigger classification. Therefore, a classification for STOT-RE is not required for sodium salts of HEDP according to Regulation (EC) No 1272/2008.
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