Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION

PRODUCT NAME

PAMIDRONIC ACID, DISODIUM SALT

NFPA

PRODUCT USE

Calcium metabolism regulator. Antipagetic; inhibitor of tumour- induced hypercalcaemia.
Technetium complex is used as a diagnostic acid (radioactive imaging agent). Remedy

SYNONYMS

C3-H9-N-O7-P2.2Na, C3-H9-N-O7-P2.2Na, H2NCH2CH2C(PO4Na)2OH, "CGP 23339 A", "disodium 3-
amino-1-hydroxypropylidene-1, 1-biphosphonate pentahydrate", "disodium 3-amino-1-
hydroxypropylidene-1, 1-biphosphonate pentahydrate", "disodium pamidronate", "pamidronate
disodium", Aminomux, "disodium salt of:", "ADP acid", AHPrBP, "3-amino-1-
hydroxypropylidene-1, 1-bisphosphonic acid", "3-amino-1-hydroxypropylidene-1, 1-
bisphosphonic acid", "(3-amino-1-hydroxypropylidene)diphosphonic acid", "(3-amino-1-
hydroxypropylidene)diphosphonic acid", "aminohydroxypropylidene diphosphonic acid",
bisphosphonate, "calcium metabolism regulator/ antipagetic"

Section 2 - HAZARDS IDENTIFICATION

CANADIAN WHMIS SYMBOLS

EMERGENCY OVERVIEW

RISK

Harmful if swallowed.
May cause long- term adverse effects in the aquatic environment.

POTENTIAL HEALTH EFFECTS

ACUTE HEALTH EFFECTS

SWALLOWED

  Accidental ingestion of the material may be harmful; animal experiments indicate that ingestion of less than 150 gram may be fatal or may produce serious damage to the health of the individual.  The phosphonic acid compounds ATMP, HEDP, DTPMP and their salts can be considered to be of low to moderate acute oral toxicity. ATMP acid was of moderate acute toxicity to mammals. The acute oral LD50 in rat was determined to be 2910 mg active acid/kg bw. In comparison, the tetrasodium and pentasodium salt of ATMP were less acutely toxic with LD50 values of 8610 and 7120 mg active salt/kg bw, respectively. HEDP acid and its salts are of moderate acute oral toxicity LD50's in rats and mice ranging from 1100 to 1878 mg active acid/kg bw. The oral LD50 values of HEDP salts were in a slightly wider range from 581 mg active salt/kg bw to greater than 5000 mg active salt/kg. DTPMP acid and salts are of low toxicity with oral LD50 values from 3870 mg active salt/kg bw to less than 8757 mg active salt/kg bw.  In pharmacology bisphosphonates (also called diphosphonates) are a class of drugs that inhibit osteoclast action and resorption of bone; they are used for the prevention and treatment of osteoporosis. osteitis deformans (Paget's disease of the bone), bone metastasis (with or without hypercalcaemia), multiple myeloma and other conditions that feature bone fragility.  The association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.  

EYE

  Limited evidence or practical experience suggests, that the material may cause eye irritation in a substantial number of individuals. Prolonged eye contact may cause inflammation characterized by a temporary redness of the conjunctiva (similar to windburn).  The observed eye irritation potential of the phosphonic acid compounds ATMP, HEDP, DTPMP and their salts, ranged from practically non-irritating to severely irritating with irreversible effects. ATMP acid tested as neat product was considered to be moderately irritating to rabbit eyes, whereas the tetra- and pentasodium salt which were tested in aqueous solutions containing around 40 % active salt were found to be practically non-  irritating. These products were evaluated without immediate rinsing the eye following application. All test animals were free of symptoms by the end of the observation period. HEDP acid was tested as a formulation containing 60 % active acid and minimal amounts of HCl with and without rinsing immediately after application. In the study without rinsing, the formulation caused severe irritation and persistent effects. Rinsing the eye directly after application, lessened the severity of the response and all effects disappeared by the end of the observations. The HEDP salts were less irritating to the rabbit eyes in studies with pure salts and formulations thereof tested without rinsing. The tetrasodium salt (i.e., tested as solution containing up to 30 % active salt) was only minimally irritating to the rabbits eyes. In general the same trend as was found with skin irritation was found for eye irritation. The acid compounds were more irritating then tested salts and duration of exposure (i.e., as mimicked by rinsing/non-rinsing immediately after product installation) increased the observed symptoms.  

SKIN

  There is some evidence to suggest that the material may cause mild but significant inflammation of the skin either following direct contact or after a delay of some time. Repeated exposure can cause contact dermatitis which is characterized by redness, swelling and blistering.  The acids and salts of ATMP, HEDP, and DTPMP can be considered to be of low acute dermal toxicity. ATMP acid and its tetra- and pentasodium salt were practically non-toxic with LD<sub>50 </sub>values exceeding the concentrations tested. Dermal LD<sub>50 </sub>values were determined to be greater than 6310 mg active acid/kg bw. No dermal toxicity was observed for HEDP acid and its salts at the highest tested concentrations tested of 1650 mg active salt/kg bw. DTPMP compounds On the basis of the studies phosphonic acid chelatants and their salts, can generally be considered to be mildly irritating to skin at most. In one study a more severe reaction was observed, when an aqueous solution containing 25 % of ATMP acid was applied to intact rabbit skin for 4 hours under occluded conditions. The same result was obtained when an aqueous solution containing 33 % active tetrasodium salt of HEDP was applied to rabbit skin for 24 hours under occlusive dressing The longer application time of 24 h caused more irritation then when the acid or salt product was only applied over 4 h where no irritation response was observed in most cases regardless of the strength of the product tested. Applying the neat acid or salt did not seem to produce a consistently greater effect, rather in some cases the neat powder product was less irritating than some tested formulations, indicating reduced potential of the applied powder product for skin reactivity.  Open cuts, abraded or irritated skin should not be exposed to this material.  Entry into the blood-stream, through, for example, cuts, abrasions or lesions, may produce systemic injury with harmful effects. Examine the skin prior to the use of the material and ensure that any external damage is suitably protected.  

INHALED

  There is some evidence to suggest that this material, if inhaled, can irritate the throat and lungs of some persons.  Persons with impaired respiratory function, airway diseases and conditions such as emphysema or chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled.  The material can cause respiratory irritation in some persons. The body's response to such irritation can cause further lung damage.  

CHRONIC HEALTH EFFECTS

  Limited evidence suggests that repeated or long-term occupational exposure may produce cumulative health effects involving organs or biochemical systems.  There is some evidence that inhaling this product is more likely to cause a sensitization reaction in some persons compared to the general population.  There is limited evidence that, skin contact with this product is more likely to cause a sensitization reaction in some persons compared to the general population.  Long term exposure to high dust concentrations may cause changes in lung function i.e. pneumoconiosis; caused by particles less than 0.5 micron penetrating and remaining in the lung. Prime symptom is breathlessness; lung shadows show on X-ray.  Long term exposure to organophosphonate chelating agents may cause adverse effects.  Rats fed on aminotri(methylenephosphonic acid) (ATMP), for up to 24 months, exhibited reduced body weight and changes in liver, spleen and kidney weights. No adverse histologic. haematologic, biochemical or urinological effects were seen. The "no-effect" level was 150 mg/kg/day. No significant teratogenic or foetotoxic effects were observed in the off-spring of rats and mice exposed to the neutral sodium salt, by gavage. No maternal toxicity was observed at any level. No adverse treatment related effects or reproductive parameters and no pathological or histopathological lesions were observed in either parental animals or pups following dietary exposure of the solid active acid at various times in the mating and birth cycle for three generations.  Rats fed on ethylenediamine(methylenephosphonic acid (EDTMP) (300 mg/kg daily for 10 weeks) before mating and up to the end of the mating period, showed reduced body weights, defects in dental enamel on the incisors and significantly reduced liver weights. In an ongoing study, several rats treated with EDTMP (50-333 mg/kg/day) died during the first twelve months and were seen to have osteosarcomas with metastases. Other adverse effects of EDTMP treatment included increased white blood cell counts in mice, anaemia and reduction in erythrocytes, haemoglobin, haematocrit, serum cholesterol, total serum protein and globulin, in rats.  In a one-generation reproductive study the off-spring of rats, fed up to 3000 ppm DTPMPA (diethylenetriaminepentakis(methylenephosphonic acid)), showed no adverse effects although there was a slight decrease in birth weights.  Exposure to small quantities may induce hypersensitivity reactions characterized by acute bronchospasm, hives (urticaria), deep dermal wheals (angioneurotic edema), running nose (rhinitis) and blurred vision . Anaphylactic shock and skin rash (non-thrombocytopenic purpura) may occur. An individual may be predisposed to such anti-body mediated reaction if other chemical agents have caused prior sensitization (cross-sensitivity).  Prolonged use may produce hypocalcaemia, a susceptibility to fracture bones, anaemia, kidney damage, and gastrointestinal irritation with ulceration. Although the material has not been subjected to controlled pregnancy studies in humans, animal experiments have produced birth abnormalities.