エチドロン酸

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Cosmetic ingredients (Etidronic Acid) -> CIR (Cosmetic Ingredient Review)

Chelating

198-199

105 °C

FCS -> FDA Cumulative Estimated Daily Intake (CEDI)

FCS -> FDA Inventory of Food Contact Substances Listed in 21 CFR

CBI; Dry Powder; Liquid; Dry Powder; Liquid

White odorless powder; [MSDSonline]

Solid

This chemical does not meet GHS hazard criteria for 1.6% (35 of 2257) of reports.

Danger

H290 (34.6%): May be corrosive to metals [Warning Corrosive to Metals]

P234, P260, P264, P264+P265, P270, P273, P280, P301+P317, P301+P330+P331, P302+P361+P354, P304+P340, P305+P354+P338, P316, P317, P321, P330, P363, P390, P405, P406, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2257 reports by companies from 33 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

Chemical: Phosphonic acid, (1-hydroxyethylidene)bis-

Phosphonic acid, P,P'-(1-hydroxyethylidene)bis- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of Phosphonic acid, P,P'-(1-hydroxyethylidene)bis- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 15-11-2021 https://echa.europa.eu/registration-dossier/-/registered-dossier/16011

Etidronic acid: Does not have an individual approval but may be used under an appropriate group standard

No human data, but not expected to increase risk of congenital abnormalities based on animal studies; [REPROTOX] Safe to use as a sequestrant in food preparation; [JECFA] Causes gastrointestinal bleeding in lethal-dose feeding studies of mice; [RTECS] A corrosive substance that can cause injury to the skin, eyes, and respiratory tract; Inhalation may cause chemical pneumonitis; [MSDSonline]

THE SYSTEMIC TOXICITY, SKIN TOLERANCE & ECOTOXICITY OF PRIMARY MATERIALS USED IN THE TREATMENT OF WATER, EG, ANTICORROSION PHOSPHONATES WAS STUDIED. HYDROXYETHANE DIPHOSPHONIC ACID HAD LOW TOXICITY & PRESENTED NO POTENTIAL HAZARD.[KASTNER W ET AL; TOXICITY AND ECOTOXICITY OF WATER TREATMENT PRODUCTS; L' EAU, L' INDUSTRIE, LES NUISANCES 72: 47 (1983)]

Met. Corr. 1 (34.6%)

Acute toxicity - category 4

Acute toxicity (Oral) - Category 4

4.3 [mg/m3]

48 [mg/m3]

290 [mg/m3]

Safe in the present practices of use and concentration. Ingredient, concentration, and use information are available in documents discoverable at https://cir-reports.cir-safety.org

Bisphosphonates, when attached to bone tissue, are absorbed by osteoclasts, the bone cells that breaks down bone tissue. Although the mechanism of action of non-nitrogenous bisphosphonates has not been fully elucidated, available data suggest that they bind strongly to hydroxyapatite crystals in the bone matrix, preferentially at the sites of increased bone turnover and inhibit the formation and dissolution of the crystals. Other actions may include direct inhibition of mature osteoclast function, promotion of osteoclast apoptosis, and interference with osteoblast-mediated osteoclast activation. Etidronic acid does not interfere with bone mineralization. In malignancy-related hypercalcemia, etidronic acid decreases serum calcium by inhibiting tumour-induced bone resorption and reducing calcium flow from the resorbing bone into the blood. Etidronic acid also reduces morbidity of osteolytic bone metastases by inhibiting tumour-induced bone resorption. Etidronic acid may promote osteoclast apoptosis by competing with adenosine triphosphate (ATP) in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone.

Clinical experience with acute etidronic acid overdosage is extremely limited. Decreases in serum calcium following substantial overdosage may be expected in some patients. Signs and symptoms of hypocalcemia also may occur in some of these patients. Some patients may develop vomiting. In one event, an 18-year-old female who ingested an estimated single dose of 4800 to 6000 mg (67 to 100 mg/kg) of etidronate was reported to be mildly hypocalcemic (7 .5 2 mg/ dl) and experienced paresthesia of the fingers.

In a perinatal and postnatal study, pregnant female Long-Evans rats (20/group, except 21/high-dose group) were orally exposed by gavage to (1-hydroxyethylidene)bis-phosphonic acid at dose levels of 16.51, 110.09, or 330.28 mg/kg/day (in one-half doses, twice daily in deionized water; 10 ml/kg/day) on gestation day (GD) 15 through the end of gestation and the period of lactation. Surviving animals were sacrificed on lactation day 21. Significant differences were observed between treated and control animals in the following: decreased implantations/dam (high-dose group), decreased live fetuses/total fetuses (low-dose group), increased pup survival (lactation days 0-4, high-dose group), increased pup body weight (high- and mid-dose groups), and decreased number of females (mid-dose group). No significant differences were observed between treated and control animals in the following: pregnancy rate, length of gestation period, number of litters delivered, maternal weight gain, mortality, physical observations, or necropsy observations, numbers of pups/dam, live or dead fetuses/litter, live fetuses/implantation, pup sex ratios, and gross pup necropsy observations.

Teratogenicity was evaluated in pregnant Long-Evans rats (20/group) orally exposed by gavage to (1-hydroxyethylidene) bis-phosphonic acid at dose levels of 0, 16.51, 110.09 or 330.28 mg/kg/day (in deionized water solutions, 10 ml/kg/day, one-half doses given twice daily) on gestation days (GD) 6-15. All surviving rats were sacrificed on GD 20. Significant differences were observed between treated and control animals with respect to a decreased incidence of soft tissue abnormalities (low-dose group). No significant differences were observed between treated and control animals in the following: maternal mortality, body weight, body weight change, pregnancy rate, physical observations, numbers of corpora lutea, implantations, live fetuses, resorptions, implantation frequency, necropsy observations, percent viable or resorbed fetuses, fetal weight, crown-rump length, sex ratio, ossification variations, and skeletal malformations.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

etidronic acid

Didronel®

Bisphosphonates

Not Applicable

no-DILI-concern

ETHANEHYDROXY DIPHOSPHONATE (EHDP) WAS ADMIN SC TO ADULT BEAGLE DOGS FOR 1-2 YR AT VARIOUS DOSE LEVELS TO DETERMINE ITS SKELETAL EFFECTS WHEN GIVEN CHRONICALLY. AT LOW DOSES (0.1 & 0.5 MG/KG/DAY), EHDP CAUSED A TIME-&-DOSE DEPENDENT REDN IN PERCENTAGE OF BONE SURFACE WITH ACTIVE MINERALIZATION, A REDN IN MINERALIZATION RATES, REDN IN RESORPTION SPACE, BUT NO CHANGES IN OSTEOID SEAM WIDTHS. EHDP CAN HAVE PROFOUND EFFECTS ON BONE REMODELING IN THE DOG, BUT THESE EFFECTS ARE DOSE-&-TIME-DEPENDENT & APPEAR TO BE REVERSIBLE.

THE ENERGY CHARGE OF THE ADENYLATE POOL & ATP & INORG PHOSPHATE CONTENT WERE NOT CHANGED BY TREATMENT OF CULTURED CALVARIA CELLS WITH ETHANE-1-HYDROXY-1,1-DIPHOSPHONATE.

FETAL MOUSE CALVARIA WERE CULTURED FOR 48 HR IN PRESENCE OF ETHANE-1-HYDROXY-1,1-DIPHOSPHONATE (EHDP) AFTER WHICH ACTIVITY OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE, 6-PHOSPHOGLUCONATE DEHYDROGENASE, HEXOKINASE, LACTATE DEHYDROGENASE, ACONITASE, & ISOCITRATE DEHYDROGENASE WAS DETERMINED. EHDP HAD NO EFFECT ON ANY OF THE ENZYMES STUDIED.

ETHANE-1-HYDROXY-1,1-DIPHOSPHONATE ADMIN TO IMMATURE RATS INHIBITED MINERALIZATION AS EVIDENCED BY WIDENED TIBIAL EPIPHYSEAL PLATES AND DECREASED BONE ASH TO DRY WT RATIOS.

For more Non-Human Toxicity Excerpts (Complete) data for 1-HYDROXY-1,1-DIPHOSPHONOETHANE (7 total), please visit the HSDB record page.

M - Musculo-skeletal system

QM - Musculo-skeletal system

Etidronic acid is a first generation bisphosphonate that inhibits the action of osteoclasts, preventing bone resporption. It has a wide therapeutic index as overdoses are not associated with severe toxicity and a long duration of action as it slowly releases from the bone. Patients should be counselled regarding the risk of upper gastrointestinal adverse reactions.

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. First generation bisphosphonates closely mimic the structure of pyrophosphate, which can be incorporated into ATP anologues that cannot be hydrolyzed, disrupting all ATP mediated actions of osteoclasts.

MALE RATS WERE INJECTED WITH VEHICLE (CONTROL GROUP), 0.4 OR 4.0 MG/KG/DAY OF ETHANE-1-HYDROXY-1,1-DIPHOSPHONATE (EHDP). AFTER 6 DAYS OF EHDP TREATMENT ALL RATS RECEIVED 6 SC INJECTIONS OF (3)H-THYMIDINE AT 8 HR INTERVALS. AFTER 6 DAYS OF EHDP PRE-TREATMENT THE MULTIPLE LABELING INDEX OF OSTEOPROGENITOR CELLS WAS REDUCED WITH 4.0 MG/KG/DAY DOSE OF EHDP. EHDP CAUSED INCR IN RATE OF INCORP & ACCUM OF (3)H-THYMIDINE NUCLEI IN OSTEOCLASTS. EHDP CAUSES AN ACCELERATED RATE OF OSTEOCLAST PRODN FROM PRECURSOR CELLS IN SPITE OF ITS ABILITY TO SLOW BONE RESORPTION.

Etidronic acid is not metabolized _in vivo_

Not metabolized. Route of Elimination: Etidronate disodium is not metabolized. Within 24 hours, approximately half the absorbed dose is excreted in urine; the remainder is distributed to bone compartments from which it is slowly eliminated. Unabsorbed drug is excreted intact in the feces. Half Life: In normal subjects, plasma half-life of etidronic acid, based on non-compartmental pharmacokinetics is 1 to 6 hours.

M2F465ROXU

ETIDRONIC ACID

Established Pharmacologic Class [EPC] - Bisphosphonate

Chemical Structure [CS] - Diphosphonates

Etidronic acid is a Bisphosphonate.

Etidronic acid has an oral bioavailability of 1-10%. Further data regarding pharmacokinetics of etidronic acid are not readily available.

Absorbed etidronic acid is eliminated in the urine, while the unabsorbed drug is eliminated in the feces.

Etidronic acid has a volume of distribution of 0.3-1.3L/kg.

Etidronic acid has a renal clearance of 0.09L/kg/h.

THE DISTRIBUTION OF TECHNETIUM-99M HEDP IN NORMAL HUMAN ORGANS WAS MEASURED.

THE BONE-SEEKING AGENT (99M)TC-SN-1-HYDROXYETHYLIDENE-1,1-DIPHOSPHONIC ACID UNEXPECTEDLY BINDS TO PARTICLES OF HUMAN ARTICULAR CARTILAGE AS WELL AS CORTICAL BONE IN VITRO. MECHANISMS ADDITIONAL TO THE SIMPLE IONIC ATTRACTION BETWEEN THE PHOSPHONATE GROUPS OF HEDP & METAL CATIONS SUCH AS CA2+ ARE RESPONSIBLE FOR THE UPTAKE OF (99M)TC-HEDP BY BODY TISSUES.

CIR ingredient: Etidronic Acid

Used as a sequestering and chelating agent; as a scale and corrosion inhibitor; as a bone resorptions inhibitor; [Merck Index]

MEDICATION

MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >1000

For the treatment of symptomatic Paget's disease of bone and in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury.

(1979) No Data

(1981) No Data

(1979) No Data

(1981) No Data

2023: 7,000,000 - <8,500,000 lb

(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS

(1981) PROBABLY GREATER THAN 2.27X10+6 GRAMS

PASSAGE OF GASEOUS PHOSPHORUS TRICHLORIDE INTO ACETIC ACID; REACTION OF GASEOUS PHOSPHORUS TRICHLORIDE & ACETIC ACID IN A LOWER ALIPHATIC TERTIARY AMINE, EG, TRIBUTYLAMINE; REACTION OF AN ANHYDROUS MIXTURE OF PHOSPHOROUS ACID, ACETIC ANHYDRIDE, & ACETIC ACID

Information on 1 consumer products that contain Etidronic Acid in the following categories is provided:

Information on 253 consumer products that contain Etidronic acid in the following categories is provided:

EPA Safer Chemical Functional Use Classes -> Oxidants and Oxidant Stabilizers

Safer Chemical Classes -> Yellow triangle - The chemical has met Safer Choice Criteria for its functional ingredient-class, but has some hazard profile issues

Fragrance Ingredients

Food Additives -> SEQUESTRANT -> JECFA Functional Classes

Cosmetics -> Chelating

Utilities

Phosphonic acid, P,P'-(1-hydroxyethylidene)bis-: ACTIVE

WAVE-SETTING HAIR PREPARATIONS ARE PREPARED BY COMBINING L-CYSTEINE WITH 1-HYDROXYETHANE-1,1-DIPHOSPHONIC ACID. THE CHELATING AGENT PREVENTS FORMATION OF DANDRUFF.

CORROSION SCALE PREVENTION IN COOLING WATER TREATMENT BY ORGANOPHOSPHATES.

1-HYDROXYETHANE-1,1-DIPHOSPHONIC ACID IS USED IN HAIRSETTING PREPARATIONS. THE CHELATING AGENT PREVENTS FORMATION OF DANDRUFF.

1-HYDROXYETHYLDIPHOSPHONATE INCREASED BOVINE TOOTH ENAMEL ION-SELECTIVITY; THE EFFECT WAS RELATED TO THE NUMBER OF PHOSPHATE GROUPS & WAS GREATER WITH THE ORGANIC THAN INORGANIC PHOSPHATES.