What is the LD50 of Vitamin F.

Cholecalciferol - small animal
CliniTox
Clinical
toxicology

I. General toxicology

1. Chemical-physical properties

Cholecalciferol (vitamin D3) forms a white, crystalline powder at room temperature with no noticeable smell or taste. It is insoluble in water, slightly soluble in oils, readily soluble in ethanol and in almost all organic solvents. In the unprocessed state, cholecalciferol is oxidized in air within a few days.
 

2. Sources

Several sources are related to an oversupply of vitamin D. In addition to dosing or mixing errors in feed preparation, poisoning occurs due to the ingestion of rat baits that have been mixed with cholecalciferol (also in combination with other rodenticides). Furthermore, especially in dogs, poisoning occurs through the ingestion of human drugs, the synthetic derivatives of vitamin D.3 contain (for example calcipotriol, tacalcitol). Such agents are prescribed for psoriasis and other proliferative skin diseases. In the case of herbivores, high amounts of cholecalciferol ultimately lead to certain plants - for example in golden oats (Trisetum flavescens) - to hypervitaminosis.
 

3. Kinetics

Cholecalciferol is absorbed through the gastrointestinal tract and transported to the liver. In addition, cholecalciferol is formed in the skin under the influence of UV rays. Storage takes place in the liver and in adipose tissue. Cholecalciferol is hydroxylated a first time in the liver and a second time in the kidneys, producing 1,25- or 24,25-dihydroxycholecalciferol, the most potent metabolites of the synthesis. In the event of poisoning, the serum concentration of 25-hydroxycholecalciferol is higher and longer than the serum concentration of dihydroxycholecalciferol.
The half-life of cholecalciferol is up to 30 days. The metabolic processes with the vegetable ergocalciferol (vitamin D2) are analogous to those of cholecalciferol.
 

4. Toxic principle

Cholecalciferol causes hypercalcemia in the organism by increasing the intestinal absorption of calcium, promoting the osteoclastic calcium release from the bone and increasing renal reabsorption. Through calcium phosphate deposition, hypercalcemia leads to the mineralization of the liver, kidneys, blood vessel walls, gastrointestinal tract and other soft tissues. Serious organ damage ensues. The demineralization of the bone tissue increases the risk of bone fractures.
 

5. Toxicity to laboratory animals

Acute oral LD50 (in mg / kg body weight):

 mouseratRabbitschicken
Calcipotriol 2.2-2.5  
Cholecalciferol (vitamin D3) 42  
Ergocalciferol (vitamin D2)23.756  
Tacalcitol3.1-3.43.3  
 

II. Special toxicology - small animals

1. Toxicity

-The toxicity of the calciferols depends on the calcium and phosphorus content of the feed, as well as on predisposing conditions such as renal insufficiency or hyperparathyroidism. In general, young animals are more sensitive than adults, cats are more sensitive than dogs (Rumbeiha, 2013).
-Synthetic vitamin D analogs, such as calcipotriol, are much more toxic than vitamin D; Vitamin D3 is 10 times more potent than vitamin D.2 (Rumbeiha, 2013).
 
Recommended doses
-National Research Council (NCR): the daily vitamin D requirement for dogs was set at 22 IU (0.55 µg) / kg body weight (Rumbeiha, 2013); for kittens, a minimum of 224 IU (5.6 µg) cholecalciferol / kg dry matter and a maximum of 30,000 IU (750 µg) cholecalciferol / kg dry matter or 7520 IU / 1000 kcal metabolizable energy are recommended (Wehner et al., 2013).
-Association of American Feed Control Officials (AAFCO): We recommend a minimum to maximum vitamin D content in dry dog ​​food of 500-5000 IU / kg, or a maximum of 1429 IU / 1000 kcal metabolizable energy in dog food and 2500 IU / 1000 kcal metabolizable energy in cat food (Rumbeiha, 2013).
-De Brito Galvao et al. (2017): We recommend cat food with less than 200 IU of vitamin D.3/ 1000 kcal and less than 2 g calcium / 1000 kcal. The need for adult cats is lower than for growing animals.
-Therapeutic dose of calcitriol (1.25 (OH)2D.3): approx. 2.5-3.5ng/ kg body weight / day, although hypercalcemia can also occur at this dosage (Rumbeiha, 2013).
 
-Cholecalciferol: 13 mg / kg body weight (520,000 IU / kg) p.o., once, in the adult dog (Humphreys, 1988; Rumbeiha, 2013).
-Calcipotriol: 65µg/ kg body weight p.o., once, for dogs (Rumbeiha, 2013).
 
-Cholecalciferol: 88 mg / kg body weight (520,000 IU / kg) p.o., in dogs (Rumbeiha, 2013).
 
1.3Minimal toxic dose
-Cholecalciferol: 2 mg / kg (80,000 IU / kg) body weight p.o., in dogs (Rumbeiha, 2013).
-Calcipotriol: 10µg/ kg body weight p.o., for dogs (Rumbeiha, 2013).
-Vitamin D3: Doses around 0.1 mg / kg (4,000 IU / kg) can cause mild gastrointestinal symptoms, doses> 0.5 mg / kg body weight (20,000 IU / kg) hypercalcemia, hyperphosphataemia and kidney failure (Rumbeiha, 2013)
 
1.4Chronic toxicity
-Dogs: 500-1000 µg cholecalciferol / kg body weight / day p.o. for 2-3 weeks (Rumbeiha, 2013).
-Dog puppies: 15 mg of vitamin D.2/ Animal / week p.o., for 2 months (Rumbeiha, 2013).
 

2. Latency

Cholecalciferol poisoning usually takes 36 hours to 3 days before the first symptoms appear. Some of the synthetic derivatives, like calcipotriol, have shorter latencies (8-24 hours).
 

3. Symptoms

3.1General condition, behavior
Lethargy, anorexia, depression, ataxia, hyperthermia, thirst, shock
  
3.2Nervous system
Paresis, rarely convulsions
  
3.3Upper gastrointestinal tract
Vomiting, sometimes bloody
  
3.4Lower gastrointestinal tract
Constipation, Melena
  
3.5Respiratory system
Dyspnea in the later stages of poisoning
  
3.6Cardiovascular
Increased blood pressure, later increased capillary refill time, bradycardia, arrhythmias
  
3.7Musculoskeletal system
Lameness
  
3.8Eyes, eyelids
No symptoms
  
3.9Urinary tract
Polyuria, pain on palpation of the kidneys
  
3.10Fur, skin, mucous membranes
Cyanotic mucous membranes
  
3.11Blood, blood formation
No symptoms
  
3.12Fertility, young animals, lactation
No symptoms
 

4. Autopsy findings

In addition to unspecific changes, bleeding in the stomach and small intestinal mucosa occurs in particular.
Histopathological findings: The histological examination reveals the multiple mineralization of the soft tissues. Practically all organs are affected: gastrointestinal tract, liver, kidneys, lungs, heart and blood vessels. Calcium phosphate is preferably deposited between elastic fibers or collagen fibers.
 

5. Further diagnostics

5.1Changed laboratory values
-Blood chemistry: increased calcium and phosphorus levels in the serum; the normal values ​​are as follows: calcium, up to 9.5-12.5 mg / dL (2.4-3.1 mmol / L); Phosphorus, 3.5-5.5 mg / dL (1.1-1.7 mmol / L). The urea and creatinine concentrations are also increased.
-Urine examination: specific gravity decreased (polyuria), proteinuria
 
-Extended PR interval
-Shortened QT interval
-Ventricular fibrillation
 
-Calcifications in various soft tissues can be seen.
 
-The echogenicity of various tissues is increased due to the calcium storage.
 

6. Differential Diagnoses

-Tumors
-Hyperparathyroidism
-Adrenal insufficiency
-Renal failure
 

7. Therapy

The therapy must be carried out for at least 2 weeks! Protect affected animals from sunlight and offer diet foods with a low calcium content.
 
-Stabilize circulation: 0.9% NaCl (100 ml / kg / day i.v.) with KCl addition (30 mmol / L)
-Stabilize breathing
-Control cramps
 
7.2Decontamination and Elimination
-Vomiting
-Repeated administration of activated charcoal and Glauber's salt (if the symptoms occur, however, decontamination is pointless)
 
7.3Forced renal elimination
 
-Pamidronate disodium (bisphosphonate) 1.3-2 mg / kg body weight in dogs, slowly (over 2-4 hours) i.v. in a 0.9% NaCl solution (must be administered IV), only to be administered once; better effect if administration within 24-36 hours after ingestion of the rodenticide; Side effect: renal tubular necrosis (increase in urea and creatinine in the blood serum) if given too quickly. Only effective if no mineralization has taken place. A second dose (96 hours after ingestion) is only necessary if very high doses of cholecalciferol (8 mg / kg) have been taken. No combination with prednisolone necessary.
-Prednisolone, 2.2 mg / kg s.c. Twice a day: Glucocorticoids have an antagonistic effect on vitamin D.3because they inhibit calcium absorption from the intestine and increase renal excretion.
-Aluminum hydroxide, 10-60 mg / kg p.o. 2-3 times a day (binds phosphates in the intestine).
 
7.5Further symptomatic measures
-Treatment of acidosis
-Antiemetics if vomiting persists: metoclopramide or domperidone
-Protection of the mucous membrane: cimetidine or ranitidine
-Antibiotic care as prophylaxis for bloody vomiting and diarrhea
 

8. Case studies

8.1A Dalmatian (30 kg, 8 years old) ingested a rodenticide containing cholecalciferol three days ago.
Symptoms: lethargy, anorexia, vomiting, ataxia, weakness
Laboratory: hypercalcemia (20 mg / dL), uremia, hyperphosphataemia (6.4 mg / dL), hyponatremia, hypochloremia, leukocytosis
Therapy: 0.9% NaCl i.v .; Salmon calcitonin 8 IU / kg s.c., every 24 hours; Furosemide; Prednisolone; Cimetidine
Course: severe dyspnoea, death
(Fooshee et al., 1990).
  
8.2A Labrador mixed breed (female, neutered, 18 months) ingested cholecalciferol 4 days ago.
Symptoms: vomiting, diarrhea
Laboratory: hypercalcemia (19 mg / dL), hyperphosphataemia (7.0 mg / dL), uremia
Therapy: 0.9% NaCl with KCl addition i.v .; Salmon calcitonin 5 IU / kg s.c., every 24 hours
Course: slow improvement, healing
(Fooshee et al., 1990).
  
8.3A cat (2 years old) ingests a rodenticide and is presented 48 hours after admission.
Symptoms: lethargy, anorexia, dehydration
Laboratory: hypercalcemia (19 mg / dL)
Therapy: 0.9% NaCl, sodium bicarbonate, furosemide i.v.
Course: improvement within 4 days
(Moore et al., 1998).
  
8.4A female Bernese mountain dog (22 months, female, 21 kg) accidentally ingests the contents of a skin ointment for psoriasis (active ingredient: a total of 0.08 mg tacalcitol).
Symptoms 36-48 hours later: lethargy, weakness, anorexia, paresis, hyperthermia
Therapy: prednisolone, amoxicillin
Further symptoms: hematemesis, death
Section: mineralization of the kidneys, lungs, myocardium, stomach, brain, lacrimal glands
(Hilbe et al., 2001).
 

9. Literature

Cumming C (1991) Suspected vitamin D rodenticide poisoning in a dog. Vet Rec 128, 600
 
De Brito Galvao JF, Parker V, Schenck PA & Chew DJ (2017) Update on Feline Ionized Hypercalcemia. Vet Clin North Am Small Anim Pract. 47, 273-292
 
Dorman DC (1990) Toxicology of selected pesticides, drugs and chemicals. Anticoagulant, cholecalciferol and bromethalin-based rodenticides. Small Anim Pract 20, 339-352
 
Dorman DC & Beasley VR (1989) Diagnosis and therapy for cholecalciferol toxicosis. In: Kirk X, Saunders, Orlando, pp 148-152
 
Dougherty SA, Center SA & Dzanis DA (1990) Salmon calcitonin as adjunct treatment for vitamin D toxicosis in a dog. J Am Vet Med Assoc 196, 1269-1272
 
Fan ™, Simpson KW, Trasti S, Birnbaum N, Center SA & Yeager A (1998) Calcipotriol toxicity in a dog. J Small Anim Pract 39, 581-586
 
Fooshee SK, Forrester SD (1990) Hypercalcemia secondary to cholecalciferol rodenticide toxicosis in two dogs. J Am Vet Med Assoc 196, 1265-1268
 
Gfeller RW & Messonnier SP (2004) Handbook of Small Animal Toxicology and Poisonings, Mosby, St. Louis, pp 316-320
 
Gorig C, Brugmann M, Zentek J, Wagner F & Farlopulos S (1999) Hypercalcemia caused by vitamin D intoxication in a Dutch shepherd dog. A case report. Tierärztl Umsch 54, 674-682
 
Gunther R, Felice LJ, Nelson RK & Franson AM (1998) Toxicity of a vitamin D3 rodenticide to dogs. J Am Vet Med Assoc 193, 211-214
 
Gwattney-Brant SM, Rumbeiha WK (2002) Functional antidotes. Vet Clinics of North America, Small animal pract 32, 333-335
 
Hilbe M, Sydler T, Fischer L & Naegeli H (2000) Metastatic calcification in a dog attributable to ingestion of a tacalcitol ointment. Vet Pathol 37, 490-492
 
Humphreys DJ (1988) Veterinary Toxicology, Bailliere Tindall, pp 126-127
 
Imaizumi T, Tsuruta M, Kitagaki T, Ono M, Shirakawa K, Nagata M & Konishi R (1996) Single dose toxicity studies of calcipotriol in rats and dogs. J Toxicol Sci 21 Suppl 2, 277-285
 
Lüllmann H, Mohr K & Ziegler A (1994) Active ingredients for maintaining calcium homeostasis. In: Pocket Atlas of Pharmacology, Thieme, Stuttgart, pp 258-259
 
Moore FM, Kudisch M, Richter K & Faggella A (1998) Hypercalcemia associated with rodenticide poisoning in three cats. J Am Vet Med Assoc 193, 1099-1100
 
Murphy MJ (1994) Toxin exposures in dogs and cats: pesticides and biotoxins. J Am Vet Med Assoc 205, 414-421
 
Rumbeiha WK (2013) Cholecalciferol. In: Small animal toxicology, 3rd ed. (ME Peterson & PA Talcott, eds) Elsevier Saunders, Missouri, pp 489-498
 
Rumbeiha WK, Kruger JM, Fitzgerald SF, Nachreiner RF, Kaneene JB, Braselton WE & Chiapuzio CL (1999) Use of pamidronate to reverse vitamin D3-induced toxicosis in dogs. Am J Vet Res 60, 1092-1097
 
Studdert VP (1990) Toxicity of cholecalciferol-containing rodenticides for dogs and cats. Aust Vet J 67, 218
 
Talcott PA & Dorman DC (1997) Pesticide exposures in companion animals. Vet Med 92, 168-181
 
Wehner A, Katzenberger J, Groth A, Dorsch R, Koelle P, Hartmann K & Weber K (2013) Vitamin D intoxication caused by ingestion of commercial cat food in three kittens. J Feline Med Surg 15, 730-736
 
Windholz M (1983) The Merck Index. Merck & Co, Rahway, New Jersey