VITAMIN D

Editor's Note: This material is not listed in the Emergency Response Guidebook. Based on the material's physical and chemical properties, toxicity, or chemical group, a guide has been assigned. For additional technical information, contact one of the emergency response telephone numbers listed under Public Safety Measures.

MOLECULAR FORMULA

VITAMIN D2: C28H44O

ERG GUIDE NUMBER

151-SUBSTANCES - TOXIC (NON-COMBUSTIBLE)

SYNONYM REFERENCE

(Budavari, 1996; HSDB , 1994)RTECS, 1994

USES/FORMS/SOURCES

USES

Vitamin D (represents D2 {ergocalciferol} or D3 {cholecalciferol} is a fat soluble vitamin (Office of Dietary Supplements, National Institutes of Health, 2011; Ginsburg, 2011). It is used for the prevention and treatment of rickets, osteomalacia, and osteoporosis, and the treatment of hypoparathyroidism (Office of Dietary Supplements, National Institutes of Health, 2011; Ginsburg, 2011). More recently, evidence suggests that it may also have a role in the prevention of cardiovascular disease, and colon, prostate, and breast cancers (Office of Dietary Supplements, National Institutes of Health, 2011; O'Keefe et al, 2011). Vitamin D is found in many dietary supplements (multivitamins, combined with calcium) or as a single dietary supplement and also commonly found in fortified foods (ie, milk, cereal, and bread) (Ginsburg, 2011).
Vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by vitamin D-25-hydroxylase. It regulates calcium homeostasis via interactions with the intestines and bones. Vitamin D it thought to act as a hormone, because it is synthesized in the body, circulates in the blood, and binds to receptors in order to evoke its biologic action. It promotes calcium absorption in the gut and aids adequate serum calcium and phosphate concentrations (Ginsburg, 2011; Office of Dietary Supplements, National Institutes of Health, 2011).

FORMS

VITAMIN D SUPPLEMENTS

SUMMARY

Vitamin D2 (ergocalciferol) is the synthetic form of vitamin D (Budavari, 1996).
Vitamin D2 crystals have a potency of 40 Units of vitamin D per microgram (Budavari, 1996).
Vitamin D is available in many formulations including capsules, tablets, and injectables.
One mg of cholecalciferol is equivalent to 40,000 International Units of vitamin D. One USP or International Unit is equal to 25 ng of cholecalciferol or ergocalciferol.
Cod liver oil contains approximately 2 mcg/mL of vitamin D3 (80 International Units) (Rice, 1983).

CHOLECALCIFEROL (D3)

Oral Capsule: 5000 IU
Oral Capsule, Liquid Filled: 1000 IU, 2000 IU
Oral Tablet: 400 IU, 1000 IU, 2000 IU, 3000 IU, 5000 IU
Oral Tablet, Chewable: 400 IU
Powder: 100,000 IU/GM
Solution: 1 Million IU/GM, 2400 U/mL

ERGOCALCIFEROL (D2)

Oral Capsule: 50000 IU
Oral Capsule, Liquid Filled: 50000 IU
Oral Solution: 8000 IU/mL
Oral Tablet: 400 IU, 2000 IU

CHEMICAL FORMULATION

White, odorless crystals (Lewis, 1993)
Commercial solutions are usually made with propylene glycol or sesame oil (Budavari, 1996).

SOURCES

Vitamin D2 is found in fish and oils and fortified foods such as milk and margarine. It undergoes biotransformation similar to that of cholecalciferol (vitamin D3). The 2 compounds are equally potent in man (HSDB, 1993).
DERIVATION: From ergosterol by irradiation with UV light (Lewis, 1993).
RICKET THERAPY/INTERNATIONAL ADOPTION: Vitamin D intoxication was reported in an infant with apparent failure-to-thrive following an international adoption in which the infant was given formula fortified with vitamin D. It was determined that massive quantities of vitamin D were likely given based on the elevated laboratory findings and physical symptoms. The patient gradually improved with supportive care (Chan et al, 2006).
SPECIFIC PRODUCTS

ADULTERATED DIETARY FISH SUPPLEMENT: Seven children (between the ages of 0.7 and 4.2 years) developed vitamin D intoxication after being given a fish oil supplement that contained a high level of vitamin D3 due to a manufacturing error. The supplement was analyzed and found to contain 3.6 mg (144,000 International Units) per gram of fish oil (each 5 mL of fish oil was calculated to contain approximately 20 mg (800,000 International Units) of vitamin D3). The estimated daily doses that these children received varied between 266,000 and 800,000 International Units or 177 to 320 times the recommended tolerable upper limits for infants and children. Each child recovered with supportive care (Kara et al, 2014).
SOLADEK is a prescription vitamin supplement (each 5 mL contains 120,000 International Units of vitamin A, 600,000 International Units of vitamin D and 5 mg of vitamin E) sold in the Dominican Republic, but it can be found in United States as an over-the-counter supplement without dosing instructions in some independent grocery stores. It purportedly is used to control pain, prevent colds and viruses, and enhances general conditioning and muscle strength. It has also been used as a performance-enhancing drug by athletes. An adult female developed symptomatic vitamin D toxicity following use, but recovered with supportive care (Leu et al, 2008).

-CLINICAL EFFECTS

GENERAL CLINICAL EFFECTS

USES: Vitamin D (represents D2 {ergocalciferol} or D3 {cholecalciferol} is a fat soluble vitamin. It is used for the prevention and treatment of rickets, osteomalacia, and osteoporosis, and the treatment of hypoparathyroidism. More recently, evidence suggests that it may also have a role in the prevention of cardiovascular disease, and colon, prostate, and breast cancers. Vitamin D is found in many dietary supplements (multivitamins, combined with calcium) or as a single dietary supplement, and also commonly found in fortified foods (ie, milk, cereal, and bread).

PHARMACOLOGY: Vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by vitamin D-25-hydroxylase. It regulates calcium homeostasis via interactions with the intestines and bones. Vitamin D is thought to act as a hormone, because it is synthesized in the body, circulates in the blood, and binds to receptors in order to evoke its biologic action. It promotes calcium absorption in the gut and aids adequate serum calcium and phosphate concentrations.

EPIDEMIOLOGY: Overdose is rare. Toxicity is mild after acute overdose, but more severe toxicity occasionally develops after chronic ingestion of large amounts. In some cases, exposure has occurred due to excessive fortification of foods or overuse of supplements.

TOXICOLOGY: Hypercalcemia is characteristic of vitamin D toxicity.

WITH POISONING/EXPOSURE

MILD TO MODERATE TOXICITY: Nausea, vomiting and abdominal cramps are likely to occur with an acute ingestion. Other symptoms include: anorexia, constipation or diarrhea, weakness, fatigue, irritability, drowsiness, headache and dizziness.
SEVERE TOXICITY: Generally, only seen after chronic ingestion of large amounts of vitamin D. Seizures, confusion, ataxia, psychotic disturbances, coma, or renal failure can occur. Cardiac dysrhythmias can develop. Polyuria and polydipsia may be present.

WITH THERAPEUTIC USE

Adverse events are not typically reported with normal use.

POTENTIAL HEALTH HAZARDS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin.
Avoid any skin contact.
Effects of contact or inhalation may be delayed.
Fire may produce irritating, corrosive and/or toxic gases.
Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution.

ACUTE CLINICAL EFFECTS

SUMMARY

USES: Vitamin D (represents D2 {ergocalciferol} or D3 {cholecalciferol} is a fat soluble vitamin. It is used for the prevention and treatment of rickets, osteomalacia, and osteoporosis, and the treatment of hypoparathyroidism. More recently, evidence suggests that it may also have a role in the prevention of cardiovascular disease, and colon, prostate, and breast cancers. Vitamin D is found in many dietary supplements (multivitamins, combined with calcium) or as a single dietary supplement and also commonly found in fortified foods (ie, milk, cereal, and bread).
PHARMACOLOGY: Vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by vitamin D-25-hydroxylase. It regulates calcium homeostasis via interactions with the intestines and bones. Vitamin D is thought to act as a hormone, because it is synthesized in the body, circulates in the blood, and binds to receptors in order to evoke its biologic action. It promotes calcium absorption in the gut and aids adequate serum calcium and phosphate concentrations.
EPIDEMIOLOGY: Overdose is rare. Toxicity is mild after acute overdose, but more severe toxicity occasionally develops after chronic ingestion of large amounts. In some cases, exposure has occurred due to excessive fortification of foods or overuse of supplements.
TOXICOLOGY: Hypercalcemia is characteristic of vitamin D toxicity.

THERAPEUTIC

ADVERSE EFFECTS: Adverse events are not typically reported with normal use.

EXPOSURE

MILD TO MODERATE TOXICITY: Nausea, vomiting and abdominal cramps are likely to occur with an acute ingestion. Other symptoms include: anorexia, constipation or diarrhea, weakness, fatigue, irritability, drowsiness, headache and dizziness.
SEVERE TOXICITY: Generally, only seen after chronic ingestion of large amounts of vitamin D. Seizures, confusion, ataxia, psychotic disturbances, coma, or renal failure can occur. Cardiac dysrhythmias can develop. Polyuria and polydipsia may be present.

CARDIOVASCULAR

CARDIAC DYSRHYTHMIAS: ECG changes may include shortening of the QT interval in patients with hypercalcemia secondary to vitamin D intoxication (Nordt et al, 2002). Premature beats were seen on ECG in a 3-month-old infant with hypercalcemia following vitamin D intoxication (Ezgu et al, 2004).
HYPERTENSION: There have been reports of hypertension as a result of vitamin D intoxication (Barrueto et al, 2005; Gurkan et al, 2004).
MYOCARDIAL INFARCTION: In one study, the average daily intake of vitamin D was higher for patients with myocardial infarction (31.28 mcg/d) than for matched controls (Linden, 1974).
ARTERIAL LESION: Degeneration of smooth muscle cells and coronary arterial abnormalities have been seen with chronic Vitamin D excess (Chesney, 1989).
HYPERCHOLESTEROLEMIA: An 11-month-old infant developed severe hypercalcemia (serum calcium 5.5 mmol/L [22 mg/dL]) and hyperlipidemia (total cholesterol 246 mg/dL, HDL-C 30 mg/dL, VLDL 54 mg/dL, LDL-C 162 mg/dL, triglyceride 271 mg/dL) after receiving bolus vitamin D at a dose of 600,000 International Units in 2 doses, 15 days apart (Evliyaoglu et al, 2001).

ENDOCRINE

INSULIN RESISTANCE: Vitamin D replacement in well-controlled non-insulin-dependent diabetic patients may result in an increase in insulin resistance and a deterioration of glycemic control (Taylor & Wise, 1998).

FLUID ELECTROLYTE

HYPERCALCEMIA: Hypercalcemia is frequently reported following chronic ingestion of excessive doses or following chronic occupational exposure (Araki et al, 2011; Jacobsen et al, 2011; Titan et al, 2009; Hatun & Cizmecioglu, 2005). It has been reported to persist for up to 14 months after discontinuing vitamin D2 (Taylor, 1972), and this may be attributed to the long-term storage of Vitamin D in adipose tissue and muscle (Jibani & Hodges, 1985; Keddie, 1987).

GASTROINTESTINAL

Gastrointestinal symptoms could include anorexia, nausea, vomiting, abdominal pain, constipation and/or diarrhea (Barrueto et al, 2005; Gurkan et al, 2004; Ezgu et al, 2004).

GENITOURINARY

RENAL INJURY: Chronic toxicity can present with metastatic calcification with renal tubular injury, resulting in albuminuria, nocturia, polydipsia, and polyuria (Paunier et al, 1968). In 12 of 27 episodes of chronic vitamin D poisoning, renal impairment was present. Persisting impairment was noted on follow-up in 3 of 9 patients evaluated (Paterson, 1980).
ACUTE RENAL FAILURE: A 22-year-old male athlete developed hypercalcemia and acute renal failure associated with hypercalcemia after starting a conditioning program and injecting himself with anabolic hormones and intramuscular injections of vitamins A, D, and E. Renal function eventually normalized after treatment with saline hydration, diuretics, and eventual pamidronate (Titan et al, 2009).
NEPHRITIS: Abnormal renal histology (tubulo-interstitial nephritis or calcium deposits) was observed in 14 of 22 patients on chronic vitamin D therapy (Curtis, 1982).
POLYURIA: Symptoms of vitamin D intoxication in infants include polyuria, polydipsia, feeding difficulties, irritability, lassitude, and poor weight gain (Araki et al, 2011; Gurkan et al, 2004).
HYPERCALCIURIA: Calciuria (33.8 and 23 mg/kg/day) was reported in 2 infants after receiving 1 mL of a multivitamin product twice daily and 1 mL of a vitamin D solution for 17 days (total dose approximately 1.5 million units per child) (Pundzien et al, 2001). Another case was reported in a 73-year-old man who had a history of chronic plaque psoriasis and developed hypercalcemia and hypercalciuria after topical application of excessive amounts of calcipotriol ointment (Georgiou & Tsambaos, 1999).

HEENT

CONJUNCTIVITIS: A 7-month-old infant developed conjunctivitis associated with chronic over-supplementation of cholecalciferol (Lukaszkiewicz et al, 1987).
ANIMAL STUDIES: Excessive vitamin D in experimental animals has produced band keratopathy, elevated lens calcium, and inhibited human retinoblastoma growth (Grant, 1986; HSDB, 2001).

HEMATOLOGIC

ANEMIA: Normocytic normochromic anemia has been described in patients with chronic vitamin D toxicity, presumably due to hypercalcemia-induced kidney or bone marrow damage (Gabriel et al, 1970) (Keddie, 1987).

HEPATIC

HEPATOMEGALY: A 7-month-old infant had moderate hepatomegaly associated with chronic over-supplementation of cholecalciferol (Lukaszkiewicz et al, 1987).

MUSCULOSKELETAL

JOINT CALCINOSIS: Widespread joint, periarticular, and nephro-calcinosis were described in a 67-year-old woman who had taken several tablespoonfuls of cod liver oil daily for 18 months. The total daily vitamin intake was estimated to be greater than 5500 International Units (Butler et al, 1985).
BONE FRACTURE: Excessive vitamin D intake can cause demineralization of bone resulting in multiple fractures from very slight trauma (Ginsburg, 2011; HSDB, 2001).

NEUROLOGIC

Toxicity symptoms are similar to those seen from hypercalcemia and can include confusion, fatigue, lethargy, headache, drowsiness, sluggishness, and weakness (Gurkan et al, 2004; Pundzien et al, 2001).
NEUROPATHY: Acute polyneuropathy with marked weakness and sensory loss was reported in a 24-year-old woman after acute vitamin D3 intoxication (Down et al, 1979).
SEIZURE: A single seizure was reported in a 52-year-old woman who presented to the ED after inadvertently taking 50,000 International Units of vitamin D 3 times a day for 7 days instead of the same dose 3 times weekly. The patient was hydrated, given IV furosemide and released 3 days later with no further seizure activity noted (Nordt et al, 2002).

PSYCHIATRIC

DEPRESSION: Extreme depression was associated with chronic vitamin D toxicity in a 58-year-old woman who had taken calciferol 1.25 mg/day for 15 years, along with 1.8 g/day calcium gluconate. Serum calcium normalized 9 weeks after discontinuation while depression improved within 3 weeks (Keddie, 1987).
FATIGUE: Apathy, confusion, and fatigue have been reported following Vitamin D intoxication (Paterson, 1980; Lee et al, 1999).

VITAL SIGNS

HYPERTENSION: Hypertension has been reported following elevated doses of vitamin D supplementation (Barrueto et al, 2005; Gurkan et al, 2004).

CHRONIC CLINICAL EFFECTS

Because vitamin D is stored in the body fat and liver, it can have CUMULATIVE TOXICITY from repeated excess intake. Chronic ingestion of more than 1600 IU (40 mcg) per day can cause toxicity. One case of hepatomegaly (increased liver size) has been reported (Lukaszkiewicz et al, 1987).

Because its mechanism of action involves transporting calcium, excess vitamin D causes hypercalcemia (excess plasma calcium). Many of the effects of chronic vitamin D toxicity are due to induced hypercalcemia. Hypercalcemia has been reported from chronic occupational exposure to vitamin D (Jibani & Hodges, 1985).

Hypercalcemia can persist for up to 14 months after discontinuation of exposure (Taylor, 1972). The excess serum calcium can arise either from increased absorption of exogenous calcium from the gastrointestinal tract, decreased excretion of calcium, or in cases of calcium deficiency, by resorption of calcium from bone (HSDB , 1996).

Kidney damage ensues due to calcification. Hypertension is a secondary consequence of kidney damage (Paunier et al, 1968; Paterson, 1980). Anemia can also ensue from hypercalcemia-induced kidney or bone marrow damage (Gabriel et al, 1980; Keddie, 1987).

Calcification can also occur in the cornea and conjunctiva (Lukaszkiewicz et al, 1987), and in the joints (Butler et al, 1985).

Chronic intake of excess vitamin D may induce cardiac arrhythmias from hypercalcemia. In a rare complication of vitamin D3 overdose, a man who had received 130 mg over 4 weeks developed an acute hypercalcemic crisis after extensive exposure to sunlight, and died 5 weeks later of cardiac failure (Laubenthal et al, 1975).

Risk of myocardial infarction (heart attack) may be increased. In one study, victims of myocardial infarction had higher daily intakes of vitamin D than a matched control group (Linden, 1974). However, a prospective study did not confirm an increased risk of myocardial infarction related to vitamin D (Hayes & Laws, 1991).

Levels of intake of vitamin D 80 to 100 times the recommended dietary intake can cause demineralization of the bones and greatly increased tendency of the bones to fracture (HSDB , 1996).

Severe mental depression has been reported in one case of chronic vitamin D toxicity; it improved within 3 weeks after administration ceased (Keddie, 1987).

Chronic excess doses of vitamin D have caused calcification of blood vessels and soft tissues in experimental animals (HSDB , 1996).

Normal levels of vitamin D may be beneficial to the cardiovascular system. Serum levels of 1,25-dihydroxyvitamin D-3, the active metabolite, were inversely related to blood pressure in a cross-sectional study of 34 middle-aged men (Lind et al, 1995).

Serum levels of vitamin D were shown to decline during the winter months in a study on 824 elderly Europeans; 36% of the men and 47% of the women had concentrations of 25-hydroxyvitamin D below 30 nmol/L (Vanderwielen et al, 1995).

Women with premenopausal osteoporosis generally have low serum levels of 1,25-dihydroxyvitamin D (calcitriol), along with some degree of calcium malabsorption. Patients treated with calcitriol (0.25 mcg BID) have normal calcium absorption and reduced numbers of fractures (Gallagher, 1996).

1-Alphahydroxyvitamin-D2 has been shown in animal studies to be at least as effective as 1 alpha-D3 in preventing bone loss, but does not induce hypercalciuria to as great an extent. Preliminary studies in osteoporotic women have indicated minimal hypercalciuria with doses of 1 alpha-D-3 up to 4 mcg/day. It is also effective in suppressing parathyroid hormone levels with minimal undesirable effects in renal dialysis patients (Coburn et al, 1996).

-FIRST AID

FIRST AID AND PREHOSPITAL TREATMENT

SUMMARY

Gastric decontamination is rarely necessary with an acute ingestion unless extremely large amounts have been ingested (more than 100 times the RDA) (Brin M, 1976). This is equivalent to 100 multiple vitamin tablets or 17 pellets of rodenticide bait.

ACTIVATED CHARCOAL

PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

CHARCOAL DOSE

Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

ADVERSE EFFECTS/CONTRAINDICATIONS

Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

-MEDICAL TREATMENT

LIFE SUPPORT

Support respiratory and cardiovascular function.

SUMMARY

FIRST AID - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Move victim to fresh air.
Call 911 or emergency medical service.
Give artificial respiration if victim is not breathing.
Do not use mouth-to-mouth method if victim ingested or inhaled the substance;give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device.
Administer oxygen if breathing is difficult.
Remove and isolate contaminated clothing and shoes.
In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes.
For minor skin contact, avoid spreading material on unaffected skin.
Keep victim warm and quiet.
Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed.
Ensure that medical personnel are aware of the material(s) involved and take precautions to protect themselves.

-RANGE OF TOXICITY

MINIMUM LETHAL EXPOSURE

ADULT

CASE REPORT: A 43-year-old man receiving 130 mg of vitamin D3 over 4 weeks (5.2 million units) (approximately 185,000 units/day) was exposed extensively to sunlight 2 weeks later and developed an acute hypercalcemic crisis. He died 5 weeks later of cardiac failure (Laubenthal et al, 1975).

ANIMAL DATA/DOGS

Lethal dose of vitamin D2 in dogs is said to be 13 mg/kg (530,000 International Units/kg) (HSDB, 2001).
Acute ingestion of as little as 10 mg/kg (400,000 International Units/kg) (1000 times the human RDA/kg) of vitamin D3 was lethal in dogs (Gunther et al, 1988).
In experimental studies in dogs, the minimum lethal dose given as a single large dose was 4 to 5 mg/kg orally, 5 mg/kg intramuscularly, 5 mg/kg intravenously, and 10 mg/kg intraperitoneally (Schettler, 1950).

MAXIMUM TOLERATED EXPOSURE

SUMMARY

A specific toxic dose has not been established and the literature varies widely. The current "no observed adverse effect level" or tolerable upper intake dose was conservatively set at 2000 International Units/day. Toxicity has been reported after Vitamin D intake of 50,000 to 150,000 International Units daily for prolonged periods (Ginsburg, 2011).
CLINICAL PRACTICE GUIDELINES: Doses of 1000 to 2000 International Units of vitamin D3 daily have been recommended by the Endocrine Society to raise a low 25-hydroxyvitamin D level to at least 30 ng/mL (Holick et al,null). However, other clinicians do not support prescribing vitamin D supplementation beyond the recommended daily needs to prevent cardiovascular disease or improve overall health. The Institute of Medicine currently supports a daily intake of 600 International Units/day for individuals 1 to 70 years of age and 800 International Units/day for individuals older than 70 years (Shapses & Manson, 2011; O'Keefe et al, 2011).
TOLERABLE UPPER INTAKE LEVELS: PEDIATRIC: 0 to 6 months: 1000 International Units/day; 7 to 12 months: 1500 International Units/day; 1 to 3 years of age: 2500 International Units/day; 4 to 8 years of age: 3000 International Units/day; ADULT: Greater or equal to 9 years of age: 4000 International Units/day (Office of Dietary Supplements, National Institutes of Health, 2011).
Individual variation may occur. However, based on reports of vitamin D toxicity evidence suggests that hypercalcemia occurs at serum 25-hydroxyvitamin D [25(OH)D] concentrations over 200 nmol/L, this would equate to an estimated daily intake of equal to or greater than 1000 mcg (40,000 International Units) (Vieth, 1999).
The following information is for vitamin D in general (Brin M, 1976):

Chronic ingestion of vitamin D in excess of 1600 units may cause toxicity.
Daily ingestion in excess of 75,000 units/day in adults will produce the toxic symptoms associated with hypervitaminosis D.
Decreased renal function may prevent excretion thereby resulting in elevated serum levels and enhance the possibility of toxicity.

INFANT: Daily ingestion of 2000 to 6300 units/day may inhibit the growth of a normal child, while as little as 1000 units/day can produce the infantile hypercalcemia syndrome in hypersensitive infants (Brin M, 1976).

CASE REPORTS

ADULT

A 42-year-old man presented with a serum 25-hydroxyvitamin D concentration of 487.3 ng/mL (normal range: 8.9 to 46.7) and hypercalcemia (15.0 mg/dL) following chronic use of a vitamin D3 supplement. Three different lot numbers of the supplement were analyzed by HPLC and found to have a much higher concentration of vitamin D3 than listed by the manufacturer. The patient had been receiving 156,000 to 2,604,000 International Units of vitamin D3 daily (78 to 1302 times the recommended safe upper limit of 2000 International Units/day) (Koutkia et al, 2001).
A 70-year-old woman ingested 50,000 International Units of Vitamin D2 daily for 78 days due to a dispensing error and developed hypercalcemia and acute renal injury. She was admitted with confusion, slurred speech and gait disturbances. An initial 25-hydroxyvitamin D level was 194 ng/mL. Treatment included IV hydration and pamidronate. The patient improved within 4 days and was discharged to home (Jacobsen et al, 2011).
A 58-year-old man was admitted obtunded with a serum calcium of 15 mg/dL after ingesting a dietary supplement for approximately 2 months that contained 186,400 International Units (instead of 1600 IU) per capsule of vitamin D3 and the bottle was mislabelled to suggest a recommended dose of 10 capsules/day (estimated dose consumed was 1,864,000 International Units (46,600 mcg) of vitamin D3 daily for 2 months). At presentation, the patient had a 25 hydroxyvitamin D (25(OH)D) level of 1220 ng/mL (normal: 30 to 80 ng/mL). His calcium level decreased with supportive care and eventually normalized once the 25(OH)D level fell below 400 ng/mL. The 25(OH)D level did not normalize completely until 13 months after exposure. No permanent sequelae occurred (Araki et al, 2011).
In a similar case, a 40 year-old-man became hypercalcemic after ingesting a dietary supplement that contained 970,000 International Units (approximately 1000 times more than the label reported) of vitamin D3. The patient was treated with IV hydration and calcium levels normalized over one month once the 25(OH)D level fell below 400 ng/mL. It took approximately 10 months for the 25(OH)D level to normalize (Araki et al, 2011).
A 53-year-old man with a history of diabetes and non-dialysis chronic renal failure developed hypercalcemia and acute renal failure associated with a compounding error resulting in vitamin D intoxication. Symptoms included pruritus, muscle weakness, decreased appetite and weight loss. Laboratory studies revealed an elevated calcium (13.4 mg/dL, range 8.4 to 10.4) and creatinine (4.67 mg/dL, range 0.6 to 1.2). An ultrasound showed a renal calculi and the patient underwent ureterolithotripsy. Despite supportive therapy and ruling out other conditions, hypercalcemia persisted. An initial vitamin D (25 hydroxyvitamin D (25(OH)D) level was 226 ng/mL (range, 30 to 100). Upon analysis the capsules were found to contain 4,000,000 International Units instead of 2,000 International Units; an estimated 40-fold higher dose than recommended (Marins et al, 2014).
LACK OF EFFECT

ADULT: A 42-year-old woman with vitamin D deficiency (serum 25-hydroxyvitamin D 12.5 ng/mL) developed a high serum Vitamin D level (serum 25-hydroxyvitamin D level of 746 ng/mL) following an inadvertent medication error (ie, took 60,000 IU of vitamin D3 once weekly for 4 months instead of 6 weeks); however, she developed no symptoms and her serum calcium level remained normal. Magnesium and phosphate levels also remained normal (Chakraborty et al, 2015).
ELDERLY PATIENTS: Two elderly patients (a 90-year-old man and a 95-year-old woman) inadvertently received 2,000,000 International Units of vitamin D3 from a concentrated solution (40 mL vitamin D3 aquosum FNA 50,000 International Units/mL) instead of a single dose of 100,000 International Units (or 2 mL vitamin D3). The error was noted a short time after ingestion and biochemical and clinical monitoring was started. Peak blood 25(OH) D3 concentrations (527 and 422 nmol/L, respectively; normal, 50 to 200 nmol/L) occurred on day 8. Calcium levels increased only slightly up to 2.68 and 2.73 mmol/L, respectively (normal, 2.2 to 2.65 mmol/L) in both patients. The patients were monitored for up to 3 months after exposure and neither patient developed any clinical effects (van den Ouweland et al, 2014).

PEDIATRIC

LACK OF EFFECT: A 3-month-old breastfed infant was receiving vitamin D supplements and inadvertently received a 30-fold (12,000 International Units daily) overdose of vitamin D for approximately 20 days after receiving a new formulation. The original formulation was 400 International Units/mL and the new formulation was 400 International Units/drop (1 mL contains 30 drops and the mother had continued to administer 1 mL/day with the new formulation). At the time of presentation, the infant was alert and doing well. Physical exam was essentially normal. Serum 25-hydroxyvitamin D [25(OH)D] was 422 ng/mL (reference range: 30 to 100 ng/mL); 1-25-dihydroxyvitamin D was normal and the parathyroid hormone was decreased (less than 3 pg/mL; range: 15 to 65 pg/mL). Laboratory testing of the product was consistent with the concentration listed on the bottle (approximately 400 International Units/drop). Infant and maternal vitamin D supplementation were stopped. The infant was closely monitored for the next 6 months and laboratory levels gradually declined with no increase in calcium or phosphorus concentrations (Rajakumar et al, 2013).
In a similar case, a healthy 2-month-old female had received 12,000 International Units/day of vitamin D (approximately 30 times the intended daily dose) for approximately 1 month. She was admitted due to a recent history of poor feeding and decreased activity. The only findings on physical exam were a slight decrease in muscle tone and a decreased sucking reflex. Her 25-hydroxyvitamin D level was measured at 750 ng/mL (normal, 25 to 80 ng/mL) and her parathyroid hormone (PTH) level was less than 3 pg/mL (consistent with expected PTH suppression). The patient was admitted and treated with normal saline, calcitonin, pamidronate and methylprednisolone and her calcium levels gradually declined from an initial level on admission of 19.1 mg/dL (normal, 8.8 to 11.3 mg/dL) to 9.6 mg/dL. She was discharged to home one week after admission in her normal state of health (Smollin & Srisansanee, 2014).
ADULTERATED DIETARY FISH SUPPLEMENT: Seven children (between the ages of 0.7 and 4.2 years) developed vitamin D intoxication after being given a fish oil supplement that contained a high level of vitamin D3 due to a manufacturing error. The supplement was analyzed and found to contain 3.6 mg (144,000 International Units) per gram of fish oil (each 5 mL of fish oil was calculated to contain approximately 20 mg (800,000 International Units) of vitamin D3). The estimated daily doses that these children received varied between 266,000 and 800,000 International Units or 177 to 320 times the recommended tolerable upper limits for infants and children. Each child recovered with IV hydration, furosemide and pamidronate infusions. Two patients initially developed evidence of nephrocalcinosis; however repeat imaging at 6 and 12 months were normal. At 1-year follow-up, no permanent sequelae occurred in any child (Kara et al, 2014).
A 2-year-old boy developed constipation, mild hypertension, abdominal pain and hypercalcemia after receiving 600,000 International Units of vitamin D daily for 4 days. He recovered with supportive care (Barrueto et al, 2005).
Severe vitamin D overdose, with sluggishness, drowsiness, hypotonia, constipation, decreasing weight, polyuria (6-11 mL/kg/h) and calciuria (33.8 and 23 mg/kg/d) was reported in two 6-month-old twins after their mother gave them 1 mL of a multivitamin product twice daily and 1 mL of a vitamin D solution for 17 days (total dose approximately 1.5 million units per child). In both infants, ultrasonography revealed nephrocalcinosis. On admission, the following total calcium, ionized calcium and phosphate levels were obtained, respectively: 3.8 and 3.9 mmol/L, 1.7 and 1.8 mmol/L, phosphate 0.8 and 1.5 mmol/L; parathyroid hormone levels were less than 0.1 pmol/L (Pundzien et al, 2001).
A 6-month-old developed anorexia, vomiting, polydipsia, polyuria, constipation, lethargy, hypertension, and hypercalcemia after receiving 300,000 International Units of vitamin D orally daily for 10 days (Gurkan et al, 2004).

TOXICITY AND RISK ASSESSMENT VALUES

TOXICITY VALUES

References: Lewis, 1992 RTECS, 1994)
- LD50- (ORAL)MOUSE:
- LD50- (ORAL)RAT:
- LDLo- (ORAL)CAT:
- LDLo- (INTRAMUSCULAR)DOG:
- LDLo- (INTRAPERITONEAL)DOG:
- LDLo- (INTRAVENOUS)DOG:
- LDLo- (ORAL)DOG:
- LDLo- (ORAL)GUINEA_PIG:
- TDLo- (ORAL)HUMAN:
- TDLo- (INTRAMUSCULAR)RABBIT:
- TDLo- (ORAL)RAT:

-STANDARDS AND LABELS

SHIPPING REGULATIONS

SURFACE

DOT -- Table of Hazardous Materials and Special Provisions (49 CFR 172.101, 2005):

Not Listed

ICAO International Shipping Name (ICAO, 2002):

Not Listed

-HANDLING AND STORAGE

STORAGE

ROOM/CABINET RECOMMENDATIONS

The following information is for vitamin D in general (HSDB, 1993):
- Vitamin D shows signs of decomposition when stored for a few days at room temperature. Storage with inert gas improves stability.

-PERSONAL PROTECTION

SUMMARY

RECOMMENDED PROTECTIVE CLOTHING - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Wear positive pressure self-contained breathing apparatus (SCBA).
Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection.
Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations where direct contact with the substance is possible.

RESPIRATORY PROTECTION

Refer to "Recommendations for respirator selection" in the NIOSH Pocket Guide to Chemical Hazards on TOMES Plus(R) for respirator information.

-PHYSICAL HAZARDS

FIRE HAZARD

SUMMARY

Editor's Note: This material is not listed in the Emergency Response Guidebook. Based on the material's physical and chemical properties, toxicity, or chemical group, a guide has been assigned. For additional technical information, contact one of the emergency response telephone numbers listed under Public Safety Measures.
POTENTIAL FIRE OR EXPLOSION HAZARDS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes.
- Containers may explode when heated.
- Runoff may pollute waterways.

FIRE CONTROL/EXTINGUISHING AGENTS

SMALL FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Dry chemical, CO2 or water spray.
LARGE FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Water spray, fog or regular foam.
- Move containers from fire area if you can do it without risk.
- Dike fire control water for later disposal; do not scatter the material.
- Use water spray or fog; do not use straight streams.
TANK OR CAR/TRAILER LOAD FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Fight fire from maximum distance or use unmanned hose holders or monitor nozzles.
- Do not get water inside containers.
- Cool containers with flooding quantities of water until well after fire is out.
- Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank.
- ALWAYS stay away from tanks engulfed in fire.
- For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn.

COMBUSTION TOXICITY

When heated to decomposition, vitamin D2 emits acrid smoke and irritating fumes (Lewis, 1992).

DUST/VAPOR HAZARD

When heated to decomposition, vitamin D2 emits acrid smoke and irritating fumes (Lewis, 1992).

REACTIVITY HAZARD

When heated to decomposition, vitamin D2 emits acrid smoke and irritating fumes (Lewis, 1992).

EVACUATION PROCEDURES

SUMMARY

Editor's Note: This material is not listed in the Table of Initial Isolation and Protective Action Distances.
SPILL - PUBLIC SAFETY EVACUATION DISTANCES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Increase, in the downwind direction, as necessary, the isolation distance of at least 25 to 50 meters (80 to 160 feet) in all directions.
FIRE - PUBLIC SAFETY EVACUATION DISTANCES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions.
PUBLIC SAFETY MEASURES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- CALL Emergency Response Telephone Number on Shipping Paper first. If Shipping Paper not available or no answer, refer to appropriate telephone number:
- For additional details see the section entitled "WHO TO CALL FOR ASSISTANCE" under the ERG Instructions.
- As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.
- Keep unauthorized personnel away.
- Stay upwind.
- Keep out of low areas.

CONTAINMENT/WASTE TREATMENT OPTIONS

SUMMARY

SPILL OR LEAK PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Do not touch damaged containers or spilled material unless wearing appropriate protective clothing.
- Stop leak if you can do it without risk.
- Prevent entry into waterways, sewers, basements or confined areas.
- Cover with plastic sheet to prevent spreading.
- Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers.
- DO NOT GET WATER INSIDE CONTAINERS.
RECOMMENDED PROTECTIVE CLOTHING - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Wear positive pressure self-contained breathing apparatus (SCBA).
- Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection.
- Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations where direct contact with the substance is possible.
At the time of this review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices (HSDB, 1993).

-ENVIRONMENTAL HAZARD MANAGEMENT

POLLUTION HAZARD

No information found at the time of this review.

ABIOTIC DEGRADATION

No information found at the time of this review.

ENVIRONMENTAL TOXICITY

No information found at the time of this review.

-PHYSICAL/CHEMICAL PROPERTIES

MOLECULAR WEIGHT

CALCIFEDIOL: 418.65 (Prod Info RAYALDEE(R) oral extended-release capsules, 2016)

VITAMIN D2: 396.63 (Budavari, 1989)

DESCRIPTION/PHYSICAL STATE

CALCIFEDIOL: White crystalline powder; soluble in alcohol and fatty oils; and practically insoluble in water (Prod Info RAYALDEE(R) oral extended-release capsules, 2016)

VITAMIN D2: White, odorless crystals (Lewis, 1993); prisms from acetone, melting point 115 to 118 degrees C (Budavari, 1989); soluble in the usual organic solvents (Budavari, 1989); soluble in alcohol, chloroform, ether, and fatty oils (Lewis, 1993); slightly soluble in vegetable oils (Budavari, 1989); insoluble in water (Budavari, 1989)

FREEZING/MELTING POINT

MELTING POINT

Vitamin D2: 115 to 118 degrees C (Budavari, 1989)

SOLUBILITY

IN WATER

Vitamin D2 is insoluble in water (Budavari, 1989).

IN ORGANIC SOLVENTS

Vitamin D2 is soluble in the usual organic solvents (Budavari, 1989).
Vitamin D2 is soluble in alcohol, chloroform, and ether (Lewis, 1993).
Vitamin D2: 1 mL acetone dissolves 0.0695 g (7 degrees C) (Budavari, 1989)

OTHER

Vitamin D2 is slightly soluble in vegetable oils (Budavari, 1989).
Vitamin D2 is soluble in fatty oils (Lewis, 1993).

OTHER/PHYSICAL

INDEX OF REFRACTION

VITAMIN D2: 1.5101 (25 degrees C/D) (HSDB , 1993)

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VITAMIN D

Classification | Information to evaluate chemical incidents

Information to evaluate chemical incidents

Information to evaluate chemical incidents

Information to evaluate chemical incidents