Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 68-26-8 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • All-trans retinol
  • VITAMIN A

Human Toxicity Excerpts

  • HUMAN EXPOSURE STUDIES: The tolerance to two alternative large dosage strengths of vitamin A preparation was determined in a double blind study involving 2471 children in two municipalities in the Philippines. Each child, aged 1-6 yr, not suffering from active zerophthalmia or from nausea and/or vomiting, headache, diarrhea, and fever, was randomly given 1 ml of a syrupy suspension later identified to contain, 0, 30, or 60 mg vitaminA. Clinical evaluation of subjects was done by physicians 24 hr and 1 wk after dosing. Nausea and/or vomiting and headache were twice as common among children given 60 mg than those given 30 mg. Severe vomiting (1.2%) was confined to those given 60 mg. Almost all experienced their symptoms within 24 hr after dosing; symptoms lasted for no more than 12-24 hr. The incidence of diarrhea and fever for vitamin A recipients was not significantly different from that of those receiving placebo. [Florentino RF et al; Am J Clin Nutr 52 (4): 694-700 (1990) ]**PEER REVIEWED**
  • HUMAN EXPOSURE STUDIES: Studies of hypervitaminosis A in animals and anecdotal reports of accidental vitamin A poisoning in humans suggest impairment of bone remodeling and increased numbers of fractures. Because of the widespread use of high dose vitamin A supplements which may produce subclinical hypervitaminosis associated with decreased bone mass and increased risk of fracture, the relationship between current vitamin A supplement use, serum retinol levels, radial bone mass and fracture history was studied in a geographically defined population of 246 postmenopausal women, 55-80 years of age. More than 36% of this population used a vitamin A supplement with 8% of these consuming an amount in excess of 2000 retinol equivalents/day. Serum retinol was measured using high pressure liquid chromatography and radial bone mass was measured using single photon absorptiometry. After controlling for age, current estrogen replacement, and current thiazide antihypertensive use, no statistically significant relationship between vitamin A supplement use or serum retinol with radial bone mass or fractures was observed. [Sowers MF, Wallace RB; J Clin Epidemiol 43 (7): 693-9 (1990) ]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Early signs and symptoms of chronic vitamin A intoxication include irritability, vomiting, loss of appetite, headache, dry and pruritic skin, skin desquamation, and erythematous dermatitis. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1778]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In addition to hepatosplenomegaly, pathological changes /after chronic vitamin A intoxication/ in the liver include hypertrophy of fat-storing cells, fibrosis, sclerosis of central veins, and cirrhosis, with resultant portal hypertension and ascites. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1779]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: /In cases of vitamin A intoxication/ the activity of alkaline phosphatase in plasma rises because of the increased osteoblastic activity, and a number of cases of hypercalcemia have been reported; a number of cases of hypercalcemia have been reported in children. Elevations in plasma triglycerides and reductions in the cholesterol of high-density lipoproteins also are observed. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1779]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: In children and adults chronic hypervitaminosis A may cause dryness of the skin and mucous membrane, alopecia, anorexia, brittle nails, myalgia, ostealgia, arthralgia, abdominal pain, splenomegaly, and hypoplastic anemia with leukopenia. [American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991., p. 1872]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Signs and symptoms of Chronic Vitamin A Toxicity: Children: Alopecia, anorexia, bone pain and tenderness, bulging of fontanelles, craniotabes, fissuring at lip corners, hepatomegaly, hyperostosis, premature epiphyseal closure, photophobia, pruritis, pseudotumor cerebri, skin desquamation, skin erythema. Adults: Alopecia, anemia, anorexia, ataxia, bone pain, bone abnormalities, brittle nails, cheilitis, conjunctivitis, diarrhea, diplopia, dryness of mucous membranes, dysuria, edema, elevated CSF pressure, epistaxis, exanthema, facial dermatitis, fatigue, fever, headache, hepatomegaly, hepatotoxicity, hyperostosis, insomnia, irritability, menstrual abnormalities, muscular stiffness and pain, nausea, negative nitrogen balance, nervous abnormalities, papilledema, petechiae, polydypsia, pruritis, pseudotumor cerebri, skin desquamation, skin erythema, skin rash, skin scaliness, splenomegaly, vomiting, weight loss. [Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 1021]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: Early manifestations of hypervitaminosis A include fatigue, malaise, lethargy, irritability, psychiatric changes mimicking severe depression or schizophrenic disorder, anorexia, abdominal discomfort, nausea and vomiting, mild fever, and excessive sweating. Children may fail to gain weight normally, and adults may lose weight. Slow growth, premature epiphyseal closure, painful hyperostosis of the long bones, arthralgia, myalgia, hypercalcemia, and hypercalciuria have been reported. CNS signs and symptoms also include increased intracranial pressure, bulging fontanelles in infants, headache, papilledema, exophthalmos, vertigo, and visual disturbances. Dryness and cracking of the skin and lips, scaling, pruritus, brittle nails, alopecia, erythema, hyperpigmentation, and massive desquamation may also occur. Hypomenorrhea, hepatosplenomegaly, cirrhosis, jaundice, elevated serum AST (SGOT) and ALT (SGPT) concentrations, urinary complaints, anemia, leukopenia, leukocytosis, and thrombocytopenia hae also been reported. Increased plasma concentrations of vitamin A usually occur but do not necessarily correlate with the severity of toxicity. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 3491]**PEER REVIEWED**
  • CASE REPORTS: A 10 month old girl with a 2 week history of increasing orange discoloration of the skin, most marked on the palms and soles, exhibited a hypercarotenemia and no other abnormalities after eating a readily available commercially prepared baby food in normal quantities. This baby food, which formed the main staple of her diet, was prepared from carrots and contained added vitamin A. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 550]**PEER REVIEWED**
  • CASE REPORTS: A 28 year old woman ingested 1.3 million units of vitamin A as a remedy for sunburn. She experienced nausea, vomiting, intense headache, and blurring of vision. Papilledema was noted on the physical examination. The symptoms gradually subsided over the next 3 days. Exfoliation began on the fourth day and lasted 2 weeks. The patient recovered. [Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 1021]**PEER REVIEWED**
  • CASE REPORTS: An 8 year-old boy with Alagille syndrome and chronic renal failure was admitted because of general deterioration, and bone pain. Severe hypercalcemia (3.9 mmol/L) was present. Serum phosphate, parathyroid hormone and 25 OH D3 levels were normal; 1-25 (OH)2 D3 levels were undetectable. Hypercalcemia was attributed to vitamin A intoxication, due to the administration of a mean daily dose of 12000 IU of vitamin A for at least 2 years. The diagnosis was confirmed by high plasma levels of retinol (1475 micrograms/L). Hypercalcemia only partially responded to treatment with bisphosphonates, calcitonin and dialysis with low calcium dialysate. Serum vitamin A levels remained elevated one month after vitamin A withdrawal. The boy died two months after admission from atrioventricular block. [Doireau V et al; Arch Pediatr 3 (9): 888-90 (1996) ]**PEER REVIEWED**
  • CASE REPORTS: Vitamin A toxicity produces protean clinical manifestations involving a wide variety of tissues and systems. Hypercalcemia can occasionally be associated with high vitamin A levels, but is rare. In this report we describe a patient who was receiving a commercially prepared enteral feeding formula for 2 years. He developed asymptomatic hypercalcemia and had serum vitamin A levels several fold above normal. Subsequently, a custom-made enteral feed was used which contained negligible amounts of vitamin A. Several months later, vitamin A levels diminished substantially and serum calcium levels returned to normal. [Bhalla A et al; J AM Diet Assoc 105 (1): 119-21 (2005) ]**PEER REVIEWED**
  • CASE REPORTS: A case of an adult presenting with respiratory symptoms caused by hepatic hydrothorax secondary to vitamin A intoxication /is reported/. The patient was a 52-year-old woman who presented to the hospital with progressive dyspnea. Evaluation demonstrated mild elevation of her liver function tests, ascites, and a right pleural effusion. The patient consumed a variety of vitamins, including vitamin A. Her estimated vitamin A intake was at least 162,300,000 international units (IU) during 18 years. She dramatically escalated her dose the year before admission for a total acute dose of 98,550,000 IU, with a daily intake of 270,000 IU. The recommended daily allowance is 4,000 IU. A transjugular liver biopsy revealed histopathologic changes consistent with vitamin A toxicity: hypertrophy and hyperplasia of hepatic stellate cells, focal pericellular fibrosis, mild perivenular fibrosis, and minimal, predominantly microvesicular steatosis. Despite the absence of cirrhosis, pressure readings demonstrated portal hypertension. During her hospitalization, the patient's symptoms and biochemical profile improved. As the large and generally unregulated United States dietary supplement industry continues to grow, it is increasingly likely that individuals will present with the signs and symptoms of vitamin excess rather than vitamin deficiency. Physicians need to remain alert to the varied presentations and toxic manifestations of excessive vitamin use. [Miksad R et al; J Clin Gastroenterol 34 (3): 275-9 (2002) ]**PEER REVIEWED**
  • CASE REPORTS: Although hypervitaminosis A is not uncommon, fatal cases are rare. /The authors/ describe a neonate who died after having ingested more than 60 times the suggested dose of vitamin A per day, for 11 days. His hospital course was marked by hypercalcemia, hyperphosphatemia, a bleeding disorder, and pulmonary insufficiency. An autopsy showed extensive calcifications of the alveolar septa and bronchioles. Metastatic calcifications were also present in the kidneys, stomach, soft tissue, and skin. The skeleton showed prominent alteration of the endochondral bone formation. There was also evidence of accelerated resorption of bone, which is presumably responsible for the development of hypercalcemia and metastatic calcification. [Bush ME, Dahms BB; Arch Pathol Lab Med 108 (10): 838-42 (1984) ]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: /It was/ recently reported that high dietary preformed vitamin A increase the risk of defects derived from cranial neural crest cells. This issue has important public health relevance given that folic acid containing multivitamins reduce the risk of neural tube defects and possible other defects. To assess this association further, /the authors/ examined data from a large population-based case-control study of major birth defects conducted by the CDC in the 1980's. In this study, mothers of 4929 infants with serious birth defects ascertained in the first year of life by the Metropolitan Atlanta Congenital Defects Program were compared to mothers of 3029 infants without birth defects, frequency-matched to cases by period of birth, race and hospital of birth. Specifically, we focused on the 1623 cases classified as cranial neural crest-derived using Rothman et al's classification. We defined vitamin A supplement use as reported consumption 3 days or more per week during the period from 1 month prior to conception to the end of the first three months of pregnancy. Overall, vitamin A users did not have an increased risk of all birth defects (odds ratio 0.74, 95% CI 0.44-1.25), or defects derived from cranial neural crest (odds ratio 1.10, 95% CI 0.58-2.07). In particular, there was no increased risk of these defects even among women who regularly took both multivitamin pills and vitamin A supplements (odds ratio 0.54, 95% CI 0.22-1.33). These results were not altered by adjustment for potential confounding variables such as race, maternal age, and education. In addition, /the authors/ reviewed clinical case records of the 35 babies with birth defects whose mothers reported vitamin A supplements. /The authors/ found no common phenotype. During the period of the study, most vitamin A supplements contained preformed vitamin A under 8,000 IU. These data /according to the authors/ provide reassurance that vitamin A supplements less than 8,000 IU do not increase the risk of birth defects. [Khoury MJ et al; Teratology 53 (2):91 (1996) ]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: A randomized, controlled, masked clinical trial was conducted in 15,419 preschool age children in southern India who were divided into 2 groups and received either a solution containing 8.7 umol (8333 IU) of vitamin A palmitate and 46 umol (20 mg) of vitamin E per ml dissolved in peanut oil or a placebo solution containing vitamin E alone every wk for one yr to determine whether the provision of vitamin A palmitate, at a level obtainable from foods, would reduce mortality. The baseline characteristics of the children were similar and documented a high prevalence of vitamin A deficiency and malnutrition. Results showed that 125 deaths occurred, of which 117 were not accidental. The risk of death in the group treated with vitamin A was less than half that in the control group. The risk was most reduced among children under 3 yr of age and among those who were chronically undernourished, as manifested by stunting. It was concluded that the regular provision of a supplement of vitamin A contributed substantially to children's survival in an area where vitamin A deficiency and malnutrition are documented public health problems; mortality was reduced on average by 54%. /Vitamin A palmitate/ [Rahmathullah L et al; N Engl J Med 323 (Oct 4): 929-935 (1990) ]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: This hospital based case control study was designed to investigate the association of low dietary vitamin A and beta carotene consumption with epidermoid lung cancer. Cases were patients with histologically confirmed epidermoid lung cancer diagnosed in six selected hospitals of southwestern France in 1983-84. Controls were selected from patients admitted to the same hospitals during the same period with diagnoses other than cancer. Cases and controls were matched for sex, age, place of residence, occupation, professional exposure to carcinogens, tobacco and alcohol consumption. A total of 106 cases of epidermoid lung cancer and 212 controls were interviewed on their typical weekly intake of 80 food items rich in preformed vitamin A and beta carotene. Index measures of the vitamin A and beta carotene daily intakes were computed for each individual patient and expressed in retinol equivalent. A statistically significant odds ratio was found for preformed vitamin A (odds ratio = 4.3; 95% confidence interval: 2.5-7.3) with the threshold of 1,000 retinol equivalent. A similar result was found for beta carotene with the same threshold (odds ratio = 4.1; 95% confidence interval: 2.3-7.4). Using the conditional logistic regression, consumption of preformed vitamin A and consumption of beta carotene were significantly and independently associated with epidermoid lung cancer. While confirming the protective role of beta carotene against epidermoid lung cancer, this study also shows that preformed vitamin A might have a distinct and important protective effect. [Dartigues JF et al; Eur J Epidemiol 6 (3): 261-5 (1990) ]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: A group of 134 school children aged 3-9 yr, with signs of conjunctival xerosis, from the rural area of the Sakorn Nakhon province in Northeast Thailand were selected for a controlled study on the short-term effect (2 wk) of a single, oral high dose of vitamin A on iron metabolism. After collection of the baseline data, children within villages were randomly assigned to receive the capsules (n = 65) or serve as control subjects (n = 69). Two weeks after supplementation significant increases of retinol, retinol binding protein, hemoglobin, hematocrit, serum iron, and saturation of transferrin were found in the supplemented group. Ferritin concentrations did not change significantly. These short-term changes completely exclude seasonal effects and change in morbidity. This study provides further evidence of a causal association between vitamin A and iron metabolism. In areas where vitamin A deficiency is endemic, periodic massive vitamin A dose programs can also improve iron status of the population. [Bloem MW et al; Am J Clin Nutr 51 (1): 76-9 (1990) ]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: To assess the relationship between maternal intake of vitamin A and cardiac outflow tract defects, /the authors/ examined data from a population-based case-control study among liveborn infants born from 1987 through 1989 to mothers residing in the Baltimore-Washington area. Case infants (126) had a nonsyndromic cardiac outflow tract defect. Control infants (679) did not have birth defects and were a stratified random sample of liveborn infants from the same area. The main exposure was average daily maternal intake of retinol and provitamin A carotenoids from foods and supplements during the year before conception. Compared with an average intake of less than 10,000 IU, retinol intake of 10,000 IU or more from supplements was associated with a ninefold increased risk for transposition of the great arteries (odds ratio = 9.2; 95% confidence interval = 4.0-21.2), but not for outflow tract defects with normally related arteries (odds ratio = 0.8; 95% confidence interval = 0.1-6.6). Similar intakes of carotenoids and dietary retinol were not associated with an increased risk for either type of outflow tract defect. [Botto LD et al; Epidemiology 12 (5): 491-6 (2001) ]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: /The/ objective was to determine whether moderate doses of vitamin A are teratogenic /in /... a geographically based case-control study. Women whose pregnancies produced offspring with neural tube defects (n = 548) or major malformations other than neural tube defects (n = 387) and normal control subjects (n = 573) were interviewed to determine periconceptional vitamin A supplement exposure levels. The proportion of women consuming doses of vitamin A between 8000 and 25,000 IU was no greater in the major malformations group or the group with neural tube defects than in the normal control group. For exposure from supplements and fortified cereals combined, women consuming >8000 and >10,000 IU daily had odds ratios for major malformations of 0.79 (95% confidence interval 0.40 to 1.53) and 0.73 (95% confidence interval 0.27 to 1.96), respectively, compared with women consuming <5000 IU. The results for neural tube defects were similar. For cranial neural crest defects the odds ratios were 0.76 (0.22 to 2.56) and 1.09 (0.24 to 4.98) for exposure to >8000 and >10,000 IU, respectively, versus exposure to <5000 IU. /The authors concluded that/ This study found no association between periconceptional vitamin A exposure at doses >8000 IU or >10,000 IU per day and malformations in general, cranial neural crest defects, or neural tube defects. If vitamin A is a teratogen, the minimum teratogenic dose appears to be well above the level consumed by most women during organogenesis. [Mills JL et al; Am J Obstet Gynecol 177(1):31-6 (1997) ]**PEER REVIEWED**
  • EPIDEMIOLOGY STUDIES: The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group. After the intervention ended, CARET participants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self-reported cancer endpoints were confirmed by review of pathology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two-sided. With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to 1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped. During the post-intervention phase, females had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36), cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males. The previously reported adverse effects of beta-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smokers. /Beta-carotene and retinol palmitate/ [Goodman GE et al; J Natl Cancer Inst 96 (23):1743-50 (2004) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Vitamin A (retinol) is a fat-soluble vitamin that is necessary for cell growth and differentiation. Excess vitamin A has been associated with teratogenic effects in animals and humans. Because vitamin A deficiency is very uncommon in the industrialized world, the current recommendation is that routine vitamin A supplementation is not necessary. If vitamin A supplements are used, they should be limited to less than 5,000 IU per day. [Monga M; Semin Perinatol 21 (2): 135-42 (1997) ]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: ... Repeated applications of large amounts of vitamin A in ointment to rabbit eyes ... /resulted in/ Blepharoconjunctivitis, with loss of hair from the lids. [Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 1084]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: /In hypervitaminotic animals/ lesions occur in the bones and result from accelerated resorption of bone and cartilage and formation of new bone. ... Other manifestations ... are anorexia, cutaneous lesions, temporary thickening of skin, exophthalmos, hypoprothrombinemia, and eventually death. [Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 1587]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Weanling cross bred pigs (36 or 48) were caged individually and fed diets containing a supplement of vitamin A (experiment 1) or vitamin D3 (experiment 2) at levels representing 1, 5, 10, 25, 50 and 100 times the NRC (1988) estimated requirements, for 4 wk. Growth rate, feed intake and feed/gain ratio were not influenced significantly. In experiment 1 the plasma retinol concentrations were at 4 weeks, respectively, 31.7, 39.4, 43.2, 42.9, 44.4, and 46.3 ug/dL (P < 0.05). In experiment 2, the plasma 25(OH)D3 concentrations were at 2 weeks, respectively, 22.5, 29.5, 35.7, 46.2, 79.9, 135.3 ng/mL (P < 0.001). Histological examination of lung, stomach, kidney, liver and heart indicated no abnormalities, but focal microscopic lesions consistent with osteochondrosis were found in pigs receiving vitamin A at levels over 10 times the requirement. The incidence of osteochondrosis at 2 weeks was, respectively, 0/8, 0/8, 0/8, 0/8, 0/8, and 1/8, and at 4 weeks was, respectively, 0/8, 0/8, 0/8, 2/8, 2/8 and 2/8. [Blair R et al; Int J Vitam Nutr Res 59 (4): 329-32 (1989) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Feeding of vitamin A deficient diet to male weanling rats for 10 wk caused significant reduction in the hepatic cytochrome p450, cytochrome b5, aminopyrine N-demethylase and arylhydrocarbon hydroxylase activities. Contrary to this, the levels of these Phase I enzymes were found to be significantly elevated in all the 3 portions (proximal, middle and distal) of the intestine in deficient animals as compared to corresponding pair fed controls. Of the Phase II enzymes studied, uridine diphosphate-glucuronyltransferase showed a significant decrease whereas glutathione S-transferase showed a significant increase in vitamin A deficient rat liver and small intestine. [Gupta PH et al; Biochem Int 19 (1): 123-33 (1989) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: ... In this study, oral therapy with vitamin A or a synthetic analoge, etretinate, was tested for the ability to protect hairless mice (Skh-hr1) from the development of skin tumors following exposure to broad band light (280-700 nm) for 25 wk. Retinoids were given by gavage 3 times weekly either at low dosage (2000 IU vitamin A or 4 mg etretinate per kg body weight) or high dosage (10,000 IU vitamin A or 20 mg etretinate per kg body weight). None of the retinol therapies compared to control mice (gavage vehicle only) modified skin tumor production in terms of time to onset of tumors, total tumor yield, or the types of tumors produced. [Kelly GE et al; Photochem Photobiol 50 (2): 213-5 (1989) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: 52% of the offspring /of rats/ tube-fed 35,000 IU of vitamin A from the 2nd, 3rd or 4th to the 16th day of gestation, were found to be abnormal. All the defective fetuses had exencephaly ... 38% had cleft palate and eye defects were also found. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 308]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: /In pregnant mice treated with vitamin A/ a number of the fetuses with genitourinary abnormalities had absence of the umbilical artery and a compensatory retention of the vitelline (superior mesenteric) artery. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 308]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Cleft palate, craniofacial, skeletal and urogenital anomalies /were found/ in pigtail monkeys treated with 10 mg /vitamin A/ per kg from day 20 through 44 /of gestation/. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 308]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Postnatal studies of rats receiving 60,000 units of vitamin A on days 14 and 15 or 17 and 18 /of gestation/ revealed learning and fine motor changes respectively. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 308]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Hypervitaminosis A in the pregnant guinea pig and hamster causes embryopathies, involving exencephaly, brachygnathia, agnathia, and other head malformations, shortened curved legs, ... fused ribs, spina bifida, shortened tails, and cardiovascular and genito-urinary system abnormalities. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 654]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Ocular teratogenic effects from excessive vitamin A have been reported in various animals, though not yet demonstrated in human beings. Effects in rats, mice, rabbits and chickens ... have included anophthalmos, microphthalmos, and cataract. Subsequently reports have appeared of abnormalities induced during pregnancy in the lenses and retinas of rats, ... anophthalmos in rats ... , coloboma in hamsters ... , and exophthalmos in hamsters and guinea pigs secondary to shallow orbits. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 979]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: To examine the effects of vitamin A administered during the preimplantation period, pregnant C3H mice were exposed to teratogenic doses of the vitamin 60 hr after copulation. Fetuses were examined for gross abnormalities on the 18th day of gestation and viability, cell number, mitotic index, and chromosome structure were assessed in 81 hr blastocysts to determine whether embryotoxic effects were apparent in the preimplantation embryo. There was a reduction in the fetal weight of 18 day fetuses treated in this manner with 15,000 and 30,000 IU vitamin A (p less than 0.0003 in each case), and doses of 10,000 IU and greater were associated with a significantly higher incidence of gross abnormalities. Malformations included exophthalmos, anophthalmia, microphthalmia, exencephaly, exomphalos, and limb defects. Administration of 30,000 IU vitamin A resulted in resorption and intrauterine death in 70% of cases. There was no indication that vitamin A adversely affected 81 hr blastocyst viability, cell number, mitotic index, and chromosome structure. The findings suggest that the teratogenic effects that were noted later in fetal life were the result of an action on the developing fetus of the vitamin at a stage later than 81 hr and are consistent with the relative resistance of the preimplantation embryo to toxic injury. Persistence of vitamin A, either in the mother or the embryo, is the most likely explanation for the later expression of toxic injury, which is characteristic of the effects that are noted as a result of exposure to the teratogen during the period of organogenesis. [Pillans PI et al; Teratology 37 (1): 7-11 (1988) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: The purpose of the research was to investigate the mechanism of reported vitamin A induced testicular degeneration. Three studies of vitamin A toxicity were conducted in male Sprague Dawley rats; a 10 day study with daily ip injections of retinol palmitate at doses of 0, 115,000 and 230,000 IU/kg/day in adult rats; a 10 day study with juvenile rats treated with 115,000 IU/kg/day, pair fed controls and ad lib. fed controls; a 13 wk dietary study in which retinol palmitate beadlets were mixed in the food of juvenile rats at doses of 0, 60,000, 120,000 and 200,000 IU/kg/day; a second untreated group was pair fed to the high dose group. Even at doses that produced overt signs of hypervitaminosis A and mortality, minimal or no changes were observed in the testes. In the 10 day ip studies, only a 20% incidence of treated juvenile rats (115,000 IU/kg) and adult rats (230,000 IU/kg) showed sloughing germ cells in some of the tubule lumens of the testes, but the structure and integrity of the seminiferous epithelium was completely intact. No change in testicular morphology or spermatid counts was observed in the 13 wk dietary study. In all studies, testicular weights of treated rats were not significantly reduced when corrected for body weight or compared with pair fed controls. In the 10 day ip studies, serum testosterone levels of treated rats did not differ from the respective pair fed control rats, but in the 13 wk study, a dose related reduction in testosterone occurred that was considered to be a direct effect of chronic vitamin A treatment. Seminal vesicle weights were decreased, as would be expected with decreased testosterone levels. Adrenal weights were increased in all studies. These findings suggest that the testes of rat are resistant to orally administered vitamin A palmitate and only slightly affected by ip administration. [Bosakowski T et al; Food Chem Toxicol 26 (9): 767-73 (1988) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: High concentrations of retinoids occur in some commercial cat food formulations as a result of the use of animal liver as an ingredient. Our objective was to study the teratogenic potential of dietary vitamin A in cats. We investigated the incidence of birth defects in kittens of queens given diets with retinyl acetate concentrations of 6,000, 306,000, or 606,000 retinol equivalents (RE)/kg diet (control, 306K, or 606K groups, respectively) for approximately 3 years [1 RE=1 ug retinol=3.3 International Units (IU)]. Each group comprised 12-15 age-matched, nulliparous domestic short-haired queens that were exposed to toms. There were a total of 396 kittens born in 97 litters. Pregnancy rate, number of kittens per gestation and gestations per year were not significantly different among treatment groups. A total of 2, 5 and 11 malformed kittens occurred in the control, 306K and 606K groups, respectively. Malformations included cleft palate, cranioschisis, foreshortened mandible, stenotic colon, enlarged heart and agenesis of the spinal cord and small intestine, which are typical foetal defects consistent with ingestion of excess retinoids in other species. This study demonstrated that a concentration of 306,000 RE/kg diet has a potential for causing birth defects in the kittens. [Freytog TL et al; J Anim Physiol Anim Nutr (Berl) 87 (1-2): 42-51 (2003) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Megadose supplements of vitamin A are under suspicion as hazards to the developing embryo after the discovery that two vitamin A related drugs, Accutane and Tigason, are human teratogens. Retinoic acid (all-trans-retinoic acid) is a natural metabolite of vitamin A which participates in many of the known functions of vitamin A and may be the active agent in teratogenesis. In this investigation we gave a single, high oral dose of vitamin A to pregnant mice to assess its transplacental pharmacokinetics as well as to measure the formation and distribution of its metabolites in the embryo. Vitamin A was estimated to be 4 fold less active than retinoic acid in the whole animal teratogenesis and 20 fold less active in the in vitro bioassay. A fully teratogenic dose, 200 mg/kg, yielded considerable quantities of retinoic acid which were transferred to the embryo with kinetics similar to that of vitamin A. During the first 8 hr after administration of vitamin A, the metabolites (including all-trans-retinoic acid, 13-cis-retinoic acid, and 4-oxo-retinoic acid) constituted almost 50% of the quantity of all vitamin A derivatives found in the embryo. A comparison of combined peak concentrations of the metabolites (or their area under the curve values) with the extent of teratogenesis associated with them individually provided sufficient evidence to implicate the metabolites themselves as mediators of vitamin A induced teratogenesis. However, since both vitamin A and retinoic acid were present in sufficient concentrations in the embryo to act as teratogens, the possibility that they may act independently can not be ruled out. [Kochhar DM et al; Toxicol Appl Pharmacol 96 (3): 429-41 (1988) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: In cell culture, vitamin A inhibits the synthesis of chondroitin sulfate by chondrocytes and cartilage rudiments, and the inhibition of chondrogenesis in the developing embryo may result in malformations of the limbs. [Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 1588]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Rat hepatic microsomal mixed function oxidase activities were not significantly affected by vitamin A deficiency. Similarly cytosolic glutathione S-transferase and glutathione reductase activities as well as total glutathione levels were unaffected by the vitamin A status. Induction of the mixed function oxidases by 3-methylcholanthrene or phenobarbitone was independent of the vitamin A status. No significant differences in microsomal chemiluminescence, before and following challenge with tertiary butyl hydroperoxide, were evident between the vitamin A deficient animals and those maintained on vitamin A supplemented diets. The present findings indicate that the protective action of vitamin A against chemical carcinogens is unlikely to involve modulation of the enzyme systems responsible for their metabolism. [Ayalogu EO et al; Ann Nutr Metab 32 (2): 75-82 (1988) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Vitamin A inhibited the growth of yeast and human cells in a dose-dependent but selective manner in cultures utilizing a non-fermentable carbon and energy source. At sub-inhibitory concentrations in yeast cultures (approximately 100 ug/ml), the vitamin had a stimulatory effect on the mitochondrial system, foreshortening the lag phase in the adaptation to nonfermentable substrate. At inhibitory concentrations, vitamin A depressed mitochondrial protein synthesis relative to cytoplasmic protein synthesis and induced the mitochondrial mutation petite but had little or no mutagenicity with respect to nuclear genes at the concentrations used. The vitamin showed a dose dependent cytotoxicity (lethality) in both yeast and human cells. All of these deleterious effects were overcome to a large extent by the presence of antioxidants implicating free radical metabolites in much of the toxicity. [Cheng LL, Wilkie D; Biochem Pharmacol 42 (6): 1237-40 (1991) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Retinoids have long been associated with wound healing, but objective data, until recently, have been scarce. Vitamin A deficiency retards repair. Secondly, retinoids restore steroid retarded repair toward normal. Because vitamin A tends to suppress fibroblasts in cell culture and stimulate steroid treated macrophages to initiate reparative behavior in tissue, the hypothesis that retinoids are particularly important in macrophagic inflammation, which plays a central role in the control of wound healing is favored. [Hunt TK; J Am Acad Dermatol 15 (4 Pt 2): 817-21 (1986) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: Supplementation of vitamin A after withdrawal of hexachlorocyclohexane accelerated the recovery and restored spermatogenesis and enzyme activities in the deficient rats. These results demonstrate the greater susceptibility of the male reproductive system to hexachlorocyclohexane toxicity during vitamin A deficiency and also the protective effect of vitamin A supplementation. [Pius J et al; Reprod Toxicol 4 (4): 325-30 (1990) ]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Mouse ip 1510 mg/kg (10 day) [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1785]**PEER REVIEWED**
  • LD50 Mouse oral 2570 mg/kg (10 day) [O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1785]**PEER REVIEWED**
  • LD50 Hen oral 3.15 - 3.7 g/kg body weight [Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988., p. 125]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Vitamin A is distributed into breast milk ... . [Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2842]**PEER REVIEWED**
  • Less than 5% of circulating vitamin A is bound to lipoproteins in blood (normal), but may be up to 65% when hepatic stores are saturated because of excessive intake. The amount of vitamin A bound to lipoproteins may be increased in hyperlipoproteinemia. When released from liver, vitamin A is bound to retinol-binding protein (RBP). Most vitamin A circulates in the form of retinol bound to RBP. [Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2841]**PEER REVIEWED**
  • Storage: Hepatic (approximately 2 years' adult requirements), with small amounts stored in kidney and lung tissues. Zinc is required for mobilization of vitamin A reserves in the liver. [Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2841]**PEER REVIEWED**
  • More than 90% of the intake of preformed vitamin A is in the form of retinol esters, usually as retinyl palmitate. ... When a large excess is ingested, some of the vitamin escapes in the feces. ... Absorption ... is related to that of lipid and is enhanced by bile. ... Aqueous dispersions ... are absorbed more rapidly than are oily solution. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1779]**PEER REVIEWED**
  • Retinol esters are hydrolyzed in the ... intestine ... Before absorption, followed by reesterification, mainly to the palmitate. ... Significant quantities of vitamin A are also absorbed directly into the circulation. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1779]**PEER REVIEWED**
  • Retinol bound to retinol-binding protein /alpha-1-globulin/ reaches the cell membrane of various target organs, where the complex binds to specific sites on the cell surface. ... retinol is converted to a retinyl ester. The retinyl ester is then cleaved by a membrane associated hydrolyase, provided that unliganded cytosolic cellular retinol-binding protein is available to accept the retinol. Cellular retinol-binding protein exists in virtually all tissues; exceptions include cardiac and skeletal muscle and the ileal mucosa ... . [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1780]**PEER REVIEWED**
  • Retinol bound to its specific carrier, the retinol binding protein, is known to be the physiological way vitamin A is transported in blood. Unspecific, lipoprotein bound vitamin A has so far only been reported under the condition of hypervitaminosis A. In this investigation vitamin A concentrations in dog plasma are reported (2300 ng/ml), showing for the first time a species which, under physiological conditions, transports most of its vitamin A in plasma as retinyl esters (70%) associated with lipoproteins. This phenomenon might indicate that dogs are less sensitive to the effects of nonspecific delivery of vitamin A than other species. This can open new aspects in retinoid research, especially with regard to hypervitaminosis A - an undesirable side effect of the beneficial use of retinoids in dermatology and oncology. [Schweigert FJ; Int J Vitam Nutr Res 58 (1): 23-5 (1988)]**PEER REVIEWED**
  • Vitamin A is readily absorbed from healthy gastrointestinal tract (duodenum and jejunum). Absorption of retinol requires presence of bile salts, pancreatic lipase, protein, and dietary fat. Excess, unabsorbed vitamin is excreted in feces. Water-miscible preparations are absorbed more readily than oil solutions. [Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2841]**PEER REVIEWED**
  • The Ito cells of the liver represent a special form of fibroblasts, about 80% of the vitamin A content of the normal liver is stored in these cells. Following to the absorption of vitamin A in the intestine, vitamin A (retinol) is transported in chylomicrons and their remnants, and taken up by hepatocytes through receptor-mediated endocytosis. Along with retinol-binding protein vitamin A is transported from the hepatocytes to the Ito cells where it is being stored as lipid droplets. The vitamin A content of the liver tissue in chronic, especially alcoholic liver disease is distinctly lowered. The vitamin A deficiency of the chronic alcoholic liver disease is caused by an accelerated microsomal metabolism of vitamin A. [Korner T et al; Gastroenterol J 49 (3): 93-7 (1989) ]**PEER REVIEWED**

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Metabolism/Metabolites

  • Retinol is converted to retinyl phosphate in epithelial tissues, and this intermediate is in turn metabolized to mannosylretinylphosphate in a reaction that is catalyzed by a microsomal enzyme and requires guanosine diphosphomannose as a glycosyl donor. ... /the vitamin A/ mediates transfer of mannose to specific glycoproteins. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1777]**PEER REVIEWED**
  • Retinol is in part conjugated to form a beta-glucuronide, which undergoes enterohepatic circulation and is oxidized to retinal and retinoic acid. [Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1781]**PEER REVIEWED**
  • Within the retina, all-trans-retinol is oxidized to retinal by alcohol dehydrogenases, and is then Isomerized to the 11-cis-isomer which combines with opsin in the rod to yield rhodopsin, and with different opsins in human cones to yield three different iodopsin pigments. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970., p. 254]**PEER REVIEWED**
  • Retinoic acid (RA) is the bioactive metabolite of vitamin A (retinol) which acts on cells to establish or change the pattern of gene activity. Retinol is converted to RA by the action of two types of enzyme, retinol dehydrogenases and retinal dehydrogenases. In the nucleus RA acts as a ligand to activate two families of transcription factors, the RA receptors (RAR) and the retinoid X receptors (RXR) which heterodimerize and bind to the upstream sequences of RA-responsive genes. [Maden M; Proc Nutr Soc 59 (1): 65-73 (2000) ]**PEER REVIEWED**

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TSCA Test Submissions

  • None found

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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