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Description of key information

A repeated dose (feed) study in rats was available on structural analogue retinyl acetate that was performed similar to OECD guideline 408:
The NOAEL was 1.43 -3.07 mg/kg bw/d (28 ppm) based on slight effects on a few clinical chemical parameters (increased plasma triglyceride levels, slightly increased activity of glutamate pyruvate transaminase and glutamate oxalacetate transaminase) and effects in the liver (increased absolute and relative liver weights, brightened livers, lipid accumulation of the Kupffer cells and decrease of the intrahepatocellular lipid droplets in the peripheral areas of the liver lobules).

Key value for chemical safety assessment

Additional information

A reliable study repeated study is available that was performed similar to OECD guideline 408. This oral 90-day (feed) study with the stuctural analogue retinyl-acetate (535 000 IU/g) was performed in rats at 28, 112 and 318 ppm (BASF 79/582). The NOAEL was 1.43 -3.07 mg/kg bw/d (28 ppm) based on slight effects on a few clinical chemical parameters (increased plasma triglyceride levels, slightly increased activity of glutamate pyruvate transaminase and glutamate oxalacetate transaminase) and effects in the liver (increased absolute and relative liver weights, brightened livers, lipid accumulation of the Kupffer cells and decrease of the intrahepatocellular lipid droplets in the peripheral areas of the liver lobules).

As supportive study, a comparable oral 90-day (feed) repeated dose toxicity study is available (similar to OECD guideline 408), performed in rats using 27, 108 and 307 ppm of the stuctural analogue retinyl-acetate (553000 IU /g; BASF 79/581). The NOAEL was 1.54 -3.19 mg/kg bw/d (27 ppm) based on changes in a few clinical chemical parameters (increased plasma triglyceride levels, increaed alkaline phosphatase and glutamate pyruvate transaminase activity), proteinuria and effects in the liver (increased absolute and relative liver weights, brightened livers, lipid accumulation of the Kupffer cells and decrease of the intrahepatocellular lipid droplets). In the low dose group, a slight and transient increase in plasma triglyceride levels of males has been observed, setting a NOEL for males below 27 ppm.

As supportive study, a comparable oral 90-day (feed) repeated dose toxicity study is available (similar to OECD guideline 408), performed in rats using 66, 263 and 746 ppm of the stuctural analogue retinyl-acetate (236000 IU/g; BASF 79/580). The NOAEL was 3.16-7.71 mg/kg bw/d (66 ppm) based on changes in clinical chemical parameters (increased plasma triglyceride levels, hypercholeterolemia, hyperkalemia, increaed alkaline phosphatase), proteinuria and effects in the liver (increased absolute and relative liver weights, brightened livers, centrolobular PAS-positive areas, lipid accumulation of the Kupffer cells and decrease of the intrahepatocellular lipid droplets). In the low dose group, a slight increase in absolute and relative liver weights or slightly brightenend livers has been observed, setting a NOEL below 66 ppm.

A high number of studies are reported in literature and reviews providing evidences on the adverse effects associated with hypervitaminosis A. These data were peer reviewed by several regulatory bodies and associations e.g., EFSA, WHO, IARC, US Cosmetic Ingredient Review.

 

Taken together, adverse systemic effects of Vitamin A may occur in almost all laboratory animals and/or humans as a result of prolonged excessive oral or parenteral intake:

 

Adverse local effects include hair loss, dry and scaly skin, fissures of the mouth or lips, dryness of mucous membranes, brittle nails, skin rashes and erythema.

 

Hepatotoxicity is one of the most severe outcomes of chronic intake of excessive doses of Vitamin A. Clinical signs of Vitamin A-induced hepatotoxicity include hepatomegaly, ascites, icterus, edema, and esophageal varices.

 

Histopathological effects include fatty change in the liver, spleen, heart and kidney, and proliferation of fat-storing cells in the liver. In addition, hemosiderosis of the spleen and glomerulonephritis as well as necrotizing nephrosis have been observed. High dose, subchronic treatment caused testicular hypertrophy in adult rats and degenerative testicular changes in weanling rats. Myocardial degeneration associated with ECG changes, and bone marrow hyperplasia were described in rats.

 

Subchronic oral administration produced decreased red blood cell values and increases in serum lipids, cholesterol, triglycerides, and alkaline phosphatase values in several laboratory animal species. Serum transaminase levels are usually moderately elevated and accompanied by signs of cholestasis.

 

High repeated oral doses of Vitamin A resulted in bone fractures secondary to growth disturbances resulting in a thin, fragile bone cortex, as demonstrated in mice, rats, dogs, cats and calves after one week of repeated daily dosing. Effects on teeth include reduced formation of dentine, atrophy of lingual odontoblasts and the degeneration of pulp andodontoblasts accompanied by amorphous calcification of dentine.

 

In adult humans, initial symptoms of systemic hypervitaminosis A may include headache, bone and joint pain, nausea and dry skin. In children, hypervitaminosis A has been described to produce reversible bulging fontanels, possibly due to increased intra-cranial pressure. In addition, nausea and vomiting has been described.

 

According to the dose response assessment by the scientific committee on food (EFSA 2006) mainly on the basis of human surveys, the lowest doses reported to produce the major adverse effects were 7500 RE/day (representing approx 13.5 mg retinyl palmitate/ day) for bulging fontanelles, hepatotoxicity and lipid metabolism, > 3000 RE/day (representing approx 5.5 mg retinyl palmitate/day) for teratogenicity. Data concerning decreased bone density with focus on postmenopausal women at lower dose levels exist, but were considered to be insufficient to provide a sound evidence of causality between vitamin A intake and increased risk for bone fractures.

 

It needs to be metioned, that a deficiency in vitamin A intake leads to a pathological condition as well, leading to increased morbidity and mortility, anaemia, night blindness, xerosis and developmental toxicity. Therefore, administration of retinol and/ or the respective ester exert beneficial or adverse effect dependet on the dose.

 

Adverse effects of hypervitaminosis A were observed at low dose levels. However, since the findings of hypervitaminosis A are considered mainly reversible, uptake of retinol and esters are essential for human health, exposure levels are low and safety values are well established, a classification of retinyl palmitate as repeated dose toxicant is not warranted.

Justification for classification or non-classification

The present data on repeated dose toxicity do not fulfill the criteria laid down in regulation 67/548/EEC and 1272/2008/EC, and therefore, a non-classification is warranted.