Retinyl propionate

Endpoint summary

Additional information

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,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 reponse 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 for bulging fontanelles, hepatotoxicity and lipid metabolism, > 3000 RE/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 toincreased 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 propionate 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 67/548/EEC and 1272/2008/EEC, and therefore, a non-classification is warranted.