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Key value for chemical safety assessment

Effects on fertility

Additional information

No reliable data from guideline conform studies on fertilty are available for retinyl palmitate. In accordance with column 2 of REACH AnnexVIII, no data of a screening study for reproductive/developmental toxicity are required, since several prenatal developmental toxicity studies equivalent to OECD guideline 414 are available, identifying retinyl palmitate as a developmental toxicant (see chapter “Developmental toxicity”).

Effects on developmental toxicity

Description of key information
Developmental studies with retinyl palmitate was performed, in cynomolgus monkeys (Hendrickx 2000):  
NOAEL developmental = 4.1 mg/kg bw/d
NOAEL maternal = 11 mg/kg bw/d. 
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
4.1 mg/kg bw/day
Additional information

A broad variety of publications is available, addressing the embryotoxic/teratogenic potential of retinol or the respective esters in different in vitro test systems or rodent/non-rodent species in vivo during different stages of development. Retinol produced more than 70 types of malformations in rats, mice, hamsters, guinea pigs, rabbits, dogs, pigs, and monkeys. The type and incidence depend on doses, stages of pregancy and on species and strains used (CIR 1987). However, a series of developmental toxicity studies in cynomolgus monkeys have been identified as suitable for substantiating classification decisions and performing a quantitiative assessment and derivation of no effect levels. These data are also used via read across for the structural analogues retinyl acetate, retinol and retinyl propionate.

In this array of developmental toxicity studies in cynomolgus monkeys (Macaca fascicularis) retinyl palmitate was orally (nasogastric intubation) administered at doses of 4.1, 11, 22 and 44 mg/kg bw/d (7 500, 20 000, 40 000, 80 000 IU/kg bw/d, respectively) from GD 16 to GD 27 (Hendrickx 2000). Mild to severe signs of hypervitaminosis A were observed in the majority of animals in the two highest dose groups (40 000 IU/kg and 80 000 IU/kg) during and/or immediately after the period of treatment. Body weight gain was delayed in the treated animals compared to the controls, especially at the higher doses (40 000 IU/kg and 80 000 IU/kg), however, mean maternal weights were comparable by the end of the observation period. Moderate to severe decreases in food intake were observed sporadically in the highest dose group (80 000 IU/kg). Normal appetite was restored in all affected animals after the cessation of treatment.

Treatment with retinyl palmitate during gastrulation and early organogenesis resulted in adverse developmental effects manifested as dose-related increases in abortions and malformations in the cynomolgus monkeys. Malformations were observed in typical retinoid target tissues in the embryo, including the craniofacial region, heart, and thymus. Evident developmental toxicity was observed at the two highest dose groups, i.e. 40 000 IU/kg (38% abortions and 33% malformations) and 80 000 IU/kg (66% abortions and 45% malformations). Moreover, a similar spectrum of craniofacial defects was observed at these dose levels. The threshold dose for the induction of terata in the cynomolgus monkey is 20 000 IU/kg retinyl palmitate. This dose, associated with a moderate level of embryotoxicity (19% abortion rate) and a low level of malformations (5%) consisting of a specific defect (hypoplastic zygomatic processes) in one fetus, is considered to be the lowest observed adverse effect level. Since no malformations were observed at 7500 IU/kg and the abortion rate (4%) was within the normal range compared to controls (7%), this dose is considered to be the no observed adverse effect level under experimental conditions chosen.

Taken together, from the variety of available data on developmental toxicity and retinoids, the cynomolgus monkey was shown to be a sensitive animal species and the results obtained are considered as most relevant for human risk assessment. In the series of prenatal developmental toxicity studies in the pregnant Cynomolgus monkeys, oral doses of retinyl palmitate at 20000 and 40000 IU/kg bw/day resulted in developmental toxicity and maternal toxicity (Hypervitaminosis A), respectively, leading to an NOAELdevelopmentalof 4.1 mg/kg bw/d and a NOAELmaternalof 11 mg/kg bw/d. 

Justification for classification or non-classification

The available data on developmental toxicity warrant the classification for developmental toxicity according to EU Directive 67/548/EEC as; Repr. Cat 2; R61. According to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008): Reproductive toxicity, Cat. 1B; H360  (May damage the unborn child ).