Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Squalene is a common component of the human diet through olive oil and other oils and fats and it is assumed in a quantity between 30 and 200 mg/day, without adverse effect in a whole human life, with no limitation during pregnancy and no effect have ever been reported in normal use on fertility, development or teratogenicity.

 

In addition Squalene has been used since decades in cosmetic formulations, creams and similar, where a daily application is performed during a lifetime by humans. No effects have ever been reported, both about eventual systemic toxicity, fertility or reproduction.

 

Apart from the epidemiological evidence deriving from the presence of squalene as a component of common edible oils and fat and cosmetic application, several studies have been performed in the framework of the use of squalene as adjuvant in recently developed influence vaccins.

 

In 2010, the European Medicines Agency (EMA) has reviewed a vaccine against the H1H1 influenza virus, called “Humenza” which contained a, then novel, squalene based adjuvant (AF03, developed and studied by Glaxo Smithkline).

The effect of AF03 and AF03-adjuvanted A/H1N1 vaccines on Reproductive system and on Pre- and Post-natal development has been investigated in 4 studies, including 1 rat study and 3 rabbit studies.

 

- 2 studies evaluating the adjuvant alone in rats and rabbits, and

- 2 rabbit studies assessing the AF03 adjuvanted Swine A/H1N1 Influenza Vaccines manufactured by the Applicant in Europe or in US

 

The applicant provided further details on the US and the EU vaccines used in these studies and showed that the differences between the two are minor. Data from the study conducted with the US vaccine are thus considered as supportive. Under test conditions of 1) 6x I.M. injections (D-21, D-7, D6, D8, D11, and D17 (rats) or D27 (rabbits)) with AF03 alone at concentrations of 1.25-2.5% (rats) or 2.5-5% (rabbits), or 2) 5x I.M. injections (D-21, D-7, D6, D11, D27) in rabbits with 7.5 μgHA + 2.5% AF03, there were no embryofetal toxicity effects noted and also no treatment related effects were noted on pup weights as well as physical, functional and neurological development (D0: first day of gestation). Immunogenicity data generated in these studies demonstrated transfer of vaccine-specific maternal antibodies to fetuses and pups.

 

In the article "Exposure to MF59-adjuvanted influenza vaccines during pregnancy—A retrospective analysis" (Tsai T., 2010) it is reported that the evaluation of the reproductive and developmental toxicity of MF59 alone and of a candidate MF59-adjuvanted H5N1 vaccine in animals demonstrated no evidence of teratogenicity or impact on fetal or early perinatal development.

Pertinent to the evaluation of the effects of MF59 in pregnancy, the adjuvant was tested for maternal/embryofetal toxicity and teratogenicity in rabbits, and for reproductive and developmental toxicity, including postnatal assessments, in rats. Animals were vaccinated approximately every 2 weeks for a total of 5 doses, prior to mating and during gestation. MF59 adjuvant was also tested in rats and rabbits on more aggressive schedules

There were no vaccine and/or adjuvant-related findings observed in any reproductive and developmental toxicity study in the non clinical assessment. MF59 adjuvant alone or in combination with the egg-derived H5N1 antigen was not maternally toxic, fetotoxic or teratogenic. Furthermore, there were no observed effects on developmental parameters in offspring.


Short description of key information:
No adverse effect observed in oral studies

Effects on developmental toxicity

Description of key information
No adverse effect observed in oral studies 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

See above discussion on fertility studies

Justification for classification or non-classification

Reproductive toxicity includes adverse effects on sexual function and fertility in sexually adult males and females animals, as well as developmental toxicity in the offspring. However, developmental toxicity essentially means all the adverse effects induced during pregnancy that can be manifested at any point of the life span of the animal, which might in turn bring to structural abnormality, altered growth and/or organs development, functional deficiency, even death.

Table 3.7.1(a) of Annex I of EC Regulation 1272/2008 states that to classify compounds "for category 2 suspected human reproductive toxicant, reproductive effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects".

In conclusion, since no adverse effects on reproduction were observed at the tested doses, classification for reproductive/developmental toxicity is not warranted under Regulation 1272/2008