Cholesterol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Data waiving:

exposure considerations

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Species:

other: human

Quality of whole database:

Cholesterol metabolism and adverse effects of high cholesterol intake/disturbed cholesterol regulation has been studied intensively for many years, not only in laboratory animals but also in humans.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Cholesterol metabolism and adverse effects of high cholesterol intake/disturbed cholesterol regulation has been studied intensively for many years, not only in laboratory animals but also in humans. Reported adverse effects related to increased cholesterol levels/disturbed cholesterol metabolism concern mainly cardiovascular effects. In addition, as the liver plays a key role in cholesterol metabolism, liver is considered as target organ for cholesterol. Cholesterol-related effects on the liver are considered a sensitive parameter for toxicity, as these effects (resulting in disturbed cholesterol metabolism) occur before other adverse effects become effective. No effects on reproduction has been reported, indicating that increased cholesterol levels/exposure does not result in reproduction toxicity at relevant exposure levels. It is therefore considered, that limit values for cholesterol exposure based on liver effects are protective for reproductive toxicity as well.

Short description of key information:
All available information on cholesterol.

Effects on developmental toxicity

Description of key information

High doses cholesterol administration by injection to pregnant rats has been used in the past (1964-1972) as an experimental model to study palate malformations . In rats daily injections of 5, 10, 15 or 20 mg cholesterol during days 8-14 of pregnancy resulted in increased numbers of pups with palate abnormalities. In a rat study with daily  6 mg/day cholesterol injections during 8 day in mid-pregnancy did not show  pups with palate abnormalities.  In rabbits, cholesterol induced developmental toxicty including palate malformations, was observed after high oral cholestrol exposure (250, 500 or 1000 mg/day) via feed. 
There was no clear dose-relationship observed in plasma cholesterol levels of the females (rat and rabbit).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

250 mg/kg bw/day

Study duration:

subacute

Species:

other: rat, rabbit

Quality of whole database:

reliable

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

Daily injections of pregnant rats with high doses cholesterol (5 to 20 mg/day) during days 8 -14 of pregnancy resulted in increased number of pups with abnormal palates. However, this route of exposure is not relevant for human exposure, and needs to be considered as extremely worst case. Moreover, the tested doses of 5 to 20 mg cholesterol per day are considered as very high doses (human equivalent doses of 467 to 1868 mg/day, additionally cholesterol, based on 60% oral absorption and human equivalent dose (HED = rat dose * 0.16).

Also the rabbit study (1972) was performed with very high daily doses in the feed: 250 to 1000 mg/day (HED = rabbit dose * 0.32, resulting in 5600 to 22400 mg/d).

Although cholesterol has been studied intensively for adverse effects, more recent studies on developmental toxicity are not present in the open literature, indicating that the observed developmmental effects observed with very high dose levels are considered not relevant for research on effects related to high/disturbed cholesterol levels. As the developmental effects in rat and rabbit are observed at extremely high dose levels (and by irrelevant exposure route for rat), these effects are considered to be not relevant under more realistic exposure conditions. Moreover, as it is generally known that the liver is considered to be the first target for cholesterol, and limit levels based on adverse effects observed on this target are considered to be protective for developmental effects as well. As the developmental effects in rat and rabbit are observed by exposure to very high doses and a non-relevant route of exposure (rat), it is concluded that these effects are not considered relevant for considering developmental toxicity for human. Consequently, cholesterol needs not te be classified for developmental effects according to

-Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011),

-Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.

Justification for selection of Effect on developmental toxicity: via oral route:
Weight of evidence based on all available studies.

Justification for classification or non-classification

Based on all available information on cholesterol in animal studies and human studies, no relevant reproductive or developmental toxicity for humans has been observed/reported. Based on these observations, cholesterol needs not to be classified for reproductive and developmental toxicity according to

-Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011),

-Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.