Cholesterol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: combination of experimental result (oral route) and assessment based on physico-chemical properties (inhalation and dermal routes)

Adequacy of study:

key study

Study period:

1982-2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Toxicokinetic assessment based on all available information from the open literature as well as on the physico-chemical properties of cholesterol.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Principles of method if other than guideline:

Toxicokinetic assessment based on human data and physico-chemical properties for the derivation of the percentage absorption after exposure by the oral, inhalation and dermal route for risk assessment purposes.

Test material

Test material information

Constituent 1

Reference substance name:

Cholesterol

EC Number:

200-353-2

EC Name:

Cholesterol

Cas Number:

57-88-5

Molecular formula:

C27H46O

IUPAC Name:

cholest-5-en-3-ol

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): cholesterol

Radiolabelling:

yes

Test animals

Species:

human

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

Data on toxicokinetics for cholesterol include information from several human studies and review articles. Various exposure regimes are considered.

Duration and frequency of treatment / exposure:

In the available studies the duration and frequency of treatment is various, including radiotracer studies.

Doses / concentrations

Remarks:

Doses / Concentrations:
variable in the several studies

Results and discussion

Main ADME results

Main ADME results 1

Type:

other: oral absorption

Results:

60%; the body cholesterol pool consists besides absorbed cholesterol also endogeneously synthesised cholesterol and cholesterol from intestine back resorption

Main ADME results 2

Type:

metabolism

Results:

main metabolic pathway in mammals: metabolism to bile acids (in the liver)

Main ADME results 3

Type:

distribution

Results:

widely distributed in the body, as cholesterol is part of the cell membrane

Main ADME results 4

Type:

excretion

Results:

via feces, urine and skin (total about 1 g/day)

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The total cholesterol pool consists intake of cholesterol (about 500 g/day), endogenous synthesis (intestine about 400 mg/day, liver about 1000 mg/day, and other organs), and back resorption from the intestine (about 50% of total excreted cholesterol). Cholesterol uptake in the intestine depends on the amount in food and synthesis in the liver. Cholesterol biosynthesis is regulated by negative feedback where the presence of cholesterol inhibits its own synthesis.

Details on distribution in tissues:

Cholesterol is incorporated, with use of bile salts, into chylomicrons (mixed micelles). Once the chylomicrons are absorbed into the lymph, they are transported to the liver, where cholesterol is incorporated (both absorbed and in liver synthesized) into very low-density lipids (VLDL) intermediate-density lipids (IDL) and low-density lipids (LDL). Cholesterol is present in 0.2% of the total human body, with most cholesterol membrane-associated. About 5% of this cholesterol is contained in the plasma. The main function in membranes is related to the fluidity of the membrane.

Details on excretion:

Elimination of cholesterol from the body occurs via the feces, urine and skin surface. Excretion of cholesterol via feces is in the form of bile salts, cellular and membrane cholesterol from cells from the intestine, unabsorbed dietary cholesterol and metabolic products of gut bacteria.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: Overall, there is a balanced system in mammals for uptake and excretion of cholesterol resulting in equilibrium.
From the available literature on toxicokinetics of cholesterol, it can be concluded that oral absorption is about 60%, as determined by radio-labeled cholesterol studies as plasma ratio oral/intravenous tracer.
For risk assessment purposes, the inhalation absorption of cholesterol is set at 100% as a worst case assumption.
The 100% dermal absorption derived from the physical/chemical properties of the substance is considered a non-realistic worst case assumption as dermal absorption is considered to be lower compared to oral absorption. For risk assessment purposes a lower dermal absorption value of 60% is considered more appropriate.

Executive summary:

Toxicokinetic assessment

oral

Absorption and Distribution:

Dietary absorption occurs from the gut via lymph, mainly from the proximal small intestine. Cholesterol is incorporated, with use of bile salts, into chylomicrons (mixed micelles). Once the chylomicrons are absorbed into the lymph, they are transported to the liver, where cholesterol is incorporated (both absorbed and in liver synthesized) into very low-density lipids (VLDL) intermediate-density lipids (IDL) and low-density lipids (LDL). LDL enters the circulatory system where it will be metabolized, as well as excreted in bile, feces, urine, milk or skin.Intake of cholesterol via food influences the total body cholesterol, as exchange between the cholesterol pools will occur. The total cholesterol pool consists intake of cholesterol (about 500 g/day), endogenous synthesis (intestine about 400 mg/day, liver about 1000 mg/day, and other organs), and back resorption from the intestine (about 50% of total excreted cholesterol). The total amount synthesized in the body is about 1.20 grams per day. In addition, about 0.30 grams is absorbed, and 0.5 grams reabsorbed. Excretion is about 1 gram per day. However uptake in the intestine depends on the amount in food and synthesis in the liver.

Cholesterol biosynthesis is regulated by negative feedback where the presence of cholesterol inhibits its own synthesis. The cholesterol turnover in plasma lipoproteins is approximately 1.11 g/day, as measured with stable and radioactive isotopes. In studies concerning cholesterol absorption from the diet (16 to 77 days), it was shown that there is a wide range of basal plasma cholesterol levels (115-717 mg/100 mL). Mean cholesterol intake in Germany (1969 -1970) was 584 mg, with individual significant deviations. Effects (disturbances) on the cholesterol balance will be observed with delay on plasma cholesterol concentration. Interruption of body synthesis provides the major controlling mechanism (70%)of the absorbed dietary cholesterol.The magnitude of the compensatory mechanisms was similar in normal and in hypercholesterolemic persons.

This information shows that there is a balanced system in mammals for uptake and excretion of cholesterol resulting in equilibrium. From the available literature on toxicokinetics of cholesterol, it can be concluded that oral absorption is about 60%, as determined by radio-labeled cholesterol studies as plasma ratio oral/intravenous tracer (30 mg oral, 15 mg i.v.). After oral administration, highest plasma levels are observed on day 2 after administration.

 

metabolism

In a repeated dose toxicity study with mice fed diets supplemented with 1% choline for 4 weeks and then switched to control diet for another 4 weeks only a slightly raised hepatic cholesterol concentration was observed. There are two major metabolic pathways of cholesterol in mammals: metabolism to bile acids (humans:~600 mg cholesterol/day) in the liver, and metabolism to steroid hormones (humans:~40 mg cholesterol/day) in the adrenals, testes, ovaries and placenta. Besides, cholesterol is also metabolized into cholesterol esters, cholesterol sulfate, cholestanol and vitamin D3. In the gut, cholesterol is also metabolized by intestinal flora to several compounds, predominantly coprostanol and coprostanone.

Recommended cholesterol intake is 300 mg/day. Cholesterol absorption from the GI-tract is a key component of whole body cholesterol metabolism (with 2-fold larger enterohepatic recirculation of endogenous cholesterol). Cholesterol is present in 0.2% of the total human body, with most cholesterol membrane-associated. About 5% of this cholesterol is contained in the plasma. The function in membranes is related to the fluidity of the membrane, whereas cholesterol also plays a role as metabolic precursor to other steroids, such as adrenal corticosteroids, sex hormones, bile salts and provitamin D2.

Excretion

Cholesterol and its derivatives are excreted in the intestine as neutral steroids and bile acids (about 500 mg/day). Cholesterol is eliminated from the body via the feces, urine and skin surface (about 100 mg/day). Excretion of cholesterol via feces is in the form of bile salts, cellular and membrane cholesterol from cells from the intestine, unabsorbed dietary cholesterol and metabolic products of gut bacteria. Cholesterol and its derivatives excreted in the feces accounts for about 50% of the total cholesterol turnover in man. In urine, cholesterol (free and conjugated and as metabolites of steroid hormones) is a normal constituent. Cholesterol is also eliminated in the milk of lactating females.

Overall, there is a balanced system in mammals for uptake and excretion of cholesterol resulting in equilibrium.

 

 

inhalation

No data on inhalation absorption are available in the open literature. Consequently, the percentage inhalation absorption will be related to the physical-chemical properties of cholesterol.

In humans, particles with aerodynamic diameters below 100µm have the potential to be inhaled. Based on the information on particle size of cholesterol, particles <100µm which have the potential to be inhaled are present. For the particles that have the potential to be inhaled, they will be settled in the nasopharyngeal region (larger particles <100µm), thoracic region (particles <50µm) or alveolar region (particles <15µm). Part of the deposits in the nasopharyngeal region will be coughed or sneezed out of the body, or swallowed, while a part will dissolve into the mucus lining of the respiratory tract epithelium. For risk assessment purposes, the inhalation absorption of cholesterol is set at 100% as a worst case assumption.

 

dermal

Cholesterol is a component of skin surface lipids and sebum. Skin surface lipids contain 2-20% sterols (90-95% being cholesterol). Sebum from the forearms generally contains about 5% cholesterol (half in the free form, half esterified). (9). No data on dermal absorption are available in the open literature. Consequently, the percentage dermal absorption will be related to the physical-chemical properties of cholesterol.

According to the criteria given in the REACH Guidance (2), 10% dermal absorption will be considered in case MW>500 and log Pow <-1 or >4, otherwise 100% dermal absorption should be used. As the criteria for 10% dermal absorption are not met, 100% dermal absorption should be considered for risk assessment purposes. It is, however, generally accepted that dermal absorption is lower compared to oral absorption. The 100% dermal absorption derived from the physical/chemical properties of the substance should therefore be considered a non-realistic worst case assumption, and for risk assessment purposes a lower dermal absorption value of 60% is considered more appropriate.