3,5-dihydroxy-2,6,6-tris(3-methylbuten-2-yl)-4-(3-methyl-1-oxobutyl)cyclohexa-2,4-dien-1-one

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Literature assessment

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Hop extracts has a long history of use in foods from naturtal sources and have some theraputic activity.
These substances have been well-evaluated for safety and are shown not to accumulate.

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline required

Version / remarks:

Literature search and review

Principles of method if other than guideline:

Work is being done by various groups to investigate toxicology and also uptake, metabolism and excretion of hop extracts and hop substances. Further animal tests are therefore not warranted, since this is becoming an active field of interest. The approach has been to examine the recent scientific literature and consider the weight of evidence.

Specific details on test material used for the study:

The review covers a range of hop extracts and oils

Species:

other: Based on human work

Sex:

male/female

Details on exposure:

Exposure is typically orally in foods and drink, but in the workplace, dermal exposure and inhalation of particulates (eg spray from liquid forms) may occur.
The research documents reviewed typically relate to oral exposure.

Type:

absorption

Results:

A high rate of absorption is known following ingestion; dermal absorption considered < 50%

Type:

distribution

Results:

No target organs were identified

Type:

metabolism

Results:

The hop extracts and oils are non-accumulative and are assumed to metabolise

Type:

excretion

Results:

It is not known if excretion is in the form of the parent compounds or as metabolites

Details on absorption:

When these substances were given orally, 5.1%, 4.7% and 15.5% of iso-α-acids, rho-iso-α-acids and tetrahydroiso-α-acids, respectively, were not absorbed, suggesting a high rate of adsorption from ingestion.

The weight of evidence does not suggest that the acute dermal toxicity of hop extract would be significantly higher than the acute oral toxicity.
Absorption is therefore assumed, but dermal penetration of 'essential oils' have suggested penetration rates of < 50% for terpenes.

Details on distribution in tissues:

No target organs have been identified, but in view of known metabolic processes, it is assumed the extracts and oils are distributed in the body.

Details on excretion:

Hop oils are used in foods and drinks and there is no indication of accumulative effects from life-time exposure.
The fate of iso-α-acids in human volunteers after consumption of beer has been investigated. The estimated half-life was approximately 0.5 hour. Only trace amounts of unmodified iso-α-acids were detected in the urine, suggesting rapid metabolism with excretion of metabolites.
The same authors also investigated reduced iso-α-acids in human volunteers.Here the half-lives were similarly short – around 0.6 – 0.8 hour.

Metabolites identified:

yes

Details on metabolites:

The rabbit liver microsome system had metabolised all of the β-acids, 77% of the α-acids, and 48% of the iso-α-acids after 120 hours of incubation.
• α-acids were transformed to iso-α-acids, and to humulinones and hulupones;
• β-acids were transformed to hulupones and to various tricyclolupulones;
• iso-α-acids were transformed to humulinic acids and various alloisohumulones.

There was considerable metabolism of
these compounds – bioavailabilities were estimated as 13%, 28% and 23%. It seemed as if
phase I metabolism was the main process for iso-α-acids, but that phase II metabolism, where
conjugation was observed, occurred for rho-iso-α-acids.

Conclusions:

The picture that emerges from these recent studies shows that hop bitter acids are bioavailable, they are fairly rapidly metabolised, principally by cytochrome-mediated phase I metabolism, and that the metabolic products are similar to the already-known oxygenated products found in aged beer and hops.

Hop essential oil is a complex mix of substances. Not surprisingly, it was found that some compounds were not changed by the in vitro digestion model, whereas others were modified. Components with a hydroxyl group (such as the oxygenated terpenes) were thought to be very bioavailable.
In line with the bitter acids, certain alcohols were predicted to undergo intestinal first pass metabolism.

Executive summary:

Hops and hop extracts are increasingly being investigated for their beneficial health effects.

• Hop extract itself is not acutely toxic (LD50 >2,000 mg per kg bw for most hop extracts; potentially 1,000 – 2,300 mg per kg bw for β-acid-enriched extracts).

• The bitter acids (α-, β- and iso-α-acids are thought to be metabolised principally by phase I, leading to oxygenated derivatives that are similar to oxygenated compounds found in aged hops and aged beer. Rabbit and human data have shown that iso-α-acids have a short half-life.

• Oxygenated derivatives, known as matured hop bitter acids, have themselves been trialled as therapeutic agents in a human trial, and were considered to be safe over the 12-week period.

• Taken together, these data suggest that further animal studies on hop toxicokinetics are not warranted. In view of the growing interest in hop-derived compounds as possible therapeutic substances, more information on safety and toxicology will emerge as new therapeutic target compounds are tested.

Description of key information

Hops and hop extracts are increasingly being investigated for their beneficial health effects.

• Hop extract itself is not acutely toxic (LD50 >2,000 mg per kg bw for most hop extracts; potentially 1,000 – 2,300 mg per kg bw for β-acid-enriched extracts).

• The bitter acids (α-, β- and iso-α-acids are thought to be metabolised principally by phase I, leading to oxygenated derivatives that are similar to oxygenated compounds found in aged hops and aged beer. Rabbit and human data have shown that iso-α-acids have a short half-life.

• Oxygenated derivatives, known as matured hop bitter acids, have themselves been trialled as therapeutic agents in a human trial, and were considered to be safe over the 12-week period.

• Taken together, these data suggest that further animal studies on hop toxicokinetics are not warranted. In view of the growing interest in hop-derived compounds as possible therapeutic substances, more information on safety and toxicology will emerge as new therapeutic target compounds are tested.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

80