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

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Intragastric administration of lupulone. Publication useful for assessment since it contains data for experiments on rats, rabbits, guinea pigs and monkeys. In view of all of these animal experiments having been published, further animal studies are not warranted.

Qualifier:

no guideline available

Principles of method if other than guideline:

Subacute intragastric toxicity was studied in young male rats, with lupulone administered once daily fo 12 days. All surviving animals were sacrificed and specimens were investiagted for pathology. Similar studies were made in rabbits, guinea pigs and monkeys, but no monkey was sacrificed.

GLP compliance:

not specified

Specific details on test material used for the study:

Lupulone was suspended in 6% gum acacia in proper concentrations.

Species:

rat

Sex:

male

Details on test animals or test system and environmental conditions:

Tests were also made on rabbits, guinea pigs and monkeys.

Route of administration:

other: Intragastric

Duration of treatment / exposure:

12 days

Frequency of treatment:

Once per day

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

450 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

6

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Stated in the publication: "Only one rat fed 300 mg per kg bw per day died on the twelfth day. Grossly there were no observable lesion in any animal."

Also: "Rats, rabbits, guinea pigs and monkeys tolerated repeated daily intragastric doses for 2 weeks without showing apparent ill effects. The growth of the rats receiving the top two doses was reduced in the second week. Laboratory findings showed no significant changes. The pathologic sections of about half the animals revealed a spotty mononuclear-leukocytic infiltration in the lungs, usually around bronchi and bronchioles."

Key result

Dose descriptor:

dose level: Only one rat fed 300 mg per kg bw per day died on the twelfth day. Grossly there were no observable lesion in any animal. The growth of the rats receiving the top two doses was reduced in the second week. Laboratory findings showed no significant changes.

Effect level:

ca. 300 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

body weight and weight gain

Key result

Critical effects observed:

no

Conclusions:

The publication shows that rats, rabbits, guinea pigs and monkeys tolerated daily intragastric doses of lupulone for two weeks without showing apparent ill effects.
The dose rate for rats was 1/4, 1/6 and 1/12 of the LD50.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

other: Summary of weight of evidence for hop beta acids

Adequacy of study:

other information

Justification for type of information:

See the attached background material. Company Report BI/YYF/REACH/2018 -006 gives a comprehensive summary of the existing data relating to hop extract toxicity and why further animal studies are not warranted. This document shows that hop extracts and their derivatives have already been assessed as safe for1. food (US FDA),2. medicinal use (EMEA assessment), and3. cosmetic use (Cosmetic Ingredient Review Panel). The other 5 documents are attached for ease of reference since they are cited in BI/YYF/REACH/2018 -006 and provide further relevant information.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

The publication cited for endpoint Repeated dose toxicity: oral.001 shows that rats, rabbits, guinea pigs and monkeys tolerated daily intragastric doses of lupulone for two weeks without showing apparent ill effects.

The dose rate for rats was 1/4, 1/6 and 1/12 of the LD50.