Hop, Humulus lupulus, ext.

Repeated dose toxicity: oral

Administrative data

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:

guideline study without detailed documentation

Data source

Reference

Reference 1

Reference Type:

other company data

Title:

Unnamed

Year:

2008

Report date:

2008

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1960

Report date:

1960

Materials and methods

Test guideline

Qualifier:

no guideline available

Version / remarks:

The experiment has been cited, discussed and referred to as evidence for low toxicity in Chappel et al. (1998) Food Chem. Toxicol. volume 36, pp. 915-922 and in Gerhauser C (2005) Eur. J. Cancer vol. 41, pp. 1941-1954.

Principles of method if other than guideline:

90-day subactue toxicity feeding study set up using 1, 0.1 and 0.01% of hop iso-alpha acids in corn oil, plus a negative control, fed to 21-day-old Sprague-Dawley rats.

GLP compliance:

not specified

Test material

Test material information

1

Reference substance name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-2-(3-methyl-1-oxobutyl)-4-(4-methyl-1-oxopent-3-enyl)cyclopent-2-en-1-one

EC Number:

247-072-1

EC Name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-2-(3-methyl-1-oxobutyl)-4-(4-methyl-1-oxopent-3-enyl)cyclopent-2-en-1-one

Cas Number:

25522-96-7

Molecular formula:

C21H30O5

IUPAC Name:

3,4-Dihydroxy-5-(3-methylbut-2-enyl)-2-(3-methyl-1-oxobutyl)-4-(4-methyl-1-oxopent-3-enyl)cyclopent-2-en-1-one

2

Reference substance name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-4-(4-methyl-1-oxopent-3-enyl)-2-(2-methyl-1-oxopropyl)cyclopent-2-en-1-one

EC Number:

246-780-8

EC Name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-4-(4-methyl-1-oxopent-3-enyl)-2-(2-methyl-1-oxopropyl)cyclopent-2-en-1-one

Cas Number:

25269-20-9

Molecular formula:

C20H28O5

IUPAC Name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-4-(4-methyl-1-oxopent-3-enyl)-2-(2-methyl-1-oxopropyl)cyclopent-2-en-1-one

3

Reference substance name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-2-(2-methyl-1-oxobutyl)-4-(4-methyl-1-oxopent-3-enyl)cyclopent-2-en-1-one

EC Number:

246-967-4

EC Name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-2-(2-methyl-1-oxobutyl)-4-(4-methyl-1-oxopent-3-enyl)cyclopent-2-en-1-one

Cas Number:

25422-83-7

Molecular formula:

C21H30O5

IUPAC Name:

3,4-dihydroxy-5-(3-methylbut-2-enyl)-2-(2-methyl-1-oxobutyl)-4-(4-methyl-1-oxopent-3-enyl)cyclopent-2-en-1-one

Test material form:

liquid

Details on test material:

Isomerized hop extract present as 50% suspension in corn oil

Specific details on test material used for the study:

Isomerized hop extract present as a 50% suspension in corn oil. This will be an extract enriched in hop iso-alpha acids.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

corn oil

Details on oral exposure:

Rats provided with test ration and water ad libitum.

Duration of treatment / exposure:

90 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm

Remarks:

Iso-alpha acids present at 0, 0.01, 0.1 and 1% in the study design

Doses / concentrations 2

Dose / conc.:

100 ppm

Remarks:

Iso-alpha acids present at 0, 0.01, 0.1 and 1% in the study design

Doses / concentrations 3

Dose / conc.:

1 000 ppm

Remarks:

Iso-alpha acids present at 0, 0.01, 0.1 and 1% in the study design

Doses / concentrations 4

Dose / conc.:

10 000 ppm

Remarks:

Iso-alpha acids present at 0, 0.01, 0.1 and 1% in the study design

No. of animals per sex per dose:

10

Examinations

Observations and examinations performed and frequency:

Animals weighed and their food consumption measured weekly. Periodic check for abnormal blood elements and urine elements made on high level groups and control.

Sacrifice and pathology:

Certain organs weighed (body, liver, heart, spleen, kidneys, gonads); certain organs examined microscopically (heart, lung, spleen, liver, pancreas, stomach and intestine, mesenteric lymph nodes, salivary glands, thyroid, kidney, urinary bladder, ovary or testis, uterus or prostate, bone and bone marrow)

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Reduced weight gain at the highest level (1%), but no changes in weights of liver, heart, spleen, kidneys or gonads, and no histopathological changes. The reduced weight gain is likely to be due to the unpalatibility of teh bitter iso-alpha acids.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced weight gain at the highest level (1%), but no changes in weights of liver, heart, spleen, kidneys or gonads, and no histopathological changes. The reduced weight gain is likely to be due to the unpalatibility of teh bitter iso-alpha acids

Effect levels

Key result

Dose descriptor:

dose level: Highest dose rate (1%) led to reduced weight gains; no changes observed in weights of liver, heart, spleen, kidneys or gonads were noted, and no histopathological changes noted.

Effect level:

ca. 10 000 ppm

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Discussion in JI Haas proprietary documents for GRAS approval of iso-alpha acids:highest dose rate (1%) led to reduced weight gains; no changes observed in weights of liver, heart, spleen, kidneys or gonads were noted, and no histopathological changes noted. If the reduced weight gain is seen as toxicologically significant, then NOAEL would be equivalent to 50-75 mg per kg bw per day, but if the weight loss was due to the unpalatability of the bitter iso-alpha acids, NOAEL would be 500 - 750 mg per kg bw per day.