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Toxicological information

Repeated dose toxicity: oral

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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

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Year:
2008
Report date:
2008
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

1
Chemical structure
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
Chemical structure
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
Chemical structure
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 / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
Iso-alpha acids present at 0, 0.01, 0.1 and 1% in the study design
Dose / conc.:
100 ppm
Remarks:
Iso-alpha acids present at 0, 0.01, 0.1 and 1% in the study design
Dose / conc.:
1 000 ppm
Remarks:
Iso-alpha acids present at 0, 0.01, 0.1 and 1% in the study design
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.

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