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

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

other: Published LD50 values for lupulone are reported in the US Library of Medicine Toxnet ChemIDplus entry for lupulone; discussed in EMEA assessment report that cites Hagers Handbuch

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

equivalent or similar to guideline

Guideline:

other: Data obtained from Handbook, and cited in EMEA assessment of hop extracts

GLP compliance:

not specified

Test type:

other: Data obtained from Handbook, and cited in EMEA assessment of hop extracts

Species:

other: rat and mouse data cited in EMEA assessment and in Handbook

Key result

Dose descriptor:

LD50

Effect level:

> 100 - <= 1 800 mg/kg bw

Remarks on result:

other: LD50 of 700 mg per kg bw is reasonable based on available data and related compounds

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

An assessment report of Humulus lupulus by the European Medicines Agency (EMEA) in 2014 is available on the web. This report also quotes LD50 values for lupulone of 525 mg/kg/bw p.o., 1,200 mg/kg/bw s.c., and 600 mg/kg/bw s.c. for mice. The EMEA report quotes further LD50 values for lupulone of 1,800 mg/kg/bw p.o. and 330 mg/kg/bw i.m. for rats. Similar LD50 values for humulone (one of the hop α-acids, with a closely-related structure to the β-acids) are also quoted: 1,500 mg/kg/bw p.o. and 600 mg/kg/bw i.m. for rats.

Since LD50 values for β-acids have been quoted in the scientific literature, further animal studies are not warranted.

The LD50 values for oral administration of lupulone range from 100 – 1,800 mg per kg bw, with a mean value of 711 mg per kg bw. A read-across value of 1,500 mg per kg bw for the closely-related humulone adds weight to this being the appropriate order of toxicity. An LD50 of ca. 700 mg/kg for β-acids triggers a classification of Category 4 for Acute Toxicity according to Regulation (EC) 1272/2008, section 3.1.2.1, with the Signal Word “Warning”, the Hazard Statement “H302: Harmful if swallowed” (Regulation (EC) 1272/2008, section 3.1.4).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

700 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Dose descriptor:

LD50

Value:

700 mg/kg bw

Justification for classification or non-classification

An assessment report of Humulus lupulus by the European Medicines Agency (EMEA) in 2014 is available on the web.  This report also quotes LD50 values for lupulone of 525 mg/kg/bw p.o., 1,200 mg/kg/bw s.c., and 600 mg/kg/bw s.c. for mice. The EMEA report quotes further LD50 values for lupulone of 1,800 mg/kg/bw p.o. and 330 mg/kg/bw i.m. for rats. Similar LD50 values for humulone (one of the hop α-acids, with a closely-related structure to the β-acids) are also quoted: 1,500 mg/kg/bw p.o. and 600 mg/kg/bw i.m. for rats.

Since LD50 values for β-acids have been quoted in the scientific literature, further animal studies are not warranted.

The LD50 values for oral administration of lupulone range from 100 – 1,800 mg per kg bw, with a mean value of 711 mg per kg bw. A read-across value of 1,500 mg per kg bw for the closely-related humulone adds weight to this being the appropriate order of toxicity. An LD50 of ca. 700 mg/kg for β-acids triggers a classification of Category 4 for Acute Toxicity according to Regulation (EC) 1272/2008, section 3.1.2.1, with the Signal Word “Warning”, the Hazard Statement “H302: Harmful if swallowed” (Regulation (EC) 1272/2008, section 3.1.4).

Further animal studies are not warranted for either the acute dermal toxicity or the acute inhalation toxicity end-points:

1. The substance is a UVCB with principal components being the hop β-acids, present as the potassium salt. There are no hop essential oils.

2. Oral LD50 values have been published for β-acids, for the closely-related α-acids, and for hop extract.

3. The weight of evidence does not suggest that the acute dermal toxicity of the β-acids would be significantly higher than the acute oral toxicity. Reported values for the intramuscular or subcutaneous LD50 of lupulone (one of the main β-acids) was of the same order of magnitude as that for oral administration.

4. The Cosmetic Ingredient Review Expert Panel and the European Flavour and Fragrances Association (EFFA) did not classify hop extract (hop extract contains β-acids) with dermal toxicity.

5. The β-acids are not volatile. The volatile component of hop extract is the essential oil, but this has been removed for the β-acids product under consideration.