1,4-dioxane

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

other: Review article on Mode of Action evaluation

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

Data source

Reference

Reference Type:

publication

Title:

Update: Mode of action (MOA) for liver tumors induced by oral exposure to 1,4-dioxane

Author:

Michael L. Dourson, Jeri Higginbotham, Jeff Crum, Heather Burleigh-Flayer, Patricia Nance, Norman D. Forsberg, Mark Lafranconi, John Reichard

Year:

2017

Bibliographic source:

Regulatory Toxicology and Pharmacology 88

Materials and methods

Type of study / information:

The mode of action of 1,4-dioxane induced liver tumor formation in rodents was evaluated. Results from previous repeated dose toxicity studies were re-evaluated and non-genotoxic pre-neoplastic events were identified.

Test guideline

Qualifier:

no guideline available

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,4-dioxane

EC Number:

204-661-8

EC Name:

1,4-dioxane

Cas Number:

123-91-1

Molecular formula:

C4H8O2

IUPAC Name:

1,4-dioxane

Results and discussion

Any other information on results incl. tables

A reanalysis of data from two chronic mouse cancer bioassays on 1,4 - dioxane, one 13-week mouse study, seven rat cancer bioassays, coupled with other data such as 1,4 -dioxane's negative mutagenicity, its lack of up-regulated DNA repair, and the appearance of liver tumors with a high background incidence, support the conclusion that rodent liver tumors, including those in mice, are evoked by a regenerative hyperplasia MOA.

The initiating event for this MOA is metabolic saturation of 1,4-dioxane. Above metabolic saturation, higher doses of the parent compound cause an ever increasing toxicity in the rodent liver as evidenced by higher blood levels of enzymes indicative of liver cell damage and associated histopathology that occurs in a dose and time related manner. Importantly, alternative modes of action can be excluded.

The observed liver toxicity has a threshold in the dose scale at or below levels that saturate metabolism, and generally in the range of 9.6 - 42 mg/kg-day for rats and 57 to 66 mg/kg-day for mice. It follows that threshold approaches to the assessment of this chemical's toxicity are supported by the non-mutagenic, metabolic saturation kinetics, and cytotoxicity generated regenerative repair information available for 1,4-dioxane promoted rodent liver tumors.