# The Approximate Subcutaneous LD50 and Associated Lesions Induced by Ivalin, Extracted and Purified from Geigeria aspera Harv., in Sprague–Dawley Rats

## TL;DR

This study examines the toxicity of ivalin in rats and finds that it causes acute mortality with minimal muscle damage, suggesting a different mechanism than in ruminants.

## Contribution

The study provides a validated LD50 for ivalin in rats and suggests a new mechanism for its toxicity.

## Key findings

- Subcutaneous ivalin exposure in rats caused acute mortality with minimal muscle pathology.
- The calculated LD50 for ivalin in rats is 135.4 mg/kg BW.
- Toxicity in rats is likely due to mitochondrial energy pathway disturbances rather than muscle damage.

## Abstract

“Vomiting disease” in ruminants is one of the most economically significant phytotoxicities in South Africa and is caused by chronic ingestion of sesquiterpene lactone compounds present in plants of the Geigeria genus. Affected livestock demonstrate mortality due to actin and myosin damage in the striated musculature; however, a validated parental-exposure laboratory animal model would be useful for further study of the toxicodynamics. We exposed Sprague–Dawley rats to ivalin in a sequential dosing procedure and evaluated clinical signs, mortality, histopathology and muscle ultrastructure. Three of the five exposed rats died acutely, and a maximum likelihood estimate method was used to calculate a Median Lethality (LD50) of 135.4 mg/kg Body Weight (BW). Striated muscle in exposed rats showed only minimal and inconsistent histopathological and ultrastructural changes. Subcutaneous ivalin exposure causes acute mortality with minimal muscle pathology, contrasting with the more protracted muscular disease seen in ruminants after plant ingestion. This suggests toxicity by parenteral exposure is due to another mechanism, most likely mitochondrial energy pathway disturbances. Whilst subcutaneously exposed rats do not appear to provide a suitable model for oral sesquiterpene lactone exposure in ruminants, this study provides a starting dose for further investigation of plant extracts in both species.