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Description of key information

The repeated dose toxicity of the test substance was investigated in several short-term and long-term oral-feeding studies in rats, mice and dogs as well as one 28d dermal study in rats.

SHORT-TERM TOXICITY

The short-term toxicity of Afidopyropen was investigated in 28- and 90-day oral feeding studies in rats, mice and dogs as well as in a 1-year feeding study in dogs. Additionally, a 28-day repeated dose dermal exposure study in rats was conducted.

Administration of Afidopyropen to rats, mice and dogs by the oral route resulted in organ weight increases and histopathological findings. The principal target organ in all studies was the liver, as indicated by organ weight changes and associated histopathological changes at high doses (lipid deposits). In the F344 rat, the uterus (weight decrease) and the heart (vacuolar changes) were additional target organs at high doses. Findings at the LOAEL were typically only mildly adverse (slight changes in clinical chemistry, organ weight changes without severe histopathological findings). At higher doses, particularly with the dog and mice, treatment was not well tolerated, with severe effects on clinical signs and mortality / moribundity. Dermal administration of Afidopyropen to rats for 28-days did not result in any treatment-related changes up to the limit dose of 1000 mg/kg. Based on the findings in short-term studies, a relevant overall short-term NOAEL of 15 mg/kg bw/d is proposed. This value is derived from the NOAEL in the 90-day dog study.

CHRONIC TOXICITY

The chronic toxicity of the test substance was evaluated in long-term studies in rats and mice.

In a chronic toxicity study with rats, Afidopyropen was administered to groups of Fischer rats at dietary concentrations of 0, 75, 150, 300 or 1000 ppm for a period of 1 year. There were no treatment-related effects reported for mortality, detailed and general observations, organ weights, functional examination, ophthalmology, feed efficiency, urinalysis, or body weight ratio in any of the treated groups. At the 1000 ppm dietary level, there were treatment-related decreases in body weights and food consumption of females, and alterations in hematology and biochemistry in both sexes, gross changes in the liver of one female and an increase in the incidence of fatty vacuolar changes in both the liver and the heart of females. Based on the results of this study, the no adverse effect level (NOAEL) was 300 ppm (14.6 mg/kg/day) in males and 150 ppm (8.9 mg/kg/day) in females.

In a second supplemental chronic toxicity study with rats, Afidopyropen was administered to groups of Fischer rats at dietary concentrations of 0, 1000 or 3000 ppm for a period of 1 year. There were no treatment-related clinical signs or neurobehavioral effects. Toxicity was observed in both sexes at both doses resulting in effects on bodyweight, food consumption, hematology, clinical chemistry, urinalysis, organ weights and gross pathology. Histopathological changes were observed in the liver, heart and pituitary of females. The NOAEL for all effects observed in this study was established in a prior chronic rat study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
8.9 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
GLP and guideline compliant
System:
hepatobiliary
Organ:
liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP and guideline compliant

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP and guideline compliant.

Additional information

Justification for classification or non-classification

The Afidopyropen PK studies revealed that at high doses there was high oral absorption coupled with saturated saturation of elimination and metabolism. This saturation leads to a disproportionate increase in plasma concentration of Afidopyropen as doses increase. Because the disproportionate increases in plasma concentrations occur at dose levels used in the Afidopyropen toxicology studies, the PK results are relevant to assess high-dose-specific toxicological effects observed with Afidopyropen.

The dose at which the inflection point for onset of saturated pharmacokinetics is observed is well separated from projected human doses resulting from Afidopyropen use. It is unlikely humans will be exposed to a dose level where superlinear kinetics would occur. Toxicological effects observed with Afidopyropen that occur only at dose levels above a kinetically derived maximum tolerated dose (KMD) are of questionable human relevance.

Therefore, classification according to Regulation (EU) 1272/2008, is not warranted.