1-Piperidinecarboxylic acid, 4-(8-chloro-5,6-dihydro-11H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-ylidene)-, ethyl ester

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference Type:

publication

Title:

Physicians' Desk Reference. 50th Ed. Montvale, NJ: Medical Economics Co. p.2349-50 (1996)

Year:

1996

Bibliographic source:

Physicians' Desk Reference. 50th Ed. Montvale, NJ: Medical Economics Co. p.2349-50 (1996)

Materials and methods

Test guideline

Qualifier:

no guideline available

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

ethyl 4-{13-chloro-4-azatricyclo[9.4.0.0³,⁸]pentadeca-1(15),3(8),4,6,11,13-hexaen-2-ylidene}piperidine-1-carboxylate

EC Number:

935-907-9

Cas Number:

79794-75-5

Molecular formula:

C22H23ClN2O2

IUPAC Name:

ethyl 4-{13-chloro-4-azatricyclo[9.4.0.0³,⁸]pentadeca-1(15),3(8),4,6,11,13-hexaen-2-ylidene}piperidine-1-carboxylate

Test material form:

solid: particulate/powder

Test animals

Species:

other: Mice and rats

Strain:

not specified

Sex:

male/female

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

18 months study (mice)
24 months study (rats)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

40 mg/kg bw/day

Remarks:

mice

Doses / concentrations 2

Dose / conc.:

25 mg/kg bw/day

Remarks:

rats

Results and discussion

Results of examinations

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Male mice given 40 mg/kg had a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) than concurrent controls.
In rats, a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg and males and females given 25 mg/kg.

Target system / organ toxicity

Critical effects observed:

yes

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

In an 18 month oncogenicity study in mice and a 2 year study in rats, loratadine was administered in the diet at doses up to 40 mg/kg (mice) and 25 mg/kg (rats). In the carcinogenicity studies, pharmacokinetic assessments were carried out to determine animal exposure to the drug. AUC data demonstrated that the exposure of mice given 40 mg/kg of loratadine was 3.6 (loratadine) and 18 (active metabolite) times higher than a human given 10 mg/kg. Exposure of rats given 25 mg/kg of loratadine was 28 (loratadine) and 67 (active metabolite) times higher than a human given 10 mg/day. Male mice given 40 mg/kg had a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) than concurrent controls. In rats, a significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg and males and females given 25 mg/kg.