CARAZOLOL

Overview

Chemical Names

4-(2-HYDROXY-3-ISOPROPYL-AMINO-PROPOXY)-CARBAZOLE, 1-(CARBAZOLE-4-YL-OXY)-2- HYDROXY-3-ISOPROPYLAMINO-PROPANE, 1-(4-CARBAZOLYLOXY)-3-(ISOPROPYLAMINO)-2- PROPANOL

CAS number

57775-29-8

Functional Class

Veterinary Drug
beta-ADRENOCEPTOR_BLOCKING_AGENT

Evaluations

Evaluation year: 2000

Comments:

The Committee considered the beta-adrenoceptor-blocking activity of carazolol to be a relevant acute effect and concluded that the establishment of an acute RfD was appropriate in this case. The Committee established an acute RfD of 0.0001 mg/kg bw, based on a NOEL of 0.5 µg/kg bw for reduced respiratory function from a clinical study in patients suffering from either chronic bronchitis or asthma and a safety factor of 5. This safety factor was used because the NOEL was observed in highly sensitive individuals with chronic bronchitis or asthma, who form a substantial part of the general population. The acute RfD provides a margin of safety of 100 in healthy subjects, and the Committee concluded that it therefore made adequate allowance for variation among individuals in the population. As residues of carazolol at the injection site 2 h after treatment could result in an intake that exceeds the acute RfD, the Committee stated that, unless appropriate measures can be taken to ensure that this does not occur, use of carazolol during the transport of animals to slaughter is not consistent with safe use of the drug.

MRL Comment:

The MRLs recommended at the forty-third meeting were not revised: 5 µg/kg (muscle & fat or skin) & 25 µg/kg (liver and kidney)

MRL Code:

MRL

Intake:

18 µg, for concentration of 60 µg/kg at the injection site 2-h after injection, where residues are at the recommended MRLs for carazolol of 5 µg/kg (muscle & fat or skin) & 25 µg/kg (liver and kidney).

Tolerable Intake:

0-0.0001 mg/kg bw (ARfD)

Meeting:

Report:

TRS 893-JECFA 52/13

Tox Monograph:

FAS 43-JECFA 52/3

Residues:

FNP 41/12-JECFA 52/137

Toxicological study

Pivotal Study:

Clinical study (Huckauf, 1981): A single oral dose of 0.1 or 0.7 mg carazolol/person administered to 2 groups of 5 patients (9 males, 1 female aged 40 to 69 years) with chronic bronchitis or asthma. Reductions in VC and FEV1 were detected 2 hours after administration at both dose levels. A no-effect levels were extrapolated to be of 0.4 µg/kg bw and 0.1 µg/kg bw for the effects on VC & FEV1, respectively. After correcting the difference in starting values of both parameters between the two dose groups, the overall NOEL was 0.5 µg/kg bw.

Animal Specie:

Human

Effect:

Decreased respiratory function

NOEL:

0.5 µg/kg bw

Point of departure:

0.5 µg/kg bw in asthmatics

Previous Years:

1994, TRS 855-JECFA 43/5, FNP 41/7-JECFA 43/9, FAS 34-JECFA 43/3. 0-0.0001. MRLs (EXPRESSED AS PARENT DRUG): MUSCLE AND FAT/SKIN (PIGS): 0.005; LIVER AND KIDNEY (PIGS): 0.025. FU. MRL 1991, TRS 815-JECFA 38/7, FNP 41/4-JECFA 38/23, FAS 29-JECFA 38/3. 0-0