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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets basic scientific principles, specific focus on prostrate, no further endpoints examined, single dose group only

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Early Stages of the Pathogenesis of Rat Ventral Prostate Hyperplasia / Induced by Citral
Author:
Servadio C, Abramovici A, Sandbank U, Savion M, Rosen M
Year:
1986
Bibliographic source:
Eur. Urol. 12, 195-200
Reference Type:
other: Abstract for scientific meeting
Title:
Further observations on the citral-induced experimental model of benign prostatic hyperplasia (BPH) in the rat
Author:
Servadio C, Abramovici A
Year:
1986
Bibliographic source:
Urol. Res. 14, 172

Materials and methods

Principles of method if other than guideline:
Specific histological examination of prostates for induction of benign hyperplasia
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Citral

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 6 weeks
- Weight at study initiation: 150 g
- Fasting period before study: none
- Diet: standard chow pellets ad libitum
- Water: ad libitum
- Special pretreatment: animals from groups II and V were subjected to bilateral surgical orchidectomy 24 hrs prior to start of citral treatment

ENVIRONMENTAL CONDITIONS: climatized environment
- Temperature (°C): not specified
- Humidity (%): not specified
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
open
Vehicle:
other: 70 % ethanol
Details on exposure:
Route of Administration: dermal
TEST SITE
- Area of exposure: shaved skin of the back
- % coverage: no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.2 mL of a solution of citral dissolved in 70 % ethanol
- Concentration (if solution): not specified

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility

USE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
10, 20, 30, 60, 90 days (intact rats)
10, 20, 30, 40, 50, 60 days (orchidectomized rats)
Frequency of treatment:
5 d/w
Doses / concentrations
Remarks:
Doses / Concentrations:
150 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
not specified (N=54 in total)
Control animals:
yes, concurrent vehicle
Details on study design:
Study groups:
I: citral treatment, intact rats
II: citral treatment, orchidectomized rats
III: untreated control
IV: vehicle control, intact rats
V: vehicle control, orchidectomized rats
Positive control:
no

Examinations

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, only prostrate
prostrate weight and macroscopic examination

HISTOPATHOLOGY: Yes, only prostrate
microscopic examination

Results and discussion

Results of examinations

Details on results:
GROSS PATHOLOGY
Prostrate weight: progressive increase in citral-treated rats (group I) with duration of treatment visible after 10 days of treatment compared to untreated and vehicle control (III and IV); significant reduction in group II (citral-treated, castrated rats) within 10 days compared to untreated and vehicle control (III and IV); weights after 60 days of treatment: group I: 1.44 +- 0.24 g, III: 0.88 +- 0.10 g, IV: 0.92 +- 0.08 g

Macroscopic examination: enlarged ventral prostrate in group I, atrophic prostrate in group II, both compared to untreated control (III)


HISTOPATHOLOGY: NON-NEOPLASTIC
Group I: definite lesions already after 10 days of treatment, becoming progressively more pronounced with duration of treatment expanding over many lobules at time;
findings after 1 mo: enhanced epithelial hyperplasia, stromal elements less reactive
findings after 3 months: significant proliferation of the acini, cystic dilatation lined by atrophic flat cuboid cells; supporting stroma more prominent than in the normal prostrate, mild chronic inflammatory foci often seen, intraluminal secretion deeply eosinophilic and more viscous

Group II: castration prior to citral administration prevented benign prostratic hyperplasia
No data specified for Group V.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion