Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: dermal
Remarks:
other: Subacute - 5 day repeated dose application
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Screening study with main focus on male reproductive organs. Meets basic scientific principles with acceptable restrictions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Principles of method if other than guideline:
Groups of 5 Fu male albino rats/dose received occluded applications of pure test material 6 h/day for 5 consecutive days. Observations conducted included mortality, body weight, general symptoms, necropsy and microscopic examination of the testes and epididymides. Sacrifice was day 7
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Source: Givaudan Vernier
- Analytical purity: 99.1%
- Physical state and appearance: liquid, colourless to pale yellow
- Stability: 1 yr (in container)
- Batch: 180949

Test animals

Species:
rat
Strain:
other: Fuellinsdorf albino (also known as ibm:RORO (SPF))
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Biological Research Laboratories Ltd., Füllinsdorf, Switzerland
- Housing: 1 animal/cage
- Age at study initiation: male, 8 weeks
- Weight at study initiation: 216.5 g
- Diet: ad libitum (Kliba maintenance diet No 343 (pellet), defined and certified for acceptable contaminant
- Water: ad libitum (tap water)
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-65
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Application site: back
- Area of exposure: 10 % of total body surface area
- After application the dressing was wraped around the abdomen and fixed with an elastic adhesive bandage
- Duration of treatement: 6h

REMOVAL OF TEST SUBSTANCE
- Washing: Yes, with absolute ethyl alcohol and warm water
- Time after start of exposure: 6h

TEST MATERIAL
- Amount(s) applied: no data
- Concentration (if solution): undiluted
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 days
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
250; 500; 1000; 2000 mg/kg
Basis:
other: nominal
No. of animals per sex per dose:
5 male animals
Control animals:
no
Details on study design:
- Justification for choice of animals: The authors stated that rats are a species acceptable by regulatory authorities with documented susceptibility to a wide range of toxic substances. Futhermore, historical data was available to the authors from studies performed in the same labs using this strain. In addition, there were adequate references in the scientific literature to assist in the assessment of the changes observed in the treated animals

The 1st treatment day was defined as day 0, week 0. The 2nd treatment day was defined as day 1, week 1. The 1st treatment week started on day 1 and terminated on day 5. After dosing, the animals were observed for another 2 days before sacrifice.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: days 0, 1, 2, 3, 4, 7
- Cage side observations checked included: behaviour, vivacity, signs of injury, signs of sickness and abnormality. All lesions or symptoms deviating from normal were recorded for each individual rat

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

MORTALITY: Yes
- Check conducted continuously

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 1, 2, 3, 4, 7

HISTOPATHOLOGY
- Organs examined: testes, epididymides, gross lesions, examined microscopically
Sacrifice and pathology:
SACRIFICE
- Schedule: at termination (day 7)
- Fasting before sacrifice: Yes, overnight
- Number of animals: all survivors
- Method: exsanguination after CO2 narcosis, incision of the aorta

GROSS PATHOLOGY: Yes

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
- No symptoms were observed during the course of the study

BODY WEIGHT AND WEIGHT GAIN
- Control; 250; 500; 1000 mg/kg: body weight increased steadily during throughout the study
- 2000 mg/kg: Mean body weight was depressed immediately after first administration. Maximum decrease observed was 2% compared to day 0 . The animals of this group did not regain the pretreatment weight until after the application of the last dose.

GROSS PATHOLOGY
- No substance related necropsy findings

HISTOPATHOLOGY:
- 2000 mg/kg: marked atrophy of testes
Seminiferous tubules with disorganization of the epithelial structure, decrease of the number of germ cells, increase of the number of degenerating germ cells (inclusive giant cells) were observed in combination with immature/degenerating germ cells in epididymides and the occurrence of spermatocele.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: testes with additional systemic toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion