Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.8 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Ziram technical
- Lot no.: V755/G8803961
- Purity: 99.4%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Charles River, England
- Age at study initiation: ca. 10 weeks
- Weight at study initiation: 312-402 g (m); 200-252 g (f)

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: 1.8-2.0 / 2.76-2.87
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 0.1, 0.3, 1.0, 3.0 µg/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 0.095, 0.318, 1.153, 2.898 µg/L
Basis:
analytical conc.
No. of animals per sex per dose:
5
Control animals:
yes, sham-exposed

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS / MORTALITY:
- At least once per day

BODY WEIGHT:
- Weekly

FOOD CONSUMPTION:
- Weekly

HAEMATOLOGY:
- During Week 4
- Parameters: Haematocrit, Haemoglobin, Red Cell Count, Mean corpuscular haemoglobin concentration, Mean corpuscular volume, Mean cell haemoglobin, Total white cell count, Differential leucocyte count, Platelet count, Reticulocyte count, Prothrombin time, Activated partial thromboplastin time, morphology

CLINICAL CHEMISTRY:
- During Week4
- Parameters: Total protein, Albumin, Globulin, Urea, Creatinine, Sodium, Potassium, Calcium, Inorganic phosphorus, Chloride, Total cholesterol, Alkaline phosphatase, Total bilirubin, Glucose, ALT, AST, gGT, CPK
Sacrifice and pathology:
GROSS PATHOLOGY & HISTOPATHOLOGY

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
leukocytosis
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increased kung weight
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Inflammatory and proliferative lesions were found in the respiratory tract
Histopathological findings: neoplastic:
no effects observed
Details on results:
Organ weights
Group mean bodyweight-adjusted lung weights of animals exposed to 3.0 µg/L or females exposed to 1.0 µg/L were slightly higher than the concurrent controls following 4 weeks of exposure. This finding showed reversibility following a 4 week withdrawal period.

Microscopic pathology
Inflammatory and proliferative lesions were found in the respiratory tract of rats from the high, high intermediate and low intermediate dose groups killed after the 28 day treatment period. In general, the changes showed a dose-relationship although, in the larynx, changes in the high and high intermediate dose groups were similar in degree. The slight increase in lung weight in high dose males and females and high intermediate dose female animals was considered to be attributable to these lesions.
Following the 28 day reversibility period there was complete recovery of the trachea and tracheal bifurcation lesions, partial recovery of the lung lesions and some evidence of recovery of the laryngeal lesions.
There were no treatment-related histological changes found in rats from the low dose group.

Effect levels

open allclose all
Dose descriptor:
NOEC
Effect level:
0.1 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: = 0.027 mg/kg/day, based on histopathological findings in the larynx, species-specific local effect.
Dose descriptor:
NOAEC
Effect level:
0.3 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: = 0.081 mg/kg/day, if the larynx effects are considered to be a species specific adaptive change, resulting from irritation.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion