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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 6 May 1999 to 3 Sept 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Data source

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

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: not stated
- Age at study initiation: 9 wk
- Weight at study initiation: 118-141 g (m); 93-121 g (f)
- Housing: suspended wire mesh cages, individually housed
- Diet: standard diet ad libitum
- Water: drinking water ad libitum (except during exposure)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-25
- Humidity (%): 29-72
- Photoperiod (hrs dark / hrs light): 12 h/ 12 h

IN-LIFE DATES: From: 1999-06-06 To: 1999-09-03

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: not applicable
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Method of holding animals in test chamber: exposure tube
- Source and rate of air: conditioned, filtered compressed air
- Air flow rate: 19-31 lpm

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: taken from 5 locations in the exposure chamber 1/hr

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
target concentrations: 0, 15, 150, 600, 2500 ppm
measured concentrations: 0, 14.9, 187, 601, 2519 ppm
Duration of treatment / exposure:
90 days, 6 hr/day, 5 days/wk
Frequency of treatment:
daily (excluding weekends)
No. of animals per sex per dose:
10 for the 15, 150 and 600 ppm groups
20 for the 2500 ppm groups
25 for controls
Details on study design:
Post-exposure recovery period in satellite groups: 4-wk (0, 2500 ppm)
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 2x/day, 1x/day at weekends

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: consumption determined weekly

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: start and completion of study
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at sacrifice
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: Yes
- How many animals: all
- Parameters examined: See Table 1

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at sacrifice
- Animals fasted: Yes
- How many animals: all
- Parameters examined: See Table 1

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see Table 2)
HISTOPATHOLOGY: Yes (see Table 2)
ORGAN WEIGHTS: Yes (see Table 2)
Other examinations:
None.
Statistics:
Mean and standard deviations were calculated for all measured parameters. Group means were compared by ANOVA. Where significant effects were identified a further comparison was made with the control group using Dunnett’s test. The level of statistical significance was p<=0.05 in all cases.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No deaths but overt clinical signs (e.g. wet/discoloured fur) were seen at >= 600 ppm

BODY WEIGHT AND WEIGHT GAIN
2500 ppm transient reduction body weight gain (males, wk 1-3)

OPHTHALMOSCOPIC EXAMINATION
No effects.

HAEMATOLOGY
Blood effects (incl. decreased haemoglobin and haematocrit) seen in males at >=600 ppm, with partial recovery. Considered to be indicative of mild reversible microcytic anaemia.

CLINICAL CHEMISTRY
>=15 ppm: alkaline phosphatase was reduced in males
>=150 ppm: alkaline phosphatase was reduced in females
The biological significance of these changes was said to be unclear.
>= 600 ppm: decreased glucose in males.
2500 ppm: various other clinical chemistry changes in both sexes (e.g. increased serum protein and gamma glutamyl transpeptidase and decreased chloride). Potassium and calcium were increased in males and triglycerides increased in females.

ORGAN WEIGHTS
Liver weight was increased in all treated groups in a dose-dependant manner. The increases were not statistically significant in all cases and the increases in 15 ppm females were slight. At recovery, liver weight was comparable to controls for 2500 ppm males and only slightly elevated for 2500 ppm females (recovery groups were limited to 0 and 2500 ppm).
Thymus weight was decreased in both sexes at 2500 ppm, but normal at recovery.
Adrenal weight was increased in females at 2500 ppm and still increased at recovery.

GROSS PATHOLOGY
No test-substance related gross necropsy findings.

HISTOPATHOLOGY: NON-NEOPLASTIC
Liver changes (generalized or centrilobular hypertrophy) occured in treated males from all groups, and in female groups at >=150 ppm. These changes were not evident in either sex (2500 ppm only) at recovery. Considered to be an adaptive or metabolic change.

Adrenal cortical cell vacuolation occured in all treated and untreated groups but was more severe at >=600 ppm at the end of exposure and similar between 2500 ppm and the controls following recovery. Considered to be an adaptive or metabolic change.

HISTORICAL CONTROL DATA (if applicable)
None presented








Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
150 ppm
Sex:
male/female
Basis for effect level:
other: overall effects: clinical signs; body weight NOAEC equivalent to 1.4 mg/l
Dose descriptor:
LOAEC
Effect level:
601 ppm
Sex:
male/female
Basis for effect level:
other: overall effects: clinical signs; body weight LOAEC equivalent to 5.5 mg/l

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The test substance induced effects at all doses but up to 150 ppm these were considered transitory, adaptive/metabolic, not clearly adverse or giving no evidence of organ toxicity.

Applicant's summary and conclusion

Conclusions:
A 90-day inhalation study, conducted largely according to the current guideline (OECD 413) and GLP, identified a NOAEC value of 150 ppm (1.4 mg/l) in male and female rats. Overt toxicity, including body weight and clinical observations were evident at 601 ppm (5.5 mg/l) which was identified as the LOAEC.