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Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jan - Feb 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
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
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
adopted 12 May 1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EG Guideline 92/69/EWG. Journal of the European Community - Legal Specifications L 2383 A, 35.
Version / remarks:
29 December 1992
Qualifier:
according to guideline
Guideline:
other: OPPTS 870.1300 (1998). US-EPA Health Effects Test Guidelines 870.1300 - Acute Inhalation Toxicity. United States Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, EPA 712C-98-193
Version / remarks:
1998
GLP compliance:
yes
Test type:
traditional method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
446-620-9
EC Name:
-
Cas Number:
120983-72-4
Molecular formula:
Hill formula: C5H6Cl2O CAS formula: C5H6Cl20
IUPAC Name:
2-Chloro-1-(1-chlorocyclopropyl)ethanone
Test material form:
liquid
Details on test material:
purity: 92.3 %
Specific details on test material used for the study:
Purity 92.1%

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Hsd Win:WU
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 2 - 3 months
- At the study start the variation of individual weights did not exceed ±10 per cent of the mean for each sex
- Housing: individually in Makrolon cages type II during the acclimation and study periods
- Diet: Altromin® 1324 diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2.0
- Humidity (%): approximately 50
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas exposure tubes (TSE, Bad Homburg, Germany)
- Exposure chamber volume: 3.8 L (dimensions of the inhalation chamber: inner diameter =14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm)

- Source and rate of air: compressed air supplied by Boge compressors
- Method of conditioning air: automatically by a VIA compressed air dryer
-Vapor generation: Under dynamic conditions the test substance was evaporated
from a glass flask from which the substance was conveyed into the intake of the
cylindrical inhalation chamber. The test substance was contained in a bubbler (glass
flask {filling height: «5-7 cm, diameter: »5 cm} filled with approximately 140 g was
equilibrated at 30 °C. Specified flows of dry air (see Table 1, result section) were fed
through the bubbler and diluted with additional air. The total air flow through the
chamber was 15 L/min;
- controlled temperature and humidity measurements

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric analysis with cellulose-acetate filter
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
nominal: 78, 144, 489 and 1975 mg/m3 ;
analytical: 52.1, 90.1, 413.5, 1749.3 mg/m3
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical signs: several times on the day of exposure and at least once daily thereafter; body weights: measured prior to exposure and on Day 3 and 7 and weekly thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology
Statistics:
Necropsy findings: If specific findings occur from the respiratory tract of surviving rats they are evaluated statistically using the pair-wise Fisher test after the R x C chisquared test. For calculation of the unilateral p value a symmetrical distribution was assumed (p unilateral = (p bilateral)/2).

Since in acute studies individual group means may differ prior to commencement of the first exposure, the body weight gain was statistically evaluated for each group. For these evaluations a one-way ANOVA (vide infra) is used.

Physiological data: Data of rectal temperature measurements are statistically evaluated using the ANOVA procedure (vide infra).

Calculation of the LC50: If calculation of a median lethal concentration (LCso) is possible, it is performed by computer (PC) according to the method of Rosiello et al. (1977) as modified by Pauluhn (1983). This method is based on the maximum likelihood method of Bliss (1938). If only 2 pairs of values with greater than 0% lethality and less than 100% are available then the first linear approximation is based on these values and a x2-homogeneity test is not performed. In this case the interpolated concentration at 50% lethality is designated the approximate LD50. Additionally, the moving average interpolation according to Schaper et al. (1994) is used for calculation, if applicable.

Analysis of variance (ANOVA): This parametric method checks for normal distribution of data by comparing the median and mean.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
124 mg/m³ air
Based on:
test mat.
95% CL:
82 - 185
Exp. duration:
4 h
Mortality:
Mortality occurred at all exposure levels tested. Rats succumbed on the exposure
day up to the first postexposure day.
LC50 (males and females combined): 124 mg/m3 air
Confidence interval (95%): 82-185 mg/m3
Clinical signs:
other: Details concerning signs and observations are provided in the Appendix in the form of various incidence tables. The following list of signs is focusing on toxicologically significant signs only. Group 1: All rats tolerated the exposure without specific si
Body weight:
Results of the evaluation of the body weights are included in the Appendix.
Comparisons between control animals with the groups exposed to the test substance
revealed transient, statistically significant effect on body weights.
Gross pathology:
Effects on organs: Animals succumbed during the exposure or post-observation period: Lung less collapsed, with dark-red foci/areas, serous foamy content in trachea, hydrothorax, clear to red
discharge from nose.

Animals sacrificed at the end of the post-observation period: In rats exposed to the test compound a conclusive, increased incidence of macroscopic findings were not observed.

Gross necropsy appears to suggest that mortality was causally related with acute lung edema
Other findings:
Results of the evaluation of the rectal (colonic) temperature are summarized in the
Appendix. Statistical comparisons between control animals with the groups exposed to the test substance revealed a conspicuous hypothermia.

Any other information on results incl. tables

Table 2: Summary of acute inhalation toxicity - 4 hour exposure to evaporated test
substance













































































































NTarget Onset and Rectal
GroupConcentrationToxicologicalDuration ofOccurrenceTemperature
/sex(mg/m3)ResultSignsof Mortality(°C)
1 /m00 / 0 / 537.5
2/m750 / 5 / 5Od-10d31.9**
3 /m1504 / 5 / 5Od-10d1d28.6**
4 /m5005 / 5 / 5Od-1d1d27.5**
5 /m20005 / 2a / 5OdOd, 1d24.7**
1/f00 / 0 / 5~38.2
2 / f751 / 5 / 5Od-7d1d32.6**
3 / f1502 / 5 / 5Od - 14d1d30.1**
4/f5005 / 4 / 5Od-1dOd,1d27.7**
5 / f20005 / 4 / 5OdOd, 1d25.9**

N = group assignment, m = males, f = females; a) any number smaller than 5 means that animals
succumbed during the exposure period, Od: exposure day, ** p < 0.05
Values given in the Toxicological results' column are:
1st = number of dead animals.
2nd = number of animals with signs after cessation of exposure.
3rd = number of animals exposed.

Applicant's summary and conclusion

Interpretation of results:
Category 1 based on GHS criteria
Conclusions:
LC50 inhalation (vapor, 4 hr) = 124 mg/m3 (0.124 mg/l) air;
Confidence interval (95%): 82-185 mg/m3 air
Executive summary:

A study on the acute inhalation toxicity of 1-Chloro-1-chloroacetylcyclopropane (hereafter referred to as test substance) on rats has been conducted in accordance with OECD Guideline No. 403. Test procedures were adapted so as to comply also with the Directive 92/69/EEC and OPPTS 870.1300. Three groups of rats were nose only exposed to a mean concentrations of 78, 144, 489, and 1975 mg test substance/m3 air.


Observations and Measurements: Vapor concentrations of 78 mg/m3 and above resulted in a concentration-dependent mortality occurring up to the first postexposure day and clinical signs, such as: bradypnea, labored breathing pattern, stridor, rales, dyspnea, serous discharge from nose, nostrils/muzzle with red discolorations and encrustations, periorbicular hyperemia/swelling, corneal opacity, forelimbs reddened, piloerection, ungroomed hair-coat, cyanosis, prostration (ventral position), apathy, motility reduced, reduced reflexes, limp, tremor, hypothermia, emaciation; and decreased body weights. The intensity and duration of clinical signs was governed by respiratory effects. Gross necropsy appears to suggest that mortality was causally related with acute lung edema.


In summary, the evaporated test substance proved to have a high acute inhalation toxicity to rats.

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