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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1979
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: To determine the sub-acute inhilation toxicity of the test substance to rats, over a series of experimental phases designed to represent short-term inhilation exposure.
- Short description of test conditions: Male and female rats were exposed daily for 6 hours, 15 times over 3 weeks in three test series (I), (II), (III), to the following concentrations (analytically determined) of triflumuron, present as an easily respirable aerosol in the breathing air of the animals:
control groupS:
(I) and (II): 0 mg/kg m3 air
(III): 20000 µL DMS/Lutrol/m3 air
concentration groups:
(I) 1: 9 mg Triflumuron/m3 air
(I) 2: 29 mg Triflumuron/m3 air
(I) 3: 92 mg Triflumuron/m3 air
(II) 1: 3 mg Triflumuron/m3 air
(II) 2: 8 mg Triflumuron/m3 air
(III) 1: 9.3 mg Triflumuron/m3 air
(III) 2: 94.3 mg Triflumuron/m3 air.
For technical reasons Triflumuron was formulated in a mixture of DMSO/Lutrol (1:1). Laboratory examinations were performed at the end of the experiment. At sacrifice, gross findings were recorded and organs weighed. A number of organs were examined histopathologically.
GLP compliance:
no
Remarks:
Study conducted pre-GLP

Test material

1
Chemical structure
Reference substance name:
2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide
EC Number:
264-980-3
EC Name:
2-chloro-N-[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]benzamide
Cas Number:
64628-44-0
Molecular formula:
C15H10ClF3N2O3
IUPAC Name:
3-(2-chlorobenzoyl)-1-[4-(trifluoromethoxy)phenyl]urea
Test material form:
not specified

Test animals

Species:
rat
Strain:
Wistar
Remarks:
TNO/W 74 albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
Rats were approx. 160-170g (females) or 180-220g (males) body weight at start of study. The rats were kept conventionally in Makrolon® cages, type III (5 animals/cage; markings: cage numbering and color markings). The animal room was illuminated daily from 7.00 to 19.00 h. The room temperature was approx. 21°C with the climate regulated by air conditioning. The animals were kept on a standard pre-prepared diet specific to the species (Altromin R) and water ad libitum.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
not specified
Vehicle:
other: The test article was formulated in various concentrations with DMSO and Lutrol (1:1)
Remarks on MMAD:
Distribution of particle size per concentration was determined once in the second test week and once at the end of the exposure. This was performed using a cascade impactor. After photographic presentation by microscope, the particles were compared by measuring with a micrometer, and their diameter converted (only test series III were determined) .
Details on inhalation exposure:
Male and female rats were exposed daily for 6 hours, 15 times over 3 weeks in three test series (I), (II), (III), to the following concentrations (analytically determined) of triflumuron, present as an easily respirable aerosol in the breathing air of the animals.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Cotton wool was used to adsorb the active ingredient from the inhalation air. The active ingredient was then quantitatively eluted with absolute ethanol. Determination of the active ingredient was made spectrophotometrically at 250 nm at a path length of 1 cm.
Duration of treatment / exposure:
exposed daily for six hours, 15 times over 3 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/m³ air
Remarks:
control series I and II
Dose / conc.:
20 000 other: µL DMS/Lutrol/m3 air
Remarks:
control series III (vehicle control only)
Dose / conc.:
9 mg/m³ air
Remarks:
test concentration series I (group 1)
Dose / conc.:
29 mg/m³ air
Remarks:
test concentration series I (group 2)
Dose / conc.:
92 mg/m³ air
Remarks:
test concentration series I (group 3)
Dose / conc.:
3 mg/m³ air
Remarks:
test concentration series II (group 1)
Dose / conc.:
8 mg/m³ air
Remarks:
test concentration series II (group 2)
Dose / conc.:
9.3 mg/m³ air
Remarks:
test concentration series III (group 1)
Dose / conc.:
94.3 mg/m³ air
Remarks:
test concentration series III (group 2)
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Triflumuron was sprayed dynamically. The tests were performed in a dynamic inhalation apparatus. For technical reasons the test article was formulated in various concentrations with DMSO/Lutrol (1:1) (dimethylsulfoxide - polyethylene glycol 400) and then nebulized dynamically into the inhalation chamber. It was not possible to formulate the test article with ethanol/Lutrol. The animals were exposed so that they could only inhale the aerosol with the breathing air. The aerosols did not come into contact with the skin. Three series of tests were performed in order to determine the concentration tolerated without lesions occurring.

Examinations

Observations and examinations performed and frequency:
The appearance and behavior of the animals were assessed daily during the study period. The body weights of the animals were determined before the start of the test and then at the end of each week (test series I, II and III).
Sacrifice and pathology:
24 hours after the end of the treatment the rats were subjected to necropsy under ether anaesthetic. The rats were killed by desanguination (heart puncture). The internal organs were grossly assessed. Following this the following organs were weighed: thyroid, heart, lung, liver, spleen, kidneys, adrenal, testes and ovaries.

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Only in test series I, behavioural disorders and pre-terminal deaths occurred. These findings were not
reproducible in test series II or III where the same conditions prevailed.
Mortality:
mortality observed, treatment-related
Description (incidence):
In test series I the following rats died:
One female rat from the control group after 5th exposure
Three female rats from the highest concentration group 92 mg/m3 air after the 2nd, 3rd and 4th exposure.
In test series II the following rats died:
One female rat from the concentration group 3 mg/m3 air in the night following the 4th exposure.
There were no mortalities in test series III.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Only in test series I, a short-term reversible loss of weight was seen. These findings were not reproducible in test series II or III where the same conditions prevailed.
Haematological findings:
no effects observed
Description (incidence and severity):
No significant variation from the norm and no group-specific deviations were observed.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No significant variation from the norm and no group-specific deviations were observed.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No significant variation from the norm and no group-specific deviations were observed.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment-related organ weight changes.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Only in test series there was a histological evidence of inflammatory changes to the respiratory tract. These findings were not reproducible in test series II or III and were thus considered incidental findings.

Effect levels

Key result
Dose descriptor:
NOAEC
Effect level:
> 94.3 mg/m³ air
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Tested up to the maximum producible concentration

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
No-observed-effect-level (NOEL) : 94.3 mg/m3 air (the maximum producible concentration).
Executive summary:

Male and female rats were exposed daily for 6 hours, 15 times over 3 weeks in three test series to concentrations (analytically determined) of triflumuron, present as an easily respirable aerosol in the breathing air of the animals.  For technical reasons, the test material was formulated in a mixture of DMSO/Lutrol (1:1). Exposure groups were 0 (controls), 9, 29, 92, 3, 8, 9.3 and 94.3 mg/m3 air. The DMSO formulation vehicle revealed clear histological evidence of inflammatory changes to the respiratory tract, particularly amongst the female rats. This led to behavioural disorders, short-term reversible loss of weight and mortalities amongst the animals in the initial test series; however, these clinical findings were not confirmed in subsequent test series using the same test conditions prevailed. Haematological, clinical chemistry and urine examinations, as well as determination of organ weight revealed no evidence of lesions in all the animals. There was no additional histopathological evidence of lesions occurring in all animals.  Treatment with triflumuron at a concentrations up to 94.3 mg/m3 air at 15 x 6 hour exposure over 3 weeks produced no lesions in male or female rats. 94.3 mg/m3 air was the maximum producible concentration.