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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: all relevant data available
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

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

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
similar to subchronic inhalation study but designed as RF-study
Principles of method if other than guideline:
similar to subchronic inhalation study but designed as RF-study
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
TGIC (technical grade, batch-no. 177108)

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male
Details on test animals and environmental conditions:
exact strain designation: CD-1(ICR)BR strain
Mice were housed two per cage in stainless-steel wire-mesh cages at 18.9 – 22.2 °C, a relative humidity of 47 - 61 %, and at a 12-hour datk/light cycle. Food and water was provided ad libitum. Individual numbering was by tail tattoo.
Acclimatization period was at least 5 days.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
4 groups of 12 male mice were exposed to TGIC at 0. 100, 350 and 750 mg/m3 air, 6 hours/day, for 5 consecutive days (whole-body exposure), followed by a 14-day recovery period for further observations.
The volume of the inhalation chamber was 1330 l, and the mouse inhalation cages were placed inside the chamber; air flow was 300 l/min, and dust was generated by an Auger Dust Feeder (Spring Tool Co., Schoolcraft, MI, USA), and concentrations (gravimetric on fiber filters) as well as particle size (using a cascade impactor) were measured several times during each daily exposure.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours / day, Whole body exposure
Frequency of treatment:
on 5 consecutive days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 350, 750 mg/m3 air
Basis:
nominal conc.
No. of animals per sex per dose:
12 male mice / group
Control animals:
yes, sham-exposed
Details on study design:
Body weights were measured shortly before the first exposure, and shortly after the last exposure, and on days 7 and 14 post exposure. Gross necropsy was performed after sacrifice on all organs , and gross lesions were preserved in 10% neutral formalin. All parameters measured were statistically analysed with appropriate methods.
Positive control:
none

Examinations

Observations and examinations performed and frequency:
Body weights were measured shortly before the first exposure, and shortly after the last exposure, and on days 7 and 14 post exposure.
Sacrifice and pathology:
Necropsy was performed after sacrifice on all organs , and gross lesions were preserved in 10% neutral formalin. All parameters measured were statistically analysed with appropriate methods.
Statistics:
yes

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:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Mortality (or sacrifice in moribund condition) was observed in all three dose groups:
at 100 mg/m3 5/12 (days 5-9),
at 350 mg/m3 12/12 (days 3-11), and
at 750 mg/m3 11/12 (days 2-4).

Clinical signs were found in all dose groups and included unkemptness, audible respiration, gasping, blepharospasm, swollen periocular tissue, and dehydration, and perioral wetness was observed at 350 and 750 mg/m3 air.

Body weights were reduced in all dose groups in a concentration-related manner, even during the recovery period additional weight loss was observed at 100 mg/m3 air.

At necropsy gas accumulation in all TGIC-treated animals was found in the gastro-intestinal tract, hyperinflation of the lungs at 350 and 750 mg/m3 air, decreased splee sizein all groups. Also treatment-related were crusts on the skin, perioral areas, perinasal area, and periocular aerea as well as color changes in the lungs.

Effect levels

Dose descriptor:
NOAEL
Effect level:
<= 100 mg/m³ air (nominal)
Sex:
male
Basis for effect level:
other: mortality
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No NOAEL or NOEL was determined

Applicant's summary and conclusion

Conclusions:
6-hour inhalation exposure for 5 consecutive days caused mortality among the male mice exposued
at 100 mg/m3 5/12 (days 5-9),
at 350 mg/m3 12/12 (days 3-11), and
at 750 mg/m3 11/12 (days 2-4).
In addition clinical signs and reduced body weights were observed in a dose-related manner.
No NOAEL or NOEL was determined
The NOEL for this study is below 100 mg/m3 air of TGIC
Executive summary:

6-hour inhalation exposure for 5 consecutive days caused mortality among the male mice exposued at 100 mg/m3 5/12 (days 5-9), at 350 mg/m3 12/12 (days 3-11), and at 750 mg/m3 11/12 (days 2-4). In addition clinical signs and reduced body weights were observed in a dose-related manner. No NOAEL or NOEL was determined The NOEL for this study is below 100 mg/m3 air of TGIC