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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
other: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Justification for type of information:
Justification for Read Across is provided in Section 13 of IUCLID

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1987
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
limited documentation
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc.
- Housing: The animals were housed individually in wire-mash cages attached to the inhalation chamber.
- Diet (e.g. ad libitum): solid chow for rats (CRF-1, Charles River Japan Inc.)
- Water (e.g. ad libitum): filtered and sterilised tap water
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 ± 15 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
not specified
Remarks on MMAD:
MMAD / GSD: not applicable
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazleton 1000 Inhalation Exposure Chamber
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical control of chamber concentration: analytical values close to nominal ones.
Duration of treatment / exposure:
12 months (total exposure time: males: 7318-7341 hours; females: 7474 - 7496 hours)
Frequency of treatment:
continuously, average about 20 h/d
Doses / concentrationsopen allclose all
Dose / conc.:
0.013 mg/L air (nominal)
Remarks:
corresponding to 10 ppm
Dose / conc.:
0.13 mg/L air (nominal)
Remarks:
corresponding to 100 ppm
Dose / conc.:
1.3 mg/L air (nominal)
Remarks:
corresponding to 1000 ppm
No. of animals per sex per dose:
20
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- DETAILED CLINICAL OBSERVATIONS: Yes
- BODY WEIGHT: Yes
- FOOD CONSUMPTION: the feed to be consumed during a week was determined for two animals, and the daily food consumption per animal was then calculated. The calculation was done weekly during the first 13 weeks of exposure, and monthly thereafter.
- HAEMATOLOGY: Yes
- CLINICAL CHEMISTRY: Yes
- URINALYSIS: Yes
Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- HISTOPATHOLOGY: Yes
Statistics:
All the data obtained were analysed by t-test, Fischer´s exact test or Armitage´s chi-square test as appropriate for any significant difference.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female rat of the 1.3 mg/L dose group and one male rat of the 0.013 mg/L dose group died or were sacrificed in extremis (on day 337 and on day 340, respectively). This was considered spontaneous on the basis of the absence of a consistent dose relationship.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
A very slight transient suppression of body-weight gain was observed for males and females of the 1.3 mg/L dose group from week 27 through 44 (less than 5 %). This has to be attributed to temporary occurrence of slight diarrhea in these groups during this period. The otherwise addressed significant decreases in body weight at the end of the study are not noticable representing the time-course of body weight development.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The high-dose males showed a minimal, but significant decrease in food consumption from week 30 to the end. However, this was not more than about 5 % of the control.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Hematologic examinations revealed no clear changes which could be attributed to exposure.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Serum biochemical examination showed a small tendency to decrease for alkaline phosphatase, the enzymatic activities of GOT, GPT, LDH and gamma-GTP did not show any differences. Free fatty acid showed lower values in all exposure groups without dose-response relationship. Cholesterol and triglyceride remained unchanged. Changes of other clinical-chemical parameters showed no correlation with exposure.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urinalysis showed no changes suggesting effects from exposure.
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Data of the organ/body weight ratio revealed a dose-related upward tendency in the liver and spleen for females which remained within a 5 % range.
Gross pathological findings:
not examined
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Histopathological examinations showed a variety of non-tumoral changes in various organs, many of them were infrequent findings which were possibly accidental. Except for swelling of chromophobic cells of the pituitary, there was no findings which could be related to exposure level.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
For tumoral changes, similarly, almost all the findings observed were considered spontaneous due to aging.
Details on results:
According to the authors, only in the 1.3 mg/L dose-group changes could be considered treatment-related. But based on the minor degree and severity, these changes have no pathological meaning and may be considered as toxicologically irrelevant.
Levels of 0.13 mg/L or less (at 20 h/d for 2 years) did not produce any effect (= NOEC). 1.3 mg/L is adopted as LOAEC, although it may be considered as a NOAEC.

Effect levels

open allclose all
Dose descriptor:
NOEC
Effect level:
0.13 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Dose descriptor:
LOAEC
Effect level:
1.3 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
NOEC (chronic, rat) = 0.13 mg/L air (corresponding to 100 ppm)
Executive summary:

The chronic toxicity of the substance via inhalation was evaluated in an experimental study conducted in a manner which was equivalent to the OECD Guideline 453, in a Combined Chronic Toxicity and Carcinogenicity study. Groups of 20 male and 20 female Fischer 344/DuCrj rats were exposed to test item concentrations of 10, 100 and 1000 ppm (corresponding to 0.013, 0.13 and 1.3 mg/L air) continuously (ca. 20 hours per day) for 12 months (males: 7318-7341 hours; females: 7474 - 7496 hours) via inhalation chambers. Negative control animals were tested in parallel.

No mortality during the study period was associated with toxicity due to the absence of a dose-depended relationship: one high-dose and one low-dose animal was eiher sacrificed in extremis or found dead. Very slight (less than 5 % difference from controls), transient suppression of body weight gain was observed among high-dose males and females between weeks 27 and 44, which was attributed to the temporary occurrence of slight diarrhea. High-dose males demonstrated a minimal, but significant, decrease in food consumption from week 30 to end of study; however this differed by less than 5 % from the controls. A dose-related increase in the ratio between liver and spleen weights and body weight was observed among female animals, but this difference was less than 5 %. Swelling of the chromophobic cells of the pituitary was also observed.

According to the authors, only the observations of the 1.3 mg/L dose group could be considered treatment-related. Based on the minor degree and severity (less than 5 % from control values), these changes have no pathological meaning and it cannot be excluded that these findings are toxicologically irrelevant. Levels of 0.13 mg/L or less did not produce any effect (NOEC), therefore, 1.3 mg/L is adopted as LOAEC, although it may be considered as a NOAEC.