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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
other: Body responsible for the test
Title:
Unnamed
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: EEC Directive 92/69, B.8 OECD 412, 1981 Japanese (MITI) guidelines, 1986
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Wistar Crl:(WI)WU BR

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: None
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Duration of exposure per day: 6 hours
Dosing regime: 5 days/week
No. of animals per sex per dose:
Male: 10 animals at 0 mg/l
Male: 5 animals at 12.41 mg/l
Male: 5 animals at 49.6 mg/l
Male: 5 animals at 124.7 mg/l
Male: 10 animals at 244.6 mg/l
Female: 10 animals at 0 mg/l
Female: 5 animals at 12.41 mg/l
Female: 5 animals at 49.6 mg/l
Female: 5 animals at 124.7 mg/l
Female: 10 animals at 244.6 mg/l

Results and discussion

Results of examinations

Details on results:
Clinical observations: No treatment-related abnormalities in clinical signs or behaviour were seen during the exposure and recovery period. Reduced body weight gain, food intake and reduced food conversion efficiency were observed in male rats of the high concentration group.

Laboratory findings: No treatment-related changes in haematological parameters were noted. Clinical chemistry parameters revealed an increase, which was not concentration-related, in glucose content in males and females of the upper mid and high concentration groups and in males of the lower mid concentration group. Significantly increased albumin levels were observed in males of the lower mid, upper mid and high concentration groups. The albumin/globulin ratio was significantly, but not concentration-related, increased in all male exposure groups. GGT was significantly increased in females of the high concentration group. Further, a significant increase in triglyceride levels was found in males of the lower and upper mid concentration groups and in females of the upper mid and high concentrations. Cholesterol levels were significantly, but not concentration-related, decreased in males of the low, lower mid and high concentration groups. A tendency towards a decreased cholesterol content was also seen in males of the upper mid concentration group. Phospholipid levels were increased in all female exposure groups reaching a statistically significant degree in females of the upper midconcentration group only. Finally, creatinine was significantly decreased in female animals of the high concentration group. At the end of the 14-day recovery period, glucose was increased in the exposed animals and the increase was significant in males. Albumin was slightly though significantly increased in exposed male animals, a similar increase in female animals was not significant. The albumine/globulin ratio was significantly increased in exposed male animals and significantly decreased in exposed female animals. Cholesterol was significantly increased in exposed female animals. Phospholipids were increased in both male and female exposed animals. Creatinine was decreased in male exposed animals, a similar decrease in female exposed animals did not reach significance. An increased mean urinary fluoride concentration was observed in males and females of the upper mid and high concentration groups, and in males of the lower mid concentration group at the end of the treatment period. Accordingly, total fluoride excretion in urine and the urinary fluoride /creatinine ratio were also significantly increased in a concentration-related fashion in these male and female groups. These parameters were still slightly increased when compared to controls at the end of the recovery period.

Effects in organs: A strong induction of liver peroxisome proliferation was observed in all male exposure groups, which practically saturated at 4,000 ppm for both lauric acid hydroxylase activity and acyl-CoA oxydase activity. A much weaker effect was observed in female rats of these groups. At the end of the recovery period, the effects of strongly induced peroxisome proliferation had clearly diminished in exposed males and was absent in exposed females. A concentration-related increase in absolute and relative liver weights was observed in all male exposure groups, and in females of the upper mid and high concentration groups. Increases in absolute and relative lung weights were observed in males and females of the upper mid and high concentration groups. Absolute and relative spleen weights were reduced in female exposure groups and in male animals of the upper mid concentration group, but a concentration-response relationship was not observed. At the end of the recovery period, increases in relative liver and lung weights were still observed in males and females of the high concentration group. Inhalation of T-7479 induced histopathological changes in the lungs and liver. Alveolar macrophage accumulation was observed in the lungs of males and females of the upper mid and high concentration group. Nucleolar enlargement was observed in the livers of all male exposure groups. A concentration-response relationship was not obtained. At the end of the recovery period, accumulation of alveolar macrophages was still present albeit to a slightly lesser degree. Liver changes were no longer present.

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 12.45 mg/L air
Remarks on result:
other: exposure duration: 6 hours/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Classified as: Not classified