Reaction product of tin, citric acid and nitric acid

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study nitrogen dioxide. The read-across rationale can be found in the category approach document attached in Section 13.

Justification for type of information:

For justification of Read-across, please refer to justification documentation attached in IULCID Chapter 13.

Cross-reference

Reason / purpose for cross-reference:

assessment report

Remarks:

justification for weight-of-evidence approach

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Reference 2

Reference Type:

other: amendment

Title:

Unnamed

Report date:

2007

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Nitrogen dioxide

EC Number:

233-272-6

EC Name:

Nitrogen dioxide

Details on test material:

nitrogen dioxide; purity: approx. 1.1%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

About 7 weeks old male and female rats were used. The animals were identified individually by tattooing the
respective animal number into the ears. The female animals were nulliparous and non-pregnant. Only animals free
from clinical signs of disease were used for the study.
During the period when the rats were not exposed they were housed singly in wire cages. Underneath the cages,
waste trays were fixed containing bedding material. The animals were kept in fully air-conditioned rooms in which
a temperature in the range of 20 - 24°C and relativ e humidity in the range of 30 - 70% were ensured by means of a
central air-conditioning system. A light/dark rhythm of 12 hours was maintained (12 h dark, 12 h light). The animals
were maintained on milled mouse/rat laboratory diet and tap water ad libitum.

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Duration of treatment / exposure:

90 days

Frequency of treatment:

6 hours a day on 5 days per week for 13 weeks (65 exposures)

Doses / concentrations

Remarks:

Doses / Concentrations:
0.1, 0.5 and 1 ppm NO2 (= 0.19 mg/m3, 0.96 mg/m3, 1.91 mg/m3); infrared photometric measurement resulted in measured concentrations of 0.25, 0.82 and 2.15 ppm NO2
Basis:

No. of animals per sex per dose:

groups of 15 male and 10 female rats

Control animals:

other: yes; exposed to clean air

Examinations

Observations and examinations performed and frequency:

During the whole study, the general state of health was controlled twice on working days and once on weekends or holidays. On exposure days clinical observation was performed before, during and after exposure. During preflow period and on post exposure day clinical findings were recorded once each working day. Body weight of the animals was determined.
Lung lavage was performed in 5 male animals from each concentration group (groups 01 – 31). Bronchoalveolar Lavage Fluid (BALF) was evaluated biochemically and cytologically. Moreover, in 10 male and 10 female animals of each concentration group (groups 0 – 3) BrdU minipumps were impanted, pulmonary cell proliferation and apoptose rates were determined. In these animals, clinical chemical and hematological examination of the blood,
as well as a complete necropsy including gross pathological evaluation and weighing of selected organs were performed. The respiratory tract and the mediatitinal lymph nodes of these animals were examined histopathologically.

Statistics:

Means and standard deviations of each test group were calculated for several parameters.

Results and discussion

Results of examinations

Details on results:

During the whole study period the animals showed no clinical signs and findings different from normal. Concerning the mean body weights, body weight changes, food consumption and food efficiency, there were no statistical significant differences between the exposed animals and the air controls. Clinical pathology examinations revealed no treatment-related changes in the hematology, clinical chemistry and bronchoalveolar lavage parameters.
Regarding pathology, a minimal increase of alveolar histiocytosis in only 3 of 10 test animals of the male group 3 animals exposed to the target concentration of 1 ppm was detected. This may be interpreted as a first indication of a compound-related irritation, but further morphological alterations of the lung parenchyma are missing. Especially,
no biological relevant increases of cell proliferation (BrdU-stain) or apoptosis (TUNEL-stain) could be detected or any kind of significant organ weight changes. Therefore, the few single cases of a minimal (grade 1) alveolar histiocytosis are regarded to be an only incidental increase and of spontaneous origin.

Effect levels

Dose descriptor:

NOAEC

Effect level:

2.15 ppm

Sex:

male/female

Basis for effect level:

other: The inhalation of measured concentrations of up to 2.15 ppm NO2 by male and female rats did not cause any treatment-related findings in all examined parameters.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The inhalation of measured concentrations of up to 2.15 ppm NO2 by male and female rats did not cause any treatment-related findings in all examined parameters including biochemical and cytological examinations of the broncho alveolar lavage fluide, hematological and clinical chemical examination of the blood, histopathological examination of the whole respiratory tract, cell proliferation and apoptosis rate in the lung.