Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
201/2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study, glp

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
not applicable
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
other: RccHanTM:WIST rats
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
> 2.7 - < 3 µm
Remarks on MMAD:
MMAD / GSD: 2.7 - 3.0 µm
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
4 weeks (6 hours per day, 5 days per week)
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 other: µg/L
Remarks:
Doses / Concentrations:
0 µg/L
Basis:
analytical conc.
Dose / conc.:
2.44 other: µg/L
Remarks:
Doses / Concentrations:
2.44 µg/L
Basis:
analytical conc.
Dose / conc.:
9.19 other: µg/L
Remarks:
Doses / Concentrations:
9.19 µg/L
Basis:
analytical conc.
Dose / conc.:
87.9 other: µg/L
Remarks:
Doses / Concentrations:
87.9 µg/L
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
effects observed, non-treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
-

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
9.91 other: µg/L
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
clinical biochemistry
Key result
Dose descriptor:
LOAEC
Remarks:
local
Effect level:
2.44 other: µg/L
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: findings were restricted to the lungs and tracheobronchial lymph nodes.

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
2.44 other: µg/L
System:
respiratory system: lower respiratory tract
Organ:
other: lungs
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Any other information on results incl. tables

Summary data are presented below:

Group Exposure level (μg/L) Particle size

Target Achieved MMAD (μm) sg

2 2.3 2.44 3.0 2.54

3 9.1 9.19 3.0 2.41

4 80 87.9 2.7 2.44

MMAD Mass median aerodynamic diameter

sg Geometric standard deviation

The achieved levels were 106, 101 and 110% of the target concentrations for Groups 2, 3 and

4 respectively. The Mass Median Aerodynamic Diameters for Groups 2, 3 and 4 are within

the ideal range (1-3 μm) for a repeat dose inhalation study.

There were no treatment related clinical signs observed during the detailed weekly physical

examination.

Lower body weight gain was evident for males exposed to 9.19 μg/L and 87.9 μg/L and for

all females exposed to tin monoxide. Food consumption was also slightly reduced for males

exposed to 87.9 μg/L.

A statistically significant increase in group mean activated partial thromboplastin times were

evident for males exposed to 9.19 and 87.9 μg/L and all females exposed to tin monoxide.

Group mean venous blood oxygen saturation levels were increased for females exposed to

9.19 μg/L and both sexes exposed to 87.9 μg/L.

Two hours after the completion of exposure in Week 4, tin was detected in the plasma of a

single male and female exposed to 9.19 μg/L and in all animals exposed to 87.9 μg/L. Tin

was not quantifiable in control animals or animals exposed to 2.44 μg/L.

Group mean lung and bronchi weights (adjusted for terminal body weight) were greater than

control for all animals exposed to tin monoxide.

Histopathological changes related to treatment were observed within the lungs (the

accumulation of pigmented and flocculent material within alveoli, variably accompanied by

both diffuse and local aggregations of alveolar macrophages, and increased cellularity of the

BALT), tracheobronchial and mediastinal lymph nodes (increased general cellularity, with or

without the accumulation of pigmented material), larynx (pigment accumulation within the

epithelium and lamina propria) and kidneys (increased tubular pigment). Observations within

the larynx and lungs were considered to reflect the accumulation of inhaled test article, with

attempted clearance by the local mononuclear-phagocyte system. Accompanying findings

within the local lymph nodes and kidneys were considered to represent the subsequent

systemic dissemination of test article. Findings were more pronounced, in terms of incidence

and severity, amongst animals dosed with 87.9 μg/L, and displayed a clear dose-related

response. Amongst animals dosed with 2.44 μg/L, findings were restricted to the lungs and

tracheobronchial lymph nodes

Applicant's summary and conclusion

Conclusions:
NOAEC (systemic) 9.19 µg/LK
LOAEC (local) 2.44 µg/L (findings were restricted to the lungs and
tracheobronchial lymph nodes)