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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Accpetable documented study report with restriction (test substance purity not indicated; the study is limited concerning the recommended particle-size distribution given in current guidelines and thus an exposure of all relevant regions of the respiratory tract was presumably not given. The biologically relevance of findings from this study, especially systemic effects are questionable, whereas local effects noted in the inhalation study could be used for supporting purpose.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Santocure MOR, Lot no. MIC 270590

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: aerodynamic mass medium diameter: 9.8 micrometer with a geometric standard deviation of 3.63
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
mean nominal concentrations: 0, 0.068, 0.168, 0.53 mg/ml; analytical concentrations: 0, 0.044, 0.0098, 0.0102 mg/l
Basis:

No. of animals per sex per dose:
10 per group and sex
Control animals:
yes

Results and discussion

Effect levels

Dose descriptor:
other: Limited study
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Nominal concentrations: 0, 0.068, 0.168, 0.53 mg/l

Analytical concentrations:

Mean analytical concentrations: 0.0044, 0.0098, 0.0102 mg/l

Gravimetric concentrations: 0, 0.0043, 0.0097, 0.0103 mg/l

Dust particle size distribution analyses:

the equivalent aerodynamic diameter: 9.8 µm, geometric standard deviation: 3.63

Clinical studies:

Appearance and general behavior:

The rats exhibited occational nasal irritation which appeared to be concentration related. Nasal irritation was observed afterexposure but was usually not observed the following morning. Several rats exhibited skin irritation in the form of alopecia which did not appear to be concentration related.

Body weights: females no effects, males a slight decrease in body weight was noted in treated males of the highest dose group (ca. 92 %) compared to control

Food consumption: no time or test substance related differences were observed

Hematology: no effects

Blood chemistry:

In males and females of all treatment groups: the SGOT values were significant elevated and the blood glucose was significant decreased when compared to control (II). The effect did not appear to be concentration related for either parameter.

All other parameters appeared comparable to both controls.

Urinalysis: no effects

Gross Pathology:

No gross lesions interpreted as compound induced observation in any animal at necropsy.

Organ weights:

Some variations in absolute and rel. organ weights were noted, but the variations did not appear to be dose dependent, except for males of the highest dose group which showed a decrease in rel. and absolute lung weights (ca. 20 % absolute lung weights, rel weights ca. 13 % compared to control I and II)

Histopathology:

No microscopic lesions interpreted as compound related were observed in any tissues examined from rats of the highest dose group.

Focal/multifocal mineralization was present in stomach, duodenum, colon, urinary bladder, meninges, eye, kidneys, liver, heart and lung ofsome animals which had inhaled 0.5 mg/ml (corresponding to mean analytical concentration of 0.0102 mg/ml). The distribution of the mineral in the affected tissues was simular to that observed in control I; however , the incidence and severity of the lesion was reduced when compared to control I. Mineral was not always present in all the above tissues from the same animal, however it appeared that only the last 5 males and females in the numerical sequene were involved. The occurence and incidence of all other microscopic lesions were simular to that observed in control I and II. Common microscopic lesions interpreted as primarily inflammatory in nature involved trachea (mononuclear infiltrate), prostate (prostatitis), meninges, (mononuclear infiltrate), kidneys (subacute/chronic neprhitis), liver (parenchymal/periportal mononuclear infiltrate), heart (mononuclear inflammatory infiltrate) and lungs (peribronchiolar lymphiod hyperplasia, perivascular mononuclear infiltrate). Common non-inflammatory lesions observed thyroids (ultimobranchial rests) uterus (hypromatra), lymph nodes (brown pigment in sinusoidal macrophages, erythrophagocytosis), kidneys of male rats (proteinaceous material within renal tubules), liver(acidophilic degeneration of hepatocytes, bile duct hyperplasia, portal fibrosis) and lungs (multifocal acute hemorrhages).

Applicant's summary and conclusion