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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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Acceptable documented study report with limitations; 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.

Data source

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

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
study is limited concerning the recommended particle-size distribution given in current guidelines
Principles of method if other than guideline:
Ten rats per sex and group were whole body exposed to CBS dust analytical concentrations of 0 (compressed filtered air controls I and II), 0.0043, 0.0144 and 0.048 mg/l (analytic values which represent ca. 9% of the nominal values) for 6 hrs/day, 5 days/week for 29 days. The equivalent aerodynamic mass medium diameter was 7.6 +/- 2.71 µm.
Animal observations for 6 hrs/day, 5 days/week for 29 days. The equivalent aerodynamic mass medium diameter was 7.6 +/-2.71 µm. Animal observations were done daily before and immediately after each 6-hr-exposure. Body weight and food consumption was recorded before start of the experiment and on study days 7, 14, and 28. At study termination haematological, biochemical and urinalysis studies were performed on all animals and all animals were sacrificed for gross and histopathological examinations.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: Santocure CBS; purity: 96.2%.

Test animals

Species:
rat
Strain:
other: Charles River CD
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
7.6 µm
Remarks on MMAD:
7.6 +/- 2.71 µm.
Details on inhalation exposure:
Whole body exposure.
Duration of treatment / exposure:
4 weeks.
Frequency of treatment:
6 h/d, 5 d/week.
Doses / concentrations
Remarks:
Doses / Concentrations:
0.0043, 0.0144 or 0.048 mg/l
Basis:

No. of animals per sex per dose:
Ten animals per dose and sex.
Control animals:
yes
Details on study design:
Post-exposure period: no

Examinations

Observations and examinations performed and frequency:
Body weight and food consumption was recorded before start of the experiment  and on study days 7, 14, and 28. At study termination haematological, biochemical and urinalysis studies were performed on all animals and all  animals were sacrificed for gross and histopathological examinations.
Sacrifice and pathology:
all  animals were sacrificed for gross and histopathological examinations.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Immediately after the 6-hr exposure period rats show occasional nasal irritation related to the exposure concentration in term of number of animals exhibiting the sign and severity. By the following morning these symptoms had generally disappeared.
Alopecia was observed in some rats but without concentration relationship.
Mortality:
no mortality observed
Description (incidence):
No treatment-related premature death.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and food consumption were normal
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Body weight and food consumption were normal
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
effects observed, treatment-related
Description (incidence and severity):
Microscopic lesions were present in the eye (conjunctivitis) in few animals of the highest dose (0.48 mg/l)(2/10 males, 2/10 females)vs. controls I(1/20).

Haematological findings:
no effects observed
Description (incidence and severity):
Hematological and urinalysis values were within the normal range of variation.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
SGOT values were elevated in the 0.0043 and 0.0144 mg/l groups as compared to control group II (increase signifcant and concentration related).
Urinalysis findings:
no effects observed
Description (incidence and severity):
Hematological and urinalysis values were within the normal range of variation.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No compound induced gross pathology or organ weight variations were observed in any animal.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound induced gross pathology or organ weight variations were observed in any animal.
Neuropathological findings:
no effects observed
Description (incidence and severity):
Microscopic lesions were present in the eye (conjunctivitis) in few animals of the highest dose (0.48 mg/l)(2/10 males, 2/10 females)vs. controls I(1/20).
Microscopic findings: within sinusoidal macrophages in the lymph nodes brown pigment in macrophages, present in 2/10 males and 4/10 females of the highest dose group compared to controls (3/20 females).
Findings in spleen: very slight to slight increase in hemosiderin storage in the spleen in 5/10 females of the highest dose (0.048 mg/l), control groups (0/20).
Findings: nasal turbinates, olfactory bulb and in the lung (at a lower incidence) or have been commonly observed in rats at this facility and therefore the possibility that they are spontaneous in origin cannot be excluded.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Effect levels

Dose descriptor:
other: limited study
Basis for effect level:
other: see 'Remark'
Remarks on result:
not measured/tested
Remarks:
Effect level not specified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Mortality: No treatment-related premature death.

Immediately after the 6-hr exposure period rats show occasional nasal irritation related to the exposure concentration in term of number of animals exhibiting the sign and severity.

By the following morning these symptoms had generally disappeared.

Alopecia was observed in some rats but without concentration relationship.

Body weight and food consumption were normal and hematological and urinalysis values were within the normal range of variation.

SGOT values were elevated in the 0.0043 and 0.0144 mg/l groups as compared to control group II (increase signifcant and concentration related).

No compound induced gross pathology or organ weight variations were observed in any animal.  

Histopathological findings:

Microscopic lesions were present in the eye (conjunctivitis) in few animals of the highest dose (0.48 mg/l)(2/10 males, 2/10 females) vs. controls I (1/20).

Microscopic findings: within sinusoidal macrophages in the lymph nodes brown pigment in macrophages, present in 2/10 males and 4/10 females of the highest dose group compared to controls (3/20 females).

Findings in spleen: very slight to slight increase in hemosiderin storage in the spleen in 5/10 females of the highest dose (0.048 mg/l), control groups (0/20).

Findings: nasal turbinates, olfactory bulb and in the lung (at a lower incidence) or have been commonly observed in rats at this  facility and therefore the possibility that they are spontaneous in origin cannot be excluded.

In summary, the study is limited concerning the recommended particle-size distribution given in current guidelines. To allow for exposure of all relevant regions of the respiratory tract, aerosols with mass median aerodynamic diameters (MMAD) ranging from 1 to 3 µm are recommended. The MMAD used was above the recommendations given (7.6 µm) and therefore, a limited systemic exposure seems reasonable. Thus, the findings of this study are questionable, especially for systemic effects. Whereas the local effects on the respiratory tract noted should be used as supporting evidence.

Applicant's summary and conclusion

Conclusions:
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 might not have been given. The biologically relevance of sporadic findings reported, especially systemic effects are questionable. In light of these limitations the data from the oral subacute toxicity study (NOAEL: 80 mg/kg bw and day, MHWJ 1997) will be used for calculation of the systemic DNEL; whereas local effects noted in the inhalation study will be used as supporting evidence. Based on the fact that signs of nasal irritation observed at clinical examination were reversible, only short in duration and could not be correlated to histopathological effects, no toxicological significance was attached to this finding, and thus, no relevant local effects were observed up to 0.048 mg/l.
Executive summary:

The inhalation toxicity of CBS was examined in a subacute inhalation study (Monsanto Co. 1981). 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 might not have been given. The biologically relevance of sporadic findings reported, especially systemic effects are questionable. In light of these limitations the data from the oral subacute toxicity study (NOAEL: 80 mg/kg bw and day, MHWJ 1997) will be used for calculation of the systemic DNEL; whereas local effects noted in the inhalation study will be used as supporting evidence. Based on the fact that signs of nasal irritation observed at clinical examination were reversible, only short in duration and could not be correlated to histopathological effects, no toxicological significance was attached to this finding, and thus, no relevant local effects were observed up to 0.048 mg/l.