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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:
weight of evidence
Study period:
14.08.1989 to 08.09.1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted specifically to identify whether an aerosol of the test substance induced laryngeal granulomas. While this study does not meet standards of the current guidelines in terms of the diversity of the examinations conducted, it is a well conducted study that achieves its objective.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The objective of this study was to confirm the development of laryngeal granulomas in rats following short-term repeated inhalation exposures to 3-trimethoxysilylpropyl methacrylate-hydrolysate aerosol.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY.
- Age at study initiation: 41 days
- Weight at study initiation: Males: 130-131 grams
- Fasting period before study: none
- Housing: One or two per cage in stainless steel wire mesh cages
- Diet (e.g. ad libitum): Ad libitum (except during exposure)
- Water (e.g. ad libitum): Ad libitum (except during exposure)
- Acclimation period: Two days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.5-21 °C
- Humidity (%): 45-77 %
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

IN-LIFE DATES: From: 14.08.1989 To: 08.09.1989

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: distilled water
Remarks on MMAD:
MMAD / GSD: 2.65 microns with standard deviation of 1.74.
Details on inhalation exposure:
The inhalation chambers were constructed from stainless steel and glass windows for animal observations. The volume was approximately 1330 litres, and the airflow was approximately 300 litres/minutes (13.5 air changes/hour). Temperature and relative humidity measurements were recorded at least twelve times per exposure.

A 2% solution of 3-(trimethoxysilyl)propyl methacrylate hydrolysate was metered from a piston pump into an atomiser. The atomiser was inserted into the top of the inhalation chamber turret where the liquid aerosol was dispersed throughout the chambers by filtered chamber supply air.

The particle size distribution was measured using a TSI Aerodynamic Particle Sizer and a 20:1 diluter. These determinations were made once per day for the duration of the study (except on day 3 due to equipment failure).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber concentrations of 3-(trimethoxysilyl)propyl methacrylate hydrolysate were determined by gravimetric methods. Four samples were obtained each day.
Duration of treatment / exposure:
4 weeks (19 days of exposure over a 4-week period, 18 days of exposure for satellite group)
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
143 mg/m³ air
Dose / conc.:
150 mg/m³ air
No. of animals per sex per dose:
15 males rats/treated group; 15 male rats/control group
5 animals from each group were designated to a satellite group for further ultrastructural evaluation of the larynges (this was cancelled)
Control animals:
yes, concurrent no treatment
Details on study design:
A group of 15 male Fischer 344 rats was exposed 6 hours per day for 19 days of exposure (18 days of exposure for the satellite group) over a 4-week period to an aerosol of 3-(trimethoxysilyl)propyl methacrylate hydrolysate (3-(trimethoxysilyl)propyl methacrylate hydrolysate; gamma-methacryloxypropyltrimethoxysilane hydrolysate; CAS: 2530-85-0) at a target concentration of 150 mg/m3. A control group of 15 male rats was exposed with the same exposure regimen to filtered air only. Five animals of the control and 3-(trimethoxysilyl)propyl methacrylate hydrolysate exposure groups were assigned to a satellite group for possible ultrastructural evaluation of the larynges, but not subsequently evaluated. 

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Preceding and following each exposure. On non-exposure days, animals were observed once per day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At the time of body weight collection and just preceding sacrifice.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on the morning prior to initiation of the first exposure. Then weekly during the four week exposure period and immediately preceding sacrifice.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes a full necropsy was performed.
HISTOPATHOLOGY: Yes, of gross lesions, larynx, lungs, trachea, nasal turbinates and kidneys.
Statistics:
The data for continuous, parametric variables were intercompared for the exposure and control groups by use of Levene's test for homogeneity of variances and by t-tests.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The only exposure-related clinical sign, observed in most of the animals, was perinasal encrustation.
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreases in body weight gain were observed for the 3-(trimethoxysilyl)propyl methacrylate-hydrolysate exposure group during the first two weeks of the study.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Nasal crust around the nares of the 3-(trimethoxysilyl)propyl methacrylate-hydrolysate exposed rats was the only gross lesion noted at necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Upon histological examination, changes were noted within the respiratory tracts of the3-(trimethoxysilyl)propyl methacrylate-hydrolysate exposed rats. Cytoplasmic hyalinization was observed within the olfactory mucosa of the nasal cavity. In addition, squamous metaplasia and foci of minimal to mild granulomatous laryngitis (laryngeal granulomas) were present within the larynges of 3-(trimethoxysilyl)propyl methacrylate-hydrolysate exposed rats. These findings concur with microscopic changes observed in previous 3-(trimethoxysilyl)propyl methacrylate-hydrolysate aerosol studies.
Histopathological findings: neoplastic:
not examined

Effect levels

Dose descriptor:
LOAEL
Effect level:
143 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Laryngeal granulomas developed.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a four week study aerosol inhalation study, not conducted according to any guideline but in compliance with GLP, a LOAEL was concluded to be 143 mg/m3 in males, based on the development of laryngeal granulomas.