Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1987-1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to a guideline study and conducted under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: not known
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Animal Species. Source. and Ouality Control:
One-hundred twenty-two (122) male and ninety-nine (99) female rats (F344/NHSD BR), 36 days of age, were received on November 17, 1986, from Harlan Sprague-Dawley, Inc. (Indianapolis, IN). Fecal samples from three male and three female rats were examined for intestinal parasites by the zinc sulfate method. In addition, these rats were sacrificed and submandibular lymph glands, lungs, trachea, larynx, kidneys, heart, liver, spleen, salivary glands, and nasal, cavities were fixed and examined microscopically. Parasitology examination for pinworms was performed on three male and three female rats using the Scotch® tape test of the perineal skin and hair. Prior to the parasitology examination, blood samples were obtained for possible serologic evaluations. Approximately two weeks later, additional blood samples were collected on five male and five female rats for serologic evaluation. Results of the physical examination, ophthalmic examination, parasitologic tests, serologic tests, and tissue histopathology indicated that the rats were free of infectious disease and suitable for use on this study.

Animal Husbandry:
The animals were housed two or three per cage in stainless steel wire-mesh cages measuring 23.5 cm x 20 cm x 18 cm high in Room 164 (Bioclean Unit A) from November 18, 1986, to December 1, 1986. From December 1, 1986, until the end of the study, animals were housed two per cage, separated by sex and test group. Animals were moved to Room 139 on December 8, 1986. The animals assigned to the recovery (nonexposure) period were housed one per cage in Room 164 (Bioclean Unit A). A layer of Deotized Animal Cage Board® (Shepherd Specialty Papers, Inc., Kalamazoo, MI) was placed under each row of cages.
Room temperature and relative humidity were monitored continuously by a Hygrothermograph® Seven-Day Continuous Recorder, Model #8368-00 (Cole-Parmer Instrument Company, Chicago, IL). The animals were kept on a l2-hour photoperiod throughout the study. During nonexposure periods, water (Municipal Authority of Westmoreland County, Greensburg, PA), supplied by an automatic watering system, and powdered feed (Purina Certified Rodent Chow #5002, Ralston Purina Company) were available to the animals ad libitum. Analyses of the food and water showed no contaminants at concentrations high enough to interfere with the outcome of the study. During the A-17l exposures, the animals were housed two per cage, separated by sex and test group, in stainless steel, wire-mesh cages (35 cm x 17 cm x 18 cm high). Food and water were withheld during the exposures.
The animal husbandry procedures for the recovery animals were similar to those used during nonexposure periods.

Animal Identification and Group Assignment:
Each animal was uniquely numbered by toe-clipping and some of the male rats had the right ear notched. The body weight and physical condition of the animals were monitored for approximately two weeks prior to placement into exposure groups. Animals were assigned to three test groups and an air control group (20 rats per sex per exposure group, with an additional 10 male rats per control and high concentration groups), using a computer-based randomization program. For each exposure group, 10 rats per sex were scheduled for sacrifice after 14 weeks of A-17l exposure. The remaining 10 rats per sex per group were scheduled for sacrifice after a 4-week recovery period. The additional 10 male rats assigned to both the control and high concentration groups were designated only for perfusion fixation of the kidneys (for examination by electron microscopy). Five of the 10 males per group were scheduled for sacrifice after 14 weeks of exposure; the remaining 5 after the 4-week recovery period. At the time of group assignment, only animals with body weights within two standard deviations of the group mean for each sex were used in the study. Any animal in poor health was rejected from group assignment.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Inhalation Chamber Description and Operation:
The inhalation chambers were constructed of stainless steel with glass windows for animal observation. Chamber volume was approximately 4320 liters and the airflow was 1000 L/min (13.9 air changes per hour) for the 0, 100, and 400 ppm chambers and 1500 L/min (20.8 air changes per hour) for the 10 ppm chamber. Chamber temperature and relative humidity were recorded using an industrial thermometer (Control Specialties, Inc., Houston, TX) and Airguide Humidity Indicator (Airguide Instrument Company, Chicago, IL), respectively. Temperature and relative humidity measurements were recorded at least 10 times per exposure.

Target Concentrations and Exposure Regimen:
The animals were acclimated to the inhalation chambers (air-only exposure) for two days prior to initiation of the A-17l exposure regimen. Target concentrations of a (control), 10, 100, and 400 ppm A-17l were selected for this study. The rats (8 weeks of age) were exposed for six hours per day. five days a week for 13 weeks, except during the third week (no exposure on December 26, 1986). Male rats received two exposures, and female and recovery group rats received three exposures during the 14th week of the study. Control (air-only exposed) animals were handled in an identical manner as A-17l-treated animals. The 6-hour chamber exposure interval was defined as the time when the vapor generation system was turned on and subsequently turned off. The position of the cages was rotated weekly in a predetermined pattern within each chamber to compensate for any possible, but undetected, variations in chamber environment or A-171 concentration.

A-17l Vapor Generation:
Liquid A-171 was metered from a piston pump (Fluid Metering, Inc., Oyster Bay, NY) into a heated glass evaporator similar in design to that described by Carpenter et al. (1975). The temperature in the evaporator was maintained at the lowest level sufficient to vaporize the liquid. Evaporator temperatures ranged from 35 to 43°C. The resultant vapor was carried into the chamber by a countercurrent airstream that entered the bottom of the evaporator.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber Concentration Analyses of A-l7l and Methanol:
Chamber concentrations of A-17l were analyzed 6 to 8 times during each 6-hour exposure by gas chromatography. In addition, methanol concentrations were determined in the high concentration chamber once a week by gas chromatography.

Measured A-171 concentrations, as mean ± SD, were 402 ± 19, 100 ±6, and 10 ± 0.7 ppm.  The concentration of methanol vapor (a product of the reaction between A-171 and water vapor) in the 400 ppm A-171 chamber was approximately 20 ppm.
Duration of treatment / exposure:
5 days/week for 14 weeks
Frequency of treatment:
6 hours/day
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
400, 100 and 10 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
402, 100 and and 10 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
60.5, 605 and 2421 mg/m3
Basis:
other: conversion from analytical ppm to mg/m3
No. of animals per sex per dose:
20/sex/dose level were exposed six hours per day, five days per week, for 14 weeks to A-171 vapor at 400, 100, 10 or 0 (control) ppm.
10/sex/dose level were sacrificed following the 14-week exposure regimen; the remaining rats were sacrificed after a 4-week recovery period.
An additional 10 male rats assigned to both the control and high concentration groups for examination of the kidneys
Control animals:
yes
Details on study design:
Four groups, each consisting of twenty male and twenty female Fischer-344 rats were exposed six hours per day, five days per week, for 14 weeks to vapor of vinyltrimethoxysilane (A-171) at target concentrations of 400, 100, 10 or 0 (control) ppm. Ten rats per sex per group were sacrificed following the 14-week exposure regimen; the remaining rats were sacrificed after a 4-week recovery period. An additional ten male rats assigned to both the control and high concentration groups were designated for perfusion fixation of the kidneys for examination by electron microscopy.

Examinations

Observations and examinations performed and frequency:
Monitors for toxicity were as follows: clinical observations; body weight; food and water consumption; hematologic analyses; serum chemistries;
urinalysis at study weeks 1, 3, 5, 8, 11, 14 and 18; organ weights (brain, liver, kidneys, lungs, spleen, thymus, and testes); and ophthalmic examinations
Sacrifice and pathology:
Gross pathologic and microscopic evaluations were conducted.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
There were no findings in the 10 ppm exposed group. Positive findings in the assessments for toxicity were present in the rats of the 400 and 100 ppm groups. These abnormalities were minimal to mild in severity and usually infrequent in occurrence.  For most of the abnormalities, a return to normality was observed following the 4-week post-exposure period, indicating recovery.  There were no mortalities throughout the study.  Clinical signs in the 400 ppm group included urogenital area wetness and alopecia. There were no treatment-related eye lesions.  Male and female rats of the 400 ppm group had decreases (11 to 16% below control values) in body weights.  Occasional decreases in body weights of the female rats of the 100 ppm group were also observed. Food consumption was not altered.  Water consumption was increased in the male rats of the 400 ppm group at study weeks 1, 5, 8, and 14 and for females during the first week. Urinalysis results indicated that male rats of the 400 ppm group had lower osmolality , lower electrolyte concentrations, and a decrease in estimated creatinine clearance.  Female rats of the 400 ppm group had similar changes, but at week 14 only.  A decrease in urine osmolality with a concomitant increase in urine volume was observed in male rats of the 100 ppm group at week 1. There were no biologically significant changes in hematology or serum chemistries in rats exposed to A-171.  At necropsy, there were no exposure-related lesions, and changes in organ weights in rats of the 400 ppm group were considered to result from body weight depression.  Noteworthy microscopic lesions in rats of the 400 ppm group were observed in two tissues, the urinary bladder and the kidney.  Minimal cystitis in the bladder submucosa was observed at 14 weeks, and submucosal mastocytosis was observed at 18 weeks.  Renal lesions in a few of the 400 ppm-exposed rats included papillary necrosis, interstitial edema, and/or papillary hyperplasia of the transitional epithelium.  Electron microscopic examination of the kidneys supported the light microscopic findings.

Effect levels

open allclose all
Dose descriptor:
LOAEC
Effect level:
100 ppm
Sex:
male/female
Basis for effect level:
other: Based on decreased urine osmolality and sodium, potassium and chloride concentrations in males and slight decrease in body weight and body weight gain in females.
Dose descriptor:
NOAEC
Effect level:
10 ppm
Sex:
male/female
Basis for effect level:
other: Based on no effects at this concentration

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Rats repeatedly exposed to 400 ppm A-171 for 14 weeks had minimal to mild alterations in body weight, water consumption, urinalysis, organ weights, and bladder and kidney histopathology. A concentration of 100 ppm was a minimum-effect concentration (LOAEC; effects included decreased urine osmolality and sodium, potassium and chloride concentrations in males and slight decrease in body weight and body weight gain in females), and 10 ppm A-171 was a no-observable-effect-concentration (NOAEC) in Fischer 344 rats.