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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
Study period:
October 15 - November 13, 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliant

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Version / remarks:
1981
GLP compliance:
yes (incl. QA statement)
Remarks:
signed on July 27, 1993
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Butyl methacrylate
EC Number:
202-615-1
EC Name:
Butyl methacrylate
Cas Number:
97-88-1
Molecular formula:
C8H14O2
IUPAC Name:
butyl methacrylate
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Supplier: Dupont, Belle plant, Belle, West Virgina
- Physical state: liquid
- Analytical purity: > 99%
- Impurities (identity and concentrations): iso-butyl methacrylate max 1%, MEHQ max. 0.002%
- Purity test date: no data
- Lot No.: SWF90319

FORM AS APPLIED IN THE TEST (if different from that of starting material)
- vapour

Test animals

Species:
rat
Strain:
other: Crl:CD BR
Details on species / strain selection:
The rat is being utilized for this study because of the large amount of comparative toxicological and physiological data on this species.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Kingston, Stone Ridge, NY, USA
- Age at study initiation: 35-day old
- Weight at study initiation: ca 260 g for males and ca 195 g for females
- Housing: individually in suspended wire-mesh cage in the inhalation chamber rooms
- Diet: Purina certified rodent chow 5002 (excepted during exposure), ad libitum (withheld during exposure)
- Water: tap water (excepted during exposure), ad libitum (withheld during exposure)
- Acclimation period: two weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 27
- Humidity (%): 40 - 60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
All chambers were operated  at an air flow rate of 400 L/min, resulting in a calculated 99% aerosol equilibrium time of 23 minutes or 6.4% of the exposure time. Vapours of the test material were generated  from the liquid form, introduced at a constant flow into heated flasks  (approx. 102-105°C) through which a constant flow of air was  metered.  The inhalation chambers were stainless steel, approximately2000 L. Chamber temperature was 22.8-25.5°C; chamber relative  humidity was 62.5-67.6%.  Fresh air was mixed with the test chemical  vapours to achieve the desired concentration. 

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The animals received a whole-body inhalation exposure under dynamic conditions in 2000-L stainless steel, glass, and Plexiglas chambers.
- Method of holding animals in test chamber: Each animal was individually housed in a suspended wire-mesh cage without food or water during the exposure. Cage positions within the chambers were rotated each day to insure that the animals were exposed at several different locations within each chamber.
- Source and rate of air: Calibrated flowmeters (Fisher-Porter Inc., Warminster, PA) delivered compressed air at a rate of 30 L/min into the air inlet of each flask
- Temperature, humidity, pressure in air chamber: The mean temperatures and relative humidities for all four chambers ranged from 22.8 to 25.5°C and 62.5 to 67.6%, respectively.
- Air flow rate: The chamber volume and air flow rate were adjusted to reach 99% of the maximum vapor concentration (t99) within 30 minutes of the total exposure time (Silver, 1946). The volume of animals loaded into the chamber was Iess than 7% of the total chamber volume.
- Air change rate: no data
- Generation of the test Atmosphere: The test material vapour concentrations were generated by metering the test material with calibrated Fluid Metering Pumps into 500 or 5000 ml three-necked round bottom flasks. The flasks were located in hemispherical heating mantles.
- Method of particle size determination: not appropriate, only vapours were generated
- Treatment of exhaust air: no data

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of the test substance in the chambers was determined using a Miran 1A gas analyzer attached to a strip chart recorder. Before the initiation of the exposure, the Miran 1A gas analyzer was calibrated using precisely measured amounts of test material delivered into a dynamic vapour generator. A calibration curve was generated to convert the readings obtained from the Miran 1A gas analyzer into parts-per-million (ppm) butyl methacrylate.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical  concentrations only of test material were determined throughout the  study. Test concentrations were measured during each daily exposure  period (every 80 minutes) and the vapours analyzed by GC to confirm purity. 
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 h/day, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
310 ppm (analytical)
Remarks:
1832 mg/m3
Dose / conc.:
952 ppm (analytical)
Remarks:
5626 mg/m3
Dose / conc.:
1 891 ppm (analytical)
Remarks:
11175 mg/m3
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Fasting period before blood sampling for clinical biochemistry: yes
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed before and after each daily exposure for general condition and signs of toxicity, and once during the post-exposure observation period.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Each animal was weighed at the day of first exposure and then weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Food consumption was measured weekly

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: Yes
- Time schedule for collection of blood: during necropsy at termination of the study
- Anaesthetic used for blood collection: Yes, sodium pentobarbital
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: hematocrit, platelet count, hemoglobin, mean cell volume, red blood cell, mean ceil hemoglobin, white blood cell count, mean cell hemoglobin conc.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: during necropsy at termination of the study
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- Parameters examined: triglyceride, cholesterol, blood urea nitrogen, glucose, alkaline phosphatase, total protein, chloride, albumin, sodium, potassium, globulin, glutamic pyruvic transaminase/alanine aminotransferase activity, glutamic oxaloacetic transaminase/aspartate aminotransferase activity, gamma-glutamyl transferase activity, albumin : globulin ratio, creatinine, bilirubin (total)
alkaline phosphatase, calcium, inorganic phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
ORGAN WEIGHTS: Absolute and relative organ weights (organ-body), measured at necropsy, included: adrenals, brain, kidneys, liver, lungs, and testes.

GROSS PATHOLOGY: Full compliment of tissues, including all male and female reproductive organs, were fixed and examined in all animals.

HISTOPATHOLOGY: The following tissues and organs were examined histologically in the high dose and control groups only: adrenals, gross lesions, heart, kidneys, larynx, liver, lungs, nasal cavity, spleen and trachea. Only identified target organs were to be examined in mid and low dose groups.
Statistics:
Distribution of body weight, body weight changes,  and organ weight were inspected for normality and homogeneity of variance  across all dose groups.  Analysis of variance models were used to assess  the presence or absence of an overall compound effect. Separate one-way  models were used within the male and female data to assess overall  treatment group effects.  Two-way models were used for treatment group,  sex and interaction between groups. Pairwise comparisons of least square  means between control and treated groups were evaluated using  Dunnett'st-test.  Hematology and clinical chemistry values were inspected  for normality and homogeneity using ANOVA. Statistical significance was  demonstrated at the p < 0.05. 

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The only treatment-related signs of toxicity observed were inactivity, lacrymation, eye squinting, and labored breathing. These signs were seen only during the six-hour exposure. Slight inactivity occurred in all exposure groups on days 1, 2, and 3. Inactivity to slight inactivity occurred at concentrations of 952 and 1891 ppm on days 4 through 20. Lacrymation was observed only twice during the first three days, once at 952 ppm and once at 1891 ppm. Eye squinting occurred only at the highest concentration from day 3 to day 20, with the exception of day 4, were no eye squinting was observed. Labored breathing occurred once during day 1, at 1891 ppm.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant increase in the body weight for the 310 ppm females was observed during Week 3. However, because this was an isolated finding, and no concentration-related trend was observed, it was judged not to be treatment-related.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant decrease in the feed consumption for the 1891 ppm females was observed during Week 1. However, because this was an isolated finding, and no effect on body weight was observed, it was judged not to be treatment-related.

Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The clinical chemistry data showed two parameters with statistically significant findings. A decrease in the alkaline phosphatase concentration for 310, 952, and 1891 ppm female animals, was observed. A statistically significant decrease in the triglyceride concentration for 952 ppm and 1891 ppm female animals, was also observed. Although these parameters were statistically different from the controls in a concentration-related trend, these findings were judged not to be of toxicological significance.
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The organ weight data showed a statistically significant increase in kidney weight to body weight ratio in males and females exposed at 1891 ppm. Absolute kidney weights for this group were not statistically different from the controls.

In the absence of any histologic effects, hematology, and clinical chemistry findings this organ weight effect was judged to be not toxicological significant.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic evaluation revealed treatment-related observations in the nasal cavities. Microscopic examination of the nasal cavities of male and female rats exposed to 1891 ppm had slight and localized bilateral degeneration of olfactory epithelium lining the dorsal meati. One male rat and one female rat exposed to 952 ppm had similar changes in the olfactory epithelium. Rats exposed to 310 ppm had no exposure related nasal cavity microscopic changes.
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
local toxicty
Effect level:
1 832 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
LOAEC
Effect level:
5 626 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEC
Remarks:
systemic toxicity
Effect level:
11 175 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no systemic toxicity up to and including the highest tested dose

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

In an OECD Guideline 412 Repeated Dose 28-day inhalation study, 5 male and 5 female rats were exposed by whole body to 0, 310, 952 and 1891 ppm (0,1832, 5626, 11175 mg/m3) of the test item as a vapour for 6 h/day, 5 days/week for 4 weeks. Treatment-related effects included lacrimation, eye squinting, and laboured breathing in the 952 and 1891 ppm (5626 and 11175 mg/m3) concentration groups throughout the study. These signs were observed sporadically during exposure throughout the study. There were no treatment-related effects on body weight or feed consumption, and no deaths occurred. Haematological measurements and clinical chemistry values generally were unaffected by treatment. At necropsy, the only organ weight effect was a statistical increase in the kidney weight to body weight ratio of the 1891 ppm males and females. In the absence of corresponding histologic effects, hematology or clinical chemistry findings, this increase in relative kidney weight was judged not to be toxicologically significant. Microscopic examination of the nasal cavities of rats exposed to 1891 ppm revealed a slight and localized bilateral degeneration of olfactory epithelium lining the dorsal meati. One male and one female rat exposed to 952 ppm had similar changes in the olfactory epithelium. Rats exposed to 31 0 ppm had no exposure related nasal cavity microscopic changes.


Based on the histopathologic changes seen in the nasal cavities, the LOAEL for local toxicity for a four-week whole-body inhalation exposure was 952 ppm. The NOAEL for local toxicity was 310 ppm. As no systemic toxicity was observed under the conditions of this study, the NOAEL for systemic toxicity was the highest tested dose of 1891 ppm.