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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
The Inhalation Toxicity of Two Commercial Dyes: Solvent Yellow 33 and Solvent Green 3
Author:
JAMES D. SUN,1 ROGENE F. HENDERSON, THOMAS C. MARSHALL, YUNG-SUNG CHENG, JOHN S. DUTCHER, JOHN A. PICKRELL, JOE L. MAUDERLY, FLETCHER F. HAHN, DEBORAH A. BANAS,2 FRITZ A. SEILER, AND CHARLES H. HOBBS
Year:
1987
Bibliographic source:
FUNDAMENTAL AND APPLIED TOXICOLOGY 8, 358-371 (1987)

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Data is from Journal with permission
Principles of method if other than guideline:
Subacute repeated inhalation toxicity study of solvent yellow 33 in rats
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
1,3-isobenzofurandione, reaction products with methylquinoline and quinoline
EC Number:
232-318-2
EC Name:
1,3-isobenzofurandione, reaction products with methylquinoline and quinoline
Cas Number:
8003-22-3
Molecular formula:
C18H11NO2
IUPAC Name:
1,3-isobenzofurandione, reaction products with methylquinoline and quinoline
Test material form:
other: Solid
Details on test material:
- Name of test material (as cited in study report): Solvent Yellow 33
2-(2'-quinolyl)-l,3-indan-dione (QI)
- Molecular formula (if other than submission substance): C18H11NO2
- Molecular weight (if other than submission substance): 273.29 g/mole
- Substance type: Organic
- Physical state: Solid
- Purity: 93%
- Impurities (identity and concentrations): 7%

Test animals

Species:
rat
Strain:
other: Fischer 344/N
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Source: Inhalation Toxicology Research Institute.
- Age at study initiation: 15-20 weeks of age.
- Weight at study initiation: 269-275 g male, 166-168 g female
- Fasting period before study: No data
- Housing: no data available
- Diet (e.g. ad libitum): Wayne Lab Blox, Allied Mills, Chicago, IL food, ad libitum. Food was withheld during exposure Periods
- Water: ad libitum
- Acclimation period: 3 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 75 ± 3°F
- Humidity (%): 35-70%
- Air changes (per hr): 0.4 m3/min
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle with the lights on at 6 AM

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Details on inhalation exposure
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Whole-body inhalation exposure chambers (Hazleton H-2000 Inhalation Chambers, Hazleton Systems, Inc., Aberdeen, MD)
- Method of holding animals in test chamber: Whole-body
- Source and rate of air: ~0.4 m3/min air
- Method of conditioning air: No data available
- System of generating particulates/aerosols: Jet-O-Mizer air jet mill
- Temperature, humidity, pressure in air chamber: 75 ± 3°F and 35-70% relative humidity
- Air flow rate: ~0.4 m3/min.
- Air change rate: No data available
- Method of particle size determination: Particle size of each aerosol was measured with a Lovelace Multi-Jet Cascade Impactor each day during the first week of exposures and then at 2- to 6-day intervals thereafter.
- Treatment of exhaust air: No data available

TEST ATMOSPHERE
- Brief description of analytical method used: The daily chamber concentration of each dye was determined by the mean of three to eight filter samples taken at regular intervals during the day.
- Samples taken from breathing zone: No data available

VEHICLE (if applicable)
- Justification for use and choice of vehicle: No data available
- Composition of vehicle: No data available
- Type and concentration of dispersant aid (if powder): No data available
- Concentration of test material in vehicle: 0, 10, 51 and 230 mg/m3.
- Lot/batch no. of vehicle (if required): No data available
- Purity of vehicle: No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The chemical composition and purity of the test materials were confirmed by mass spectrometry and high-performance liquid chromatography (HPLC). Analysis of dye compounds by HPLC was done using a reverse-phase column (Alltech C-18, 10 n, 25 cm X 4.6 mm). When SY alone was being analyzed, the column was eluted isocratically with 90% acetonitrile in water (1 ml/min). HPLC analysis for SY was done by eluting the column with a 90 to 100% acetonitrile gradient made with water in 10 min (1 ml/min), with a 10-min hold at 100% acetonitrile. Dye compounds were detected by uv absorbance at 435 nm (SY). Retention times and peak heights of the bulk test materials were compared with those of purified SY dye standards. These same methods of analysis were also used to determine the chemical stability of each dye after aerosol generation by analyzing filter samples of the aerosols obtained from exposure chambers during test runs.
Duration of treatment / exposure:
4 -week exposures
Frequency of treatment:
6 hr/day 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 51, and 230 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
Total: 176
0 mg/m3 : 22 male 22 female
1 mg/m3 : 22 male 22 female
11 mg/m3 : 22 male 22 female
100 mg/m3 : 22 male 22 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): Animals were randomly assigned to experimental groups by body weight.
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included: Morbidity and mortality were observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: No data Animals were weighed before and after each exposure.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

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 data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations: No data available

- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined: No data available

OPHTHALMOSCOPIC EXAMINATION: Yes, Analysis of pigment in olfactory epithelium. No data available

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of study
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined: Hematocrit, hemoglobin concentration, numbers of erythrocytes, erythrocyte indices
(Mean cellular volume, mean cellular hemoglobin, mean cellular hemoglobin concentration), and differential and total leukocyte numbers were examined.

CLINICAL CHEMISTRY:
- Parameters checked in table [No.?] were examined: Yes. Total protein and albumin, glutamic pyruvic
transaminase, alkaline phosphatase, bilirubin (total), blood urea nitrogen, creatinine, calcium, inorganic phosphorus, sodium, potassium, chloride, glucose, cholesterol, and thyroxine (T4) were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Lung content of Ql and TA after exposures to SY, Respiratory function, Lung biochemistry and Lung connective tissue biochemistry were examined.
Sacrifice and pathology:
HISTOPATHOLOGY: Yes
Routine hematoxylin
and eosin-stained slides were prepared from the lung (4), larynx, trachea, and nasal cavity (3), skin, tracheobronchial lymph node, popliteal lymph node, spleen, femur, heart, stomach, duodenum, cecum, colon, liver, pancreas, kidney, urinary bladder, epididymis, testis, prostate,uterus, ovary, adrenal, thyroid, brain, pituitary, and eye for a total of 32 tissues for males and 31 tissues for females. These slides were examined microscopically, and histopathologic evaluations were made for each animal.
Statistics:
Data were analyzed by an analysis of variance, followed by tests for equality of the means by either simple two-tailed t tests or multiple comparison two-tailed t tests

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Mortality: No data available Clinical signs: No signs of toxicity were observed in treated rat as compared to control.
Mortality:
no mortality observed
Description (incidence):
Mortality: No data available Clinical signs: No signs of toxicity were observed in treated rat as compared to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 230 mg/m3, significant decrease was observed in body weight of male and female rat as compared to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No histological abnormalities were observed in treated rats
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical chemistry:
Changes in serum CO2, inorganic phosphate, creatinine, protein, albumin, cholesterol, glucose, bilirubin, glutamic pyruvic transaminase, and alkaline phosphatase.
However, these changes were slight and only barely statistically significant in multiple comparison
Thus, none of these changes were of clinical significance because the degree of change for each of these parameters is much greater when a disease process exists.

Decreased lung elastic recoil and increased resting lung volume consistent with some breakdown of pulmonary connective tissue leading to more compliant lungs were observed in 230 mg/m3 treated rats.

Effect levels

Dose descriptor:
LOEL
Effect level:
230 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effect on respiratory function, Lung biochemistry and Lung connective tissue biochemistry.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The lowest-observed-effect level (LOEL) was considered to be 230 mg/m3 when F344/N male and female rat were exposed to Solvent Yellow 33 (SY).
Executive summary:
In a repeated dose inhalation toxicity study,F344/Nmale and female rat exposed to Solvent Yellow 33 (SY)bywhole-body inhalationin the concentrations of0, 10, 51, and 230 mg/m3,The results showed thatSolvent Yellow 33 (SY) toxic. Toxic changes were observed as significant decrease in body weight of treated rats. In addition, decreased in lung elastic recoil and increased in resting lung volume consistent with some breakdown of pulmonary connective tissue leading to more compliant lungs were observed in 230 mg/m3treated rats. Therefore, LOEL was considered to be 230 mg/m3when F344/N male and female rat were exposed to Solvent Yellow 33 (SY) bywhole-body inhalation for 4 weeks.