Registration Dossier

Administrative data

Description of key information

The substance 1,3-isobenzofurandione, reaction products with methylquinoline and quinoline (D & C Yellow No. 11) does not exhibit repeated dose toxicity by oral, inhalation and dermal route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal
Qualifier:
according to
Guideline:
other: Chronic repeated dose toxicity
Principles of method if other than guideline:
Chronic repeated dose toxicity study of D & C yellow no.11 orally in mice.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
Source: Taconic Farms
- Age at study initiation: Four week old
- Weight at study initiation: 19.1–20.0 g male, 16.7–17.6 g female
- Fasting period before study: No data
- Housing: mice were individually caged
- Diet: NIH 07 diet ad libitum
- Water : ad libitum
Acclimation period :Quarantined 13–15 days before the studies began

ENVIRONMENTAL CONDITIONS
- Temperature -70-76°F (21-24°C )
- Humidity (%):44–56%
- Air changes (per hr) - more than 10 room air changes per hour.
Photoperiod (hrs dark / hrs light): 12h/d
Route of administration:
oral: feed
Vehicle:
other: NIH 07 diet
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Daily

VEHICLE
- Justification for use and choice of vehicle (if other than water): NIH 07 diet
- Concentration in vehicle: 0, 500, 1700, 5000, 17,000, and 50,000 ppm
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
13 Weeks
Duration of treatment / exposure:
Daily
Frequency of treatment:
0, 500, 1700, 5000, 17,000, and 50,000 ppm (0, 83, 283, 833, 2833 and 8333 mg/kg/day)
No. of animals per sex per dose:
Total : 120
0 ppm: 10 male, 10 female
500 ppm: 10 male, 10 female
1700 ppm: 10 male, 10 female
5000 ppm: 10 male, 10 female
17000 ppm: 10 male, 10 female
50000 ppm: 10 male, 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day
- Cage side observations checked in table [No.?] were included: Morbidity and mortality were examined.

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available
BODY WEIGHT: Yes
Time schedule-Once per week

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 available

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

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
data available
OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes No data available
- Time schedule for collection of blood: After 13 week exposure No data available
- Anaesthetic used for blood collection: Yes -Bio-Tal barbiturate No data available
- Animals fasted: No data No data available
- How many animals: 10 animals No data available
- Parameters checked were examined-Yes No data available

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On termination of study.
- Animals fasted: No data available
- How many animals: All 60 animals were examined.
- Parameters checked in table [No.?] were examined: Serum activities of sorbitol dehydrogenase (SDH), alanine aminotransferase (ALAT), glutamic dehydrogenase (GDH), and ornithine carbamoyltransferase
(OCT) were examined.

URINALYSIS: No

CLINICAL CHEMISTRY: Yes
Time schedule for collection of blood: After 13 week exposure

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Organ weight: Yes,
Brain, heart, kidney, liver, lung, right testis and thymus weighted.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
34 and 36 organs and tissues were observed for gross lesions.

Organs and tissues were preserved in 10% buffered formalin and routinely processed for preparation of histologic sections for microscopic examination.

HISTOPATHOLOGY: Yes
All histologic sections were examined from the high-dose and control mice.
Other examinations:
Brain, heart, kidney, lung, right testis, and thymus, were examined.
Statistics:
Statistical analysis were performed by Jonckheere’s test was used to evaluate the significance of dose-response trends for data on organ weight to body weight ratios, serum enzyme activities.
If the analysis indicated a significant trend, the nonparametric multiple comparison procedure of Shirley test was used to assess the significance of pairwise comparisons between dosed and control groups; otherwise, Dunn’s test was used for pairwise comparisons.
Clinical signs:
no effects observed
Description (incidence and severity):
Mortality: No effect were observed on survival of treated mice as compared to control. Clinical signs: Yellow colored fur was observed in treated female mice.
Mortality:
no mortality observed
Description (incidence):
Mortality: No effect were observed on survival of treated mice as compared to control. Clinical signs: Yellow colored fur was observed in treated female mice.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and weight gain: In male mean body weight were decreased as compared to control. In all treated females, slightly increased weight gain was observed as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was similar in all groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Compound intake: Estimated daily compound intake was 9.9 g /k g.
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Kidney weights were slightly increased for all groups of treated females and Relative kidney weights were increased in males that 5000 ppm or more.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Carcasses were yellow in most male and female mice receiving 5,000 ppm or more. Pigment was noted in the large and small intestines of males and females receiving 500 ppm or greater.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical chemistry:
In male, alanine aminotransferase(ALAT) were significantly increased in 50000 ppm & in female at all dose groups as compared to control.
In female, ornithine carbamoyltransferase (SDH) at 1700 & 50000 ppm dose and glutamic dehydrogenase (OCT) at 17000 and 50000 ppm dose were increased but the values were not dose related & differences were not biologically significant.

Histopathology:
Mild to moderate yellow-brown pigmentation that increased with increasing dose was found in periportal hepatocytes , Kupffer cells , and the biliary epithelium of all treated animals .
Hepatocellular degeneration of minimal severity was observed in 50,000 ppm dose group mice.
Dose descriptor:
NOEL
Effect level:
83 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No effect were observed on survival, clinical chemistry, organ weights and histopathology
Dose descriptor:
LOEL
Effect level:
8 333 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Effect on body weight, clinical chemistry, organ weight, gross pathology and histopathology
Critical effects observed:
not specified
Conclusions:
The No Observed effect level (NOEL) for male was considered to be 500 ppm (83 mg/kg/day) and Low Observed effect level (LOEL) for female was considered to be 50,000 ppm (8333 mg/kg/day) when B6C3F1 male and female mice were treated with D &C Yellowno.11.
Executive summary:

In a Chronic repeated dose toxicity study, B6C3F1male and female mice were exposed to D & C yellow no.11 in theconcentration of 0, 500, 1700, 5000, 17000 and 50000 ppm (0, 83, 283, 833, 2833 and 8333 mg/kg/day)orally. No effect was observed on survival of treated mice. In male, decreased in body weight, increase in aminotransferase (ALAT) and relative kidney weights were observed and in female Yellow colored fur, slightly increased weight gain, changes in ornithine carbamoyltransferase (SDH), glutamic dehydrogenase (OCT) and aminotransferase (ALAT) level and slightly increased kidney weight were observed in treated mice. In addition, yellow Carcasses, Pigment in large and small intestines in 5,000 ppm or more dose group and Mild to moderate yellow-brown pigmentation in periportal hepatocytes , Kupffer cells and biliary epithelium, and minimal severity of hepatocellular degeneration observed in 50,000 ppm dose group mice. Therefore, NOEL for male was considered to be 500 ppm (83 mg/kg/day) and LOEL for female was considered to be 50,000 ppm (8333 mg/kg/day) when B6C3F1male and female mice were treated with D &C Yellowno.11.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
83 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
K2 data from publication.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
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
Qualifier:
according to
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
Species:
rat
Strain:
other: Fischer 344/N
Sex:
male/female
Details on test animals 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
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
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
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
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.
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.
Critical effects observed:
not specified
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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
230 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
K2 data from publication.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Data is from study report
Qualifier:
according to
Guideline:
other: Repeated dose dermal toxicity study of Solvent yellow 33 in Albino Rabbits
Principles of method if other than guideline:
Repeated dose dermal toxicity study of Solvent yellow 33 in Albino Rabbits
GLP compliance:
no
Limit test:
yes
Species:
rabbit
Strain:
other: Albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Pine Acres Rabbi try, West Brattleboro,
Vermont

- Age at study initiation: 17 weeks
- Housing: Animals were housed in individually stainless steel cages.
- Diet (e.g. ad libitum): Charles River Rabbit Formula (Agway), ad libitum
- Water (e.g. ad libitum):untreated municipal water via water bottle, ad libitum
- Acclimation period: They were quarantined for two weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.44 to 22.22 °C
- Humidity (%): 35% to 65%
- Air changes (per hr): 12-16 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light cycle (1 AM to 7 PM).

IN-LIFE DATES: From: No data available
Type of coverage:
occlusive
Vehicle:
not specified
Details on exposure:
Details on dermal exposure
PREPARATION OF DOSING SOLUTIONS: No data available

TEST SITE
- Area of exposure: Back and sides
- % coverage: 6 in. x 6 in
- Type of wrap if used: plastic wrap & then stockinette
- Time intervals for shavings or clipplings: Prior to testing of animals
REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data available
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50, 200 and 1000 mg/kg
- Concentration (if solution):
- Constant volume or concentration used: yes
- For solids, paste formed: yes
VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 hours/ 5 days a week for 2 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
1000, 200 and 50 mg/kg
Basis:
no data
No. of animals per sex per dose:
Total: 30
50 mg/kg: 5 male, 5 female
200 mg/kg: 5 male, 5 female
1000 mg/kg: 5 male, 5 female
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available
Observations and examinations performed and frequency:
Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily
- Cage side observations checked in table [No.?] were included: Mortality were observed

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

DERMAL IRRITATION (if dermal study): No data available
- Time schedule for examinations: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly

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

FOOD EFFICIENCY: No data available
- 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: No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- 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. No data available

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

On all animals dying intercurrently as well as those surviving treatment and sacrificed on day 14.

HISTOPATHOLOGY: Yes, Histopathologic examination on multiple skin sections of treated and untreated skin.

Organ examined.
Treated skin, one section of untreated skin, all gross lesions, heart, liver and kidney for all animals were examined.
Other examinations:
No data available
Statistics:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mortality- All the animals survived throughout the entire study. Clinical signs: Mild diarrhea and nasal discharge were observed in treated rabbits. When treated with 200 mg/kg, Scattered mild nasal discharge and mild to moderate diarrhea during the study in treated rabbits. When treated with 50 mg/kg, One male rabbit displayed mild diarrhea on day 14.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Dermal irritation score were recorded daily based on draize method. There was no erythema & edema observed at 50, 200 and 1000 mg/kg treated sites of rabbits during the 14 day observation period.
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality- All the animals survived throughout the entire study. Clinical signs: Mild diarrhea and nasal discharge were observed in treated rabbits. When treated with 200 mg/kg, Scattered mild nasal discharge and mild to moderate diarrhea during the study in treated rabbits. When treated with 50 mg/kg, One male rabbit displayed mild diarrhea on day 14.
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
When treated with 50 mg/kg, significantly decreased in food intake of two rabbit and one female rabbits were observed.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Hyperkeratosis, acanthosis and adnexal hyperplasia were observed.
Histopathological findings: neoplastic:
not specified
Details on results:
Body weight and weight gain:
When treated with 1000 mg/kg, Two female rabbits decreased in weight between days 0 and 3.
Female rabbit increased in weight on day 7 and maintained or gained weight during the remainder of the study.
The body weight of female rabbit remained constant between days 3 and 7, increased by day 10, and decreased again on day 14.
Male rabbit decreased in weight between days 7 and 10 and maintained weight between days 10 and 14.
Male rabbit decreased in weight between days 7 and 10 but regained the weight by day 14.
All other rabbits either maintained or gained weight during the study.
When treated with 200 mg/kg, Four male and three female rabbits maintained or increased body weight during the 14 day study. One male and one female rabbit decreased in weight between days 0 and 3 but increased in weight by day 7.
The other female rabbit decreased in weight between days 7 and 10 but increased in weight by day 14.
When treated with 50 mg/kg, significantly decreased in body weight between days 3 and 7, and days 1 and death (day 10) were observed.
One male and one female rabbit lost weight between days 0 and 3. Three male and four female rabbits maintained or gained weight between days 0 and 3. By day 7, these two rabbits increased in weight.
The body weight of female rabbit decreased between days 7 and 10 but increased again by day 14. Only one male rabbit decreased in weight between days 10 and 14.

Gross pathology:
One male rabbit was observed to have scattered 1 mm X 1 mm white lesions on the lobes of the liver. Petechial hemorrhages were observed on both kidneys of the remaining female rabbit when treated with 1000 mg/kg.
The medial liver lobe of one male rabbit displayed a circular pattern with 2 mm X 2 mm white circular lesions. The colon of another male rabbit was gaseous, and the large intestine of the remaining male rabbit was gaseous and contained watery diarrhea when treated with 200 mg/kg.
Both kidneys of two female rabbits displayed scattered beige areas, and both kidneys of one of these rabbits displayed petechial hemorrhages. The colon of one male rabbi t appeared gaseous, arid the lobes of the 1iver of one female rabbit displayed scattered white circular lesions, 1 mm X1 mm in size when treated with 50 mg/kg.

Details on results:
Pathologic changes are graded on a four-point scale: mild, moderate, marked, severe. No definitive dose related increase in severity of these skin lesions.
The test material caused skin changes after repeated contact. These changes were confined to thickening of the epidermal prickle cell layer, the outer horny layer and accessory cells of the denims. Systemic toxicity was not evident.
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Dermal irritation parameters and other observations based on body weights .
Critical effects observed:
not specified
Conclusions:
The no-adverse-effect-level (NOEL) was considered to be 1000 mg/kg when albino male and female rabbits treated with CI Solvent Yellow 33.
Executive summary:

In a subacute repeated dose dermal toxicity study, albino male and female rabbits treated with CI Solvent Yellow 33 in the concentration of 50, 200 and 1000 mg/kg for 6 hours/ 5 days a week. Results shows that CI Solvent Yellow 33 was not toxic dermaly. No effect was observed on survival of treated rabbits. There was no erythema & edema observed at 50, 200 and 1000 mg/kg treated sites of rabbits during the 14 day observation period. Changes in body weight and food consumption were observed in treated rabbits but the changes are not constant. In addition, mild to moderate degrees of one or more of hyperkeratosis, acanthosis and adnexal hyperplasia were observed. The treated skin sections were compared with untreated skin sections from the same rabbit. There was no definitive increase in severity of skin lesions with increasing dose levels. All other lesions found on organs were of an incidental nature and it could not be determined whether or not these changes were related to the absorption and toxicity of CI Solvent Yellow 33. Therefore, NOEL was considered to be 1000 mg/kg when albino male and female rabbits treated with CI Solvent Yellow 33 by dermal application for 2 weeks. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
K4 data from Study report.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity - Oral

Summary of 8003-22-3 for repeated dose toxicity

Based on the various studies available with Klimish rating 2 for the target substances CAS: 8003-22-3 the results is summarized as follows

Sr. No

End point

Value

Species

Route

Effects

Remarks

1

NOEL

83 mg/kg bw/day (nominal)

Mouse

Oral

No effect were observed on survival, clinical chemistry, organ weights and histopathology

Data from publication for CAS: 8003-22-3

2

NOAEL

35 mg/ kg bw/ d (nominal)

Rat

Oral

No adverse effect on survival, clinical sign, body weight and body weight gain, food consumption and compound intake

Study report

3

LOEL

8333 mg/kg bw/day (nominal)

Mouse

Oral

Effect on body weight, clinical chemistry, organ weight, gross pathology and histopathology

Data from publication for CAS: 8003-22-3

4

LOEL

2833 mg/kg bw/day (nominal)

Rat

Oral

Effect on clinical sign, body weight, clinical chemistry, organ weight, gross pathology and histopathology

Data from publication for CAS: 8003-22-3

5

NOEL

78.5 mg/kg bw (total dose)

Rat

Oral

Data predicted for CAS: 8003-22-3

 

Based on the studies summarized in the above table it can be observed that NOAEL value found to be 

35 mg/ kg bw/ d (nominal), where the NOEL values varies from 78.5 to 83 mg/Kg bw/d. The LOEL values varies from 2833 to 8333 mg/Kg bw/d. The effects observed on the higher doses was listed as follows:

·         No adverse effect on survival, clinical sign, body weight and body weight gain, food consumption and compound intake

·         No effect were observed on survival, clinical chemistry, organ weights and histopathology

·         Effect on body weight, clinical chemistry, organ weight, gross pathology and histopathology

·         Effect on clinical sign, body weight, clinical chemistry, organ weight, gross pathology and histopathology

 

Thus based on above values it can be concluded that substance CAS: 8003-22-3 is expected to show no toxicological effect based on low effective dose value (LOEL) as this value is 8333 mg/Kg bw/d (mouse) and 2833 mg/Kg bw/d (rat), thus based on this value it can be concluded that substance CAS: 8003-22-3 is considered to be not toxic to repeated dose via oral route below the above mentioned dose level.

 

Repeated dose toxicity - Inhalation

The effect LOEL for 3-aminophenol following 90 days repeated dose toxicity study in Sprague-Dawley rats is considered to be 628.64 mg/kg bw/day (2802.76 mg/m3)based on the effects on enzyme activity.

Based on the studies available with Klimish rating 2 for the target substances CAS: 8003-22-3 the results is summarized as follows

Sr. No

End point

Value

Species

Effects

Remarks

1

LOEL

230 mg/m³ air (analytical)

Rat

Effect on respiratory function, Lung biochemistry and Lung connective tissue biochemistry.

Data from publication for CAS: 8003-22-3

2

NOAEL

11 mg/m³ air (analytical)

Rat

No effect on survival, clinical signs, body weight, clinical chemistry, gross pathology and histopathology

Data from publication for CAS: 8003-22-3

 

Based on the studies summarized in the above table it can be observed that NOAEL value found to be 

11 mg/m³ air (analytical), whereas the LOEL values found to be 230 mg/m³ air (analytical) thus based on this value it can be concluded that substance CAS: 8003-22-3 is considered to be not toxic to repeated dose via inhalation route.

 

Repeated dose toxicity - Dermal

In a subacute repeated dose dermal toxicity study, albino male and female rabbits treated with CI Solvent Yellow 33 in the concentration of 50, 200 and 1000 mg/kg for 6 hours/ 5 days a week. Results shows that CI Solvent Yellow 33 was not toxic dermaly. No effect was observed on survival of treated rabbits. There was no erythema & edema observed at 50, 200 and 1000 mg/kg treated sites of rabbits during the 14 day observation period. Changes in body weight and food consumption were observed in treated rabbits but the changes are not constant. In addition, mild to moderate degrees of one or more of hyperkeratosis, acanthosis and adnexal hyperplasia were observed. The treated skin sections were compared with untreated skin sections from the same rabbit. There was no definitive increase in severity of skin lesions with increasing dose levels. All other lesions found on organs were of an incidental nature and it could not be determined whether or not these changes were related to the absorption and toxicity of CI Solvent Yellow 33. Therefore, NOEL was considered to be 1000 mg/kg when albino male and female rabbits treated with CI Solvent Yellow 33 by dermal application for 2 weeks. 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

In summary, administration of D&C yellow no. 11 by the oral route studies appeared to No Observed effect level (NOEL) for male was considered to be 500 ppm (83 mg/kg/day) and Low Observed effect level (LOEL) for female was considered to be 50,000 ppm (8333 mg/kg/day) when B6C3F1 male and female mice were treated with D &C Yellowno.11.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

Very little SY as QI was retained in lungs after exposures of rats to SY for  13 week. After exposure, both dynamic and quasistatic lung compliance were greater in exposed than in control rats. No physiologically significant effects on respiratory function were caused by 13-week exposures to SY. Inhalation of SY at the highest level used for the 13-week study resulted in minimal focal accumulations of vacuolated alveolar macrophages, minimal hypertrophy of Type II pulmonary epithelial cells, and deposition of pig-merits in the nasal epithelium, kidneys, liver, and bronchial epithelium. The macrophages were accumulated in alveoli adjacent to the terminal bronchioles and alveolar ducts. The pigment was yellowish brown and present as irregular masses that ranged from less than a 1 µm in diameter to clumps greater than 15µm in diameter.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

NOEL was considered to be 1000 mg/kg when albino male and female rabbits treated with CI Solvent Yellow 33.

Justification for classification or non-classification

The substance1,3-isobenzofurandione, reaction products with methylquinoline and quinoline (D & C Yellow No. 11)does not exhibit repeated dose toxicity by oral, inhalation and dermal route.