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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data available from study report.

Data source

Reference
Reference Type:
other: study report
Title:
TOXICOLOGY AND CARCINOGENESIS STUDIES OF D&C YELLOW NO.11
Author:
W.C. Eastin, G.A. Boorman, D.A. Bridge,J.R. Bucher, et. al.
Year:
1997
Bibliographic source:
NTP report April 1997 NTP TR 463 NIH Publication No. 97-3379

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Data is from Journal with permission
Principles of method if other than guideline:
Reproductive toxicity study of D&C Yellow No. 11 orally in rat orally
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Solid
Details on test material:
- Name of test material (as cited in study report): D& C yellow 11
- Substance type: Organic
- Physical state: Solid
-Purity: 1%
- Impurities (identity and concentrations): 99%

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:

Source: Taconic Farms (Germantown, NY)
- Age at study initiation: (P) Thirty-two-day-old male and female(F0)
-(F1) x wks: No data 42 days
- Age at study initiation: (P) 112 days old
- Weight at study initiation: (P) No data available
- Fasting period before study: No details available
- Housing: Rats were housed five per cage
Animals were housed in Solid-bottom polycarbonate changed twice weekly except from day 18 of gestation through delivery. Animals were bedded on Sani-Chips changed twice weekly except from day 18 of gestation through delivery. Reemay® spun-bonded polyester Rack Filters changed once every 2 weeks except from day 18 of gestation through delivery Stainless steel changed once every 2 weeks except from day 18 of gestation through delivery. Identified by Tail tattoo. Animals were housed 5 per cage before cohabitation, 1 pair during cohabitation and 5 males or 1 dam and litter aafter cohabitation.
- Use of restrainers for preventing ingestion (if dermal): No details
- Diet : NIH-07 open formula mash ad libitum
Water: : Tap water via automatic watering system, ad libitum
- Acclimation period: Animals were quarantined for 10 Days

ENVIRONMENTAL CONDITIONS
Temperature (°C): 20.0-25.6’c
Humidity :23.3% to 81.2%
- Air changes (per hr): minimum of 10 changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours/day

IN-LIFE DATES:
From: 18 December 1989

To: male: 13 March 1990
Female: 24 april 1990

Administration / exposure

Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: NIH-07 open formula mash
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS: Dose were prepared by mixing D&C Yellow No. 11 in the concentration of 0, 500, 1,700, and 5,000 ppm with NIH-07 open formula mash feed. D&C Yellow No. 11/feed premix was made by hand and then blended with feed in a Patterson-Kelly twin-shell blender for 15 minutes with the intensifier bar on for the first 5 minutes.
- Rate of preparation of diet (frequency): every 2 weeks
- Mixing appropriate amounts with (Type of food):The dose formulations were prepared every 2 weeks by mixing D&C Yellow No. 11 with feed (Table G1). A D&C Yellow No. 11/feed premix was made by hand and then blended with feed in a Patterson-Kelly twin-shell blender for 15 minutes with the intensifier bar on for the first 5 minutes. 0, 500, 1,700, and 5,000 ppm in NIH-07 open formula mash feed.
- Storage temperature of food:During the studies, dose formulations were stored in double-thickness plastic bags in rigid plastic containers at room temperature protected from light for up to 3 weeks.
VEHICLE
- Justification for use and choice of vehicle (if other than water): NIH-07 open formula mash feed
- Concentration in vehicle: 0, 500, 1,700, and 5,000 ppm
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
- M/F ratio per cage: During cohabitation -one male and one female per cage
- Length of cohabitation: 7 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
During cohabitation, vaginal smears were taken daily from females to determine the presence of sperm.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data
- After successful mating each pregnant female was caged (how): 1 dam per cage
- Any other deviations from standard protocol:
Analytical verification of doses Yes

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity and stability studies of the 500 ppm dose formulation were performed by the analytical chemistry laboratory using high-performance liquid chromatography. Homogeneity was confirmed and the stability of the dose formulations was confirmed for at least 3 weeks when stored protected from light at room temperature and for 7 days when stored open to air and light. Periodic analyses of the dose formulations of D& C Yellow No. 11 were ferpormed by using visible spectrometry. During the reproductive study the formulations wer e analyzed approximately every 8 weeks.
Duration of treatment / exposure:
Total: 125 weeks
Male: 13 weeks
Female: 19 weeks
F1: 106 week
Frequency of treatment:
Daily
Details on study schedule:
First-generation (F0 ) rats started on D&C Yellow No. 11 in feed---->70-day precohabitation period---->7-day cohabitation period---->21-day gestation period---->28-day lactation period---->Second-generation (F1 ) rats continued on same concentrations of D&C Yellow No. 11 in feed as dams for 2 years---->Terminal sacrifice
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 500, 1,700 and 5,000 ppm (0, 35, 120 and 350 ma/kg body weight /day for male and 0, 35, 120 and 370 ma/kg body weight /day for female )
Basis:
nominal in diet
No. of animals per sex per dose:
Total: 480
0 ppm : 60 male, 60 female
25 ppm : 60 male, 60 female
85 ppm : 60 male, 60 female
250 ppm : 60 male, 60 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The results of the 13-week rat study were used to select doses of 500, 1,700, and 5,000 ppm for the current F344/N rat study. In the 13-week feed study, rats were given 500, 1,700, 5,000, 17,000 and 50,000 ppm. There was no perinatal exposure, and animals were about 6 weeks old when placed on dosed feed. Mean body weights of males and females were significantly reduced after 13 weeks of exposure to 17,000 and 50,000 ppm, and there was mild hepatocellular periportal degeneration in 7 males given 17,000 ppm, in all 10 given 50,000 ppm, and in 2 females given 50,000 ppm. This lesion was minimal at doses of 1,700 and 5,000 ppm in males (4/4, 9/10) and females (2/2, 7/7) and in females at 17,000 ppm (9/10) and was not observed in groups given 500 ppm. In addition, a range-finding study was conducted in which female rats were given 5,000, 17,000, or 50,000 ppm D&C Yellow No. 11 in feed for 4 weeks before mating and during mating, gestation, and the first 4 weeks after having litters. Pups were weaned at week 4 and continued on the same feed as their dams for an additional 4 weeks. Litters would have been potentially exposed in utero, through lactation, and feed. There was no difference between study groups in reproductive performance. However, pup body weights in the 17,000 and 50,000 ppm groups were decreased at 8 weeks of age. Microscopic evaluation showed that the liver lesions in exposed pups were similar to those described for the 13-week study.

- Rationale for animal assignment (if not random): Rats were distributed randomly into groups of approximately equal initial mean body weights.

- Other: No data available
Positive control:
No data

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included: Mortality were observed.

DETAILED CLINICAL OBSERVATIONS: Yes clinical findings on day one and weekly before cohabitation for F0 Males and Females And on day 0, 6, 15 and 21of gestation for females & on days 1, 4, 14, and 21 of lactation for F females and F1 pups.

BODY WEIGHT: Yes on day one and weekly before cohabitation for F0 Males and Females And on day 0, 6, 15 and 21of gestation for females & on days 1, 4, 14, and 21 of lactation for F females and F1 pups.

Feed consumption was recorded by cage weekly before cohabitation, ondays 0, 6, 15, and 21 during gestation, and on days 1, 4, 14, and 21 during lactation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated.
Sperm parameters (parental animals):
No data available
Litter observations:
Survival, clinical sign, number and sex of pups, body weight, feed consumption were examined.
Postmortem examinations (parental animals):
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated were prepared for microscopic examination and weighed, respectively-Yes
Postmortem examinations (offspring):
Hematology, Organs weighed and histopathology were examined.
Statistics:
Body weight data for F rats, maternal body weight data during gestation and lactation, litter weight data, pup delivery data, percent male pups, and pups surviving on days 4 and 21 were analyzed by using Williams’ or Dunnett’s test. Feed consumption data for F0 rats were analyzed by using Dunn’s or Shirley’s test.
Reproductive indices:
Fertility index and implantation sites were examined.
Offspring viability indices:
Viability on day 4 were observed

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: Dietary levels of 500, 1,700, and 5,000 ppm D&C Yellow No. 11 resulted in average daily doses of approximately 35, 120, and 350 mg /kg body weight for males and 35, 120, and 370 mg/kg for females.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effect were observed on Reproductive function of treated rat as compared to control.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect were observed on Reproductive performance of treated rat as compared to control.

Details on results (P0)

Clinical signs:
Mortlity:
No effect were observed on survival of treated rat as compared to control.
Clinical signs:
Yellow discoloration of the entire body or fur in all males and females observed at 1,700 and 5,000 ppm dose and in all males and seven females at 500 ppm dose .
In all rats at 1,700 and 5,000 pp m, urine-stained abdominal fur were observed.
Yellow discoloration of the fur was observed in all exposed female rats during gestation and lactation as compared to control.


Body weight and food consumption:
Prior to cohabitation, mean body weight gains of males (days 1 to 71) at 500, 1,700 and 5,000 ppm and of females (days 1 to 66) at 5,000 ppm were significantly decreased as compared to controls.
The mean body weight gains of exposed females during gestation and lactation were generally similar to those of the controls

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
35 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight and body weight gain, food consumption and compound intake
Remarks on result:
other: not specified

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
not specified
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Significant increase in absolute and relative liver weights were observed in all the treated pups as compared to control.
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
effects observed, treatment-related

Details on results (F1)

Clinical signs:
Mortlity:
When treated with 1700 and 5000 ppm , significant decrease were observed in survival of male pups and at 5000 ppm in female as compared to control.
Clinical signs:
Yellow discoloration of the entire body in all exposed male and female pups from day 1 and head swelling and edema in 1,700 and 5,000 ppm males pups were observed as compared to control.

Body weight:
The mean body weights of exposed pups were significantly less than those of the control litters on days 14 and 21 in 1700 and 5000 ppm dose group.
Food consumption:
No effect was observed on food consumption of treated pups as compared to control.

Test substance intake:
Dietar y levels of 500, 1,700, and 5,000 ppm D&C Yellow No. 11 resulted in average daily doses of approximately 25, 85, and 250 mg /kg body weight for males and 25, 100, and 280 mg/kg body weight for females.

Gross pathology:
Renal tubule adenomas, Hepatocellular adenoma in 1700 and 5,000 ppm treated males pups and Renal tubule adenomas, hepatocellular adenoma or carcinoma (combined) in 1700 and 5,000 ppm treated females pups were observed as compared to control.
Squamous cell carcinomas of the tongue were observed in one 500 ppm male pup at 12 months and one 5,000 ppm female pup at 2 years were observed.
Renal tubule pigmentation were observed in all the treated male and female pups as compared to control.
Squamous cell papillomas were observed in the oral cavity (oral mucosa or tongue) of 1700 and 15000 ppm treate male pups.

Histopathology:
Mixed cell foci and clear cell foci in 1700 and 5000 ppm treated male and female pups were observed.
Cytologic alterations (basophilia and granularity) o f hepatocytes, and pigmentation in bile duct epithelium, hepatocytes, and Kupffer cells in treated male and female pups were observed.
Necrosis and regeneration of the renal tubule epithelium were observed in all the treated male and female pups.
Hyperplasia of the transitional epithelium in the kidney of 1700 ppm treated male and female pups.

other findings:
Hematology:
Minimal anemia in all the treated males were observed ; this anemia was characterized by decreased hematocrit values, hemoglobin concentra tions, and erythrocyte counts.
Th e minimal anemia was characterized as normocytic , normochromic, and nonresponsive. Normocytic , normochromic, nonresponsive anemias have been related to selective suppression of erythropoiesis in a variety of disorders and may be due to decreased erythropoietin elaboration, bone marrow suppression, or defective iron metabolism.
Therefore, the observed effect is not biologically or statistically significant than control.

Effect levels (F1)

Dose descriptor:
LOAEL
Generation:
F1
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effect on organ weight, gross pathology and histopathology
Remarks on result:
other: not specified

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect level (NOAEL) for F0 generation was considered to be 500 ppm (35 mg/kg body weight /day) and The Low observed adverse effect level (LOAEL) LOAEL for F1 generation was considered to be 500 ppm (25 mg/kg body weight /day) when F344/N male and female rats were treated with D&C Yellow No. 11.
Executive summary:

 In a reproductive toxicity study,F344/N male and female rats were treated with D&C Yellow No. 11. in the concentration of0, 500, 1,700 and 5,000 ppmorally in diet.Yellow discoloration of the entire body or fur and urine-stained abdominal fur. Significantly decreased in mean body weight gains ofF0males were observed at 500, 1,700 and 5,000 ppm. The mean body weights of exposed litters were significantly less than those of the control litters on days 14 and 21 in 1700 and 5000 ppm dose.In F1 generation, effect were observed as significant decreasein survival,Yellow discoloration of the entire bodyof pups, head swelling and edema in 1,700 and 5,000 ppm males pupsand Significant increase in absolute and relative liver weights were observed in all the treated pups as compared to control. In addition, Renal tubule adenomas, Hepatocellular adenoma in 1700 and 5,000 ppm treated males pups and Renal tubule adenomas, hepatocellular adenoma or carcinoma (combined) in 1700 and 5,000 ppm treated females pups, Squamous cell carcinomas of the tongue were observed in one 500 ppm male pup at 12 months and one 5,000 ppm female pup at 2 years, Renal tubule pigmentation in all the treated pups and Squamous cell papillomas of oral cavity (oral mucosa or tongue) in 1700 and 15000 ppm treated male pups were observed. Histopathological changes such as Mixed cell foci and clear cell foci in 1700 and 5000 ppm, Cytologic alterations (basophilia and granularity) o f hepatocytes, and pigmentation in bile duct epithelium, hepatocytes, and Kupffer cells in treated male and female pups, Necrosis and regeneration of the renal tubule epithelium in all the treated male and female pups and Hyperplasia of the transitional epithelium in the kidney of 1700 ppm treated male and female pups were observed as compared to control. Therefore,NOAEL for F0 generation was considered to be 500 ppm (35 mg/kg body weight /day) and LOAEL for F1 generation was considered to be 500 ppm (25 mg/kg body weight /day) when F344/N male and female rats were treated with D&C Yellow No. 11. Orally in diet for125 weeks.