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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
three-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from secondary source

Data source

Referenceopen allclose all

Reference Type:
other: authoritative database
Title:
Multi-generation reproduction study in rats.
Author:
U.S. National Library of Medicine
Year:
2017
Bibliographic source:
HSDB (Hazardous Substances Data Bank); US national Library of Medicine reviewed by SRC, 2017.
Reference Type:
secondary source
Title:
Multi-generation reproduction study was performed in rats.
Author:
HPVIS
Year:
2007
Bibliographic source:
Robust summary posted to the HPV Challenge Program , 2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
The reproductive effects of test material on male and female Charles River CD rats by oral (Diet) route at different dose levels was examined.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium 6-hydroxy-5-[(4-sulphonatophenyl)azo]naphthalene-2-sulphonate
EC Number:
220-491-7
EC Name:
Disodium 6-hydroxy-5-[(4-sulphonatophenyl)azo]naphthalene-2-sulphonate
Cas Number:
2783-94-0
Molecular formula:
C16H12N2O7S2.2Na
IUPAC Name:
disodium 6-hydroxy-5-[(4-sulfonatophenyl)diazenyl]naphthalene-2-sulfonate
Details on test material:
- Name of test material: FD&C Yellow No. 6
- Molecular formula: C16H12N2O7S2.2Na
- Molecular weight: 454.38g/mole
- Substance type: organic
- Physical state: solid
Specific details on test material used for the study:
No data available

Test animals

Species:
rat
Strain:
other: Charles River CD
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:No data available
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: (P) x wks; (F1) x wksNo data available
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x gNo data available
- Fasting period before study:No data available
- Housing:Animals were housed individually
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum):the test diet ad libitum
- Water (e.g. ad libitum):No data available
- Acclimation period:No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C):No data available
- Humidity (%):No data available
- Air changes (per hr):No data available
- Photoperiod (hrs dark / hrs light):
IN-LIFE DATES: From: To:No data available

Administration / exposure

Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: test material mixed with food

Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Pre-Mating Exposure / Males and Females: 60 days and test material adminstered upto three generation
Frequency of treatment:
Daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
Doses / Concentrations:
5, 50, 150 or 500 mg/kg bw/day
Basis:

No. of animals per sex per dose:
Total :150
0mg/kg bw/day : 10 males and 20 females
5 mg/kg bw/day : 10 males and 20 females
50 mg/kg bw/day :10 males and 20 females
150 mg/kg bw/day :10 males and 20 females
500 mg/kg bw/day : 10 males and 20 females


Control animals:
yes
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes
Clinical observations were recorded twice daily with at least 5 hours between observations

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: Detailed physical examinations and palpation for masses were performed weekly.



BODY WEIGHT: Yes
Time schedule for examinations: weekly for the first fourteen weeks, bi-weekly for the next 12 weeks and every 4 weeks thereafter until the end of the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes weekly for the first fourteen weeks, bi-weekly for the next 12 weeks and every 4 weeks thereafter until the end of the study..

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes ,

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

OTHER: Haematology tests, including hemoglobin, hematocrit, erythrocyte and total and differential leukocyte counts, and erythrocyte morphology, were conducted on ten randomly selected animals at months 3, 6, 12, 18 and 24 of the study.
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]

GROSS NECROPSY
Necropsies were conducted on all animals dying prior to study termination, killed in a moribund condition or killed on schedule,Tissues examined included adrenal glands, aorta, blood smear, brain, cecum, colon, duodenum, epididymus or uterus, esophagus, eyes, femur including marrow, tissue masses, gallbladder, heart, ileum, jejunum, duodenum, kidneys, liver, lungs and bronchi, mammary gland, nerves (sciatic), ovaries, lymph nodes, pancreas, parathyroids, pituitary gland, prostrate, rectum, skin, spleen, seminal vesicles, skeletal muscle, testes with ep ididymides, stomach, thymus, thyroid gland including parathyroid, trachea, urinary bladder, uterus


HISTOPATHOLOGY / ORGAN WEIGHTS
Histological examinations were conducted on all animals from both control groups, the highest dose group (2.0 or 5.0%) from each study and also on 10 rats randomly selected from each group for an interim sacrifice at 12 months. Histology was also performed on any animal with gross lesions or masses
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No treatment-related effects were reported on survival
Body weight and weight changes:
not specified
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
Description (incidence and severity):
No treatment-related effects were reported on haematological finding
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were reported on clinical chemistry
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were reported on urinalysis.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
no compound related lesions in any tissue examined histologically, including kidneys and adrenal glands from parental rats.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Histological evaluation revealed a variety of lesions, including neoplasms, present at similar incidences in control and treated animals.The authors considered the lesions to be spontaneous and not related to administration of the test material.
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no compound related effects on fertility, gestation, pup viability or lactation indices, on reproductive organs of females, or on organ weights among parents.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
reproductive performance
other: see 'Remark'
Remarks on result:
other: No effects on reproductive performance was observed

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:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
no compound related effects on pup viability or lactation indices.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was similar for control and treated animals at the lower dietary levels, but was slightly higher in the 500 mg/kg bw dose group although not statistically significant.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were reported on Haematological finding
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were reported on clinical chemistry
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
no compound related effects on organ weights
Gross pathological findings:
no effects observed
Description (incidence and severity):
Necropsies did not reveal any treatment-related gross or microscopic changes.
Histopathological findings:
no effects observed
Description (incidence and severity):
There were no compound related lesions in any tissue examined histologically, including kidneys and adrenal glands from offspring.
Other effects:
no effects observed
Description (incidence and severity):
There were no compound related effects on fertility, gestation, pup viability or lactation indices, on reproductive organs of females, or on organ weights among offspring.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: Overall no developmental toxic effects were observed

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

Results: F2 generation

General toxicity (F2)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was similar for control and treated animals at the lower dietary levels, but was slightly higher in the 500 mg/kg bw dose group although not statistically significant.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were reported on Haematological finding
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were reported on clinical chemistry
Urinalysis findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were reported on urinalysis
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
no compound related effects on organ weights
Gross pathological findings:
no effects observed
Description (incidence and severity):
Necropsies did not reveal any treatment-related gross or microscopic changes.
Histopathological findings:
no effects observed
Description (incidence and severity):
There were no compound related lesions in any tissue examined histologically, including kidneys and adrenal glands from offspring.
Other effects:
no effects observed
Description (incidence and severity):
There were no compound related effects on fertility, gestation, pup viability or lactation indices, on reproductive organs of females, or on organ weights among offspring.

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Effect levels (F2)

Dose descriptor:
NOAEL
Generation:
F2
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: overall no developmental effects were observed

Target system / organ toxicity (F2)

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:
NOAEL was considred to be 500mg/kg bw/day for F0, F1 and F2 generation. When male and female Charles River CD rats were treated with test material orally.
Executive summary:

Three generation reproductive study of test material was performed on male and female Charles River CD rats. Animals were housed individually and fed the test diet ad libitum. The test material mixed with food in dose concentration 0, 5, 50, 150 or 500 mg/kg bw/day and 10 males and 20 females/group/generation were used .Pre-Mating Exposure / Males and Females were 60 days. Clinical observations were recorded twice daily with at least 5 hours between observations. Detailed physical examinations and palpation for masses were performed weekly. Body weights and food consumption were determined weekly for the first fourteen weeks, bi-weekly for the next 12 weeks and every 4 weeks thereafter until the end of the study. The intake of the test substance was determined from body weight, food consumption and dietary concentration. Haematology tests, including haemoglobin, haematocrit, erythrocyte and total and differential leukocyte counts, and erythrocyte morphology, were conducted on ten randomly selected animals at months 3, 6, 12, 18 and 24 of the study. Necropsies were conducted on all animals dying prior to study termination, killed in a moribund condition or killed on schedule. Histological examinations were conducted on all animals from both control groups, the highest dose group (2.0 or 5.0%) from each study and also on 10 rats randomly selected from each group for an interim sacrifice at 12 months. Histology was also performed on any animal with gross lesions or masses. Also tissues examined included adrenal glands, aorta, blood smear, brain, cecum, colon, duodenum, epididymus or uterus, esophagus, eyes, femur including marrow, tissue masses, gallbladder, heart, ileum, jejunum, duodenum, kidneys, liver, lungs and bronchi, mammary gland, nerves (sciatic), ovaries, lymph nodes, pancreas, parathyroids, pituitary gland, prostrate, rectum, skin, spleen, seminal vesicles, skeletal muscle, testes with epididymides, stomach, thymus, thyroid gland including parathyroid, trachea, urinary bladder, uterus.

 At the end of study, no treatment-related effects were reported on survival. No treatment-related changes were reported at gross necropsy. Histological evaluation revealed a variety of lesions, including neoplasms, present at similar incidences in control and treated animals. The authors considered the lesions to be spontaneous and not related to administration of the test material. There were no compound related effects on fertility, gestation, pup viability or lactation indices, on reproductive organs of females, or on organ weights among parents and offspring. There were no compound related lesions in any tissue examined histologically, including kidneys and adrenal glands from parental rats or from offspring. There was no toxicity to either the F1 or F2 generation. Food consumption was similar for control and treated animals at the lower dietary levels, but was slightly higher in the high-dose study, although not statistically significant. Haematological, clinical chemistry and urinalysis parameters did not differ significantly from the controls. Necropsies at one year did not reveal any treatment-related gross or microscopic changes. Hence NOAEL was considered to be 500mg/kg bw/day for F0, F1 and F2 generation. When male and female Charles River CD rats were treated with test material orally.