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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1977 - 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non GLP, but level of detail and signatures indicate adequate quality control. No individual weights for pups, only litter weights. No necropsy of pups, as the animals were used in the long-term feeding study. (Detailed examinations performed on aged animals that were exposed via the feed.)
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
yes
Remarks:
Both males and females were treated 60 days prior to mating. Pup weight only deterimined for litters. Histopathology of reproductive organs performed for adult F1 animals. Study design combines fertility, developmental and long-term exposure elements.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate
EC Number:
227-497-9
EC Name:
Disodium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate
Cas Number:
5858-81-1
Molecular formula:
C18H14N2O6S.2Na
IUPAC Name:
disodium 3-hydroxy-4-[(4-methyl-2-sulfonatophenyl)diazenyl]-2-naphthoate
Details on test material:
- Name of test material (as cited in study report): D&C no. 6, K-7034
- Molecular formula (if other than submission substance): CAS no. 5858-81-1
- Molecular weight (if other than submission substance):
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: pigment (dark-orange red powder)
- Physical state: solid
- Analytical purity: 95% (Lot no. AA3473) and 96% (Lot no. AA 5169)
- Impurities (identity and concentrations): no information available
- Lot/batch No.: AA 3473 and AA 5169
- Expiration date of the lot/batch: no data
- Stability under test conditions: stable
- Storage condition of test material: not indicated. Not critical for an organic pigment
- Other: supplier H. Kohnstamm and Company Inc. New York (USA)

Test animals

Species:
rat
Strain:
other: Charles river CD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Wilmington, Massachusetts (USA)
- Age at study initiation: no information
- Weight at study initiation: 75 - 155 g (males) and 75 - 144g (females)
- Fasting period before study: not applicable
- Housing: individually, except for mating period and nursing period
- Diet (e.g. ad libitum): yes (Supplier Ralston Purina company)
- Water (e.g. ad libitum): yes
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled at 71° Fahrenheit (recorded weekly starting week 31)
- Humidity (%): controlled at 53% (recorded weekly starting week 31)
- Air changes (per hr): controlled, no further data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: Sept 2, 1977 To: January 6, 1978 (F0-Generation) and December 1977 To:June 3, 1980 (F1-Generation)

Individual ear tags were used for identification. Rats were examined for physical abnormalities prior to entering the study. Rats were then randomly assigned to groups.


Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): not indicated
- Mixing appropriate amounts with: Purina Laboratory Chow
- Storage temperature of food: room temperature
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: maximum 7 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged single.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The main batch of feed for each group was sampled (three sub-samples representing three distinct areas of the batch) and assayed weekly during the first 13 weeks and every 4 weeks thereafter. Concentrations were determined to be 95 - 99% of target values.
Homogenicity was also confirmed.
Chemical analysis was performed at the sponsor's laboratories.
Duration of treatment / exposure:
60 days prior to mating, maximum of 7 days for mating, during gestation and until post-partum day 21

F1-animals
exposure started in-utero. After weaning, rats received the control diet for two weeks and were then exposed via the diet until a survival rate of 20% was reached for the highest dose group; this was 95 weeks for males and 126 weeks for females.
Frequency of treatment:
daily
Details on study schedule:
not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.05, 0.3 and 2 % in the diet
Basis:
actual ingested
No. of animals per sex per dose:
60 males and 60 females
Control animals:
yes, plain diet
Details on study design:
Investigation fo F1-generation:
Clinical signs: Daily (pup stage), twice daily (adult stage)
Body weight and food consumption: weekly for the first 14 weeks, biweekly for the next 12 weeks and monthly thereafter. At the pup stage, weighing of the litter was done on days 0, 4 and 14
Hematology, biochemistry and urinalysis were performed for 10 animals per sex and dose group at 3, 6, 12, 18 and 21 months for both genders, for females, also after 24 months. Rats were fasted overnight prior to blood and urine collection.
Virology, haematology and microbiology was evaluated in a few rats at 20 months.

Hematology parameters: hemoglobin, hematocrit, total and differential leucocyte counts, total erythrocyte counts and total reticulocyte counts; for the 20,21 and 24 month investigation also mean corpulscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration

Biochemistry parameters: glucose, blood urea nitrogen, serum SGOT, SGPT, ALP, creatinine and total protein

Urinalysis parameters: pH, specific gravity, qualitative tests for protein, glucose, bilirubin, ketones and occult blood; description of color and appearance, microscopic analysis of sediments. Volumes were inadvertently recorded at 3, 6, 12 and 24 months.
Positive control:
no

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly, females also on days 0, 6, 15 and 21 of gestation and 0,4, 14 and 21 of lactation


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes

Ophthalmoscopic examinations were performed for all rats at 15 weeks of study.
Oestrous cyclicity (parental animals):
vaginal smears
Sperm parameters (parental animals):
Parameters not examined in male parental generations, but investigated in F1 males at the age of 12 months:
testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no


PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain (for litters, individual weights only at day 21), physical or behavioural abnormalities


GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after the last litter was weaned
- Maternal animals: All surviving animals after the last litter was weaned.

GROSS NECROPSY: no data

HISTOPATHOLOGY / ORGAN WEIGHTS: not examined
Postmortem examinations (offspring):
Clinical signs: Daily (pup stage), twice daily (adult stage)
Body weight and food consumption: weekly for the first 14 weeks, biweekly for the next 12 weeks and monthly thereafter. At the pup stage, weighing of the litter was done on days 0, 4 and 14
Hematology, biochemistry and urinalysis were performed for 10 animals per sex and dose group at 3, 6, 12, 18 and 21 months for both genders, for females, also after 24 months. Rats were fasted overnight prior to blood and urine collection.
Virology, haematology and microbiology was evaluated in three rats at 20 months.

Hematology parameters: hemoglobin, hematocrit, total and differential leucocyte counts, total erythrocyte counts and total reticulocyte counts; for the 20,21 and 24 month investigation also mean corpulscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration

Biochemistry parameters: glucose, blood urea nitrogen, serum SGOT, SGPT, ALP, creatinine and total protein

Urinalysis parameters: pH, specific gravity, qualitative tests for protein, glucose, bilirubin, ketones and occult blood; description of color and appearance, microscopic analysis of sediments. Volumes were inadvertently recorded at 3, 6, 12 and 24 months.

Histopathology was performed after 12 month and at terminal sacrifce at 20% survival rate.
Statistics:
For Fertility indices, gestation, pup survival indices: Chi-square test criterion with Yates correction on 2x2 contingency tables and/or Fisher's exact probability test

For mean number of liveborn pups per litter and litter mean pup weight: analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test as described by Steel and Torrie (1960) using Dunnett's multiple comparison tables (1964).
Reproductive indices:
fertility index
Offspring viability indices:
Indicies for live birth and survival to weaning were calclulated.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

No adverse effects were noted for any of the investigated parameters for parental animals.

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
>= 2 other: % in the diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects on fertility observed. (2 % in diet corresponds to ca. 1000 mg/kg bw for adult rats)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

No adverse effects were noted during weaning. After life-long exposure via the feed the offspring showed higher incidence of chronic nephritis at high age.

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
>= 2 other: % in the diet
Based on:
test mat.
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Pigment Red 57, which is the sodium salt analogue of Pigment Red 57:1, does not affect fertility, does not cause embryotoxicity and does not cause adverse effects via lactation. Specific investigation regarding teratogenicity were not performed.