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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
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:
Evaluation of the Teratogenicity of Fluorescein sodium
Author:
JAMES K. MCENERNEY, B.S., WENDEL P. WONG, B.S., AND GHOLAM A. P E Y M A N , M.D.
Year:
1977
Bibliographic source:
American Journal of Ophthalmology, december, 1977, VOL. 84, NO. 6, 847-850

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Teratogenicity study of Fluorescein sodium in rabbits
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Fluorescein sodium
- Molecular formula (if other than submission substance): C20H12O5.2Na
- Molecular weight (if other than submission substance): 376.274 g/mole
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): No data available

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
female
Details on test animals and environmental conditions:
EST ANIMALS
- Source: No data available
- Age at study initiation: (P) x wks; (F1) x wks No data available
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: 4.5 kg
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- 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): No data available

Administration / exposure

Route of administration:
intravenous
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 10% water solution (Funduscein)
Details on mating procedure:
- M/F ratio per cage: No data available
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy No data available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: Nineteen rabbits immediately after copulation with male rabbits of the same species were used.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
3 days (5,6 and 8 day after copulation)
Frequency of treatment:
Once daily on 5,6 and 8 day after copulation
Details on study schedule:
No data available
Doses / concentrations
Remarks:
Doses / Concentrations:
1.4 ml (2241.4 mg/kg)
Basis:
actual ingested
No. of animals per sex per dose:
Total: 19
0 ml: 4 female
2241.4 mg/kg: 15 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Survival and clinical sign were examined.
Estrous cyclicity (parental animals):
Any irriggularty in Estrous cyclicity were examined.
Sperm parameters (parental animals):
No data available
Litter observations:
Delayed appearance of birth defects were examined.
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
Gross pathology and histopathology were examined.
Statistics:
The difference between the number of offspring that died at one month in the experimental vs the control group was analyzed with the Chi-square test. The probability that the distribution occurred by chance was found to be at the 5% level of significance (P = .05).
Reproductive indices:
No data available
Offspring viability indices:
Viability till four weeks were observed

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

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

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

No effect on survival were observed in trated rats as compared to control.

Clinical signs:
No abortion or miscarriage were observed in trated rats as compared to control.

Body weight and food consumption: No data available

Test substance intake: No data available

Reproductive function: estrous cycle: No data available

Reproductive function: sperm measures: No data available

Reproductive performance:No effect on live-born offspring and stillbirth were observed in treated rats as compared to control.

Organ weights No data available

Gross pathology: No data available

Histopathology: No data available

other findings No data available

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
2 241.4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No effect on survival, clinical sign and Reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

Mortality:
No effect on live-born offspring were observed in trated rats as compared to control.

At 4 week, 14 offspring (19%) from four mothers subsequently died.
The observed effect were due to poor mothers not due to treatment.

Clinical signs:
One stillbirth and all other offspring were normal and no delayed appearance of birth defects were observed in offspring as compared to control.

Body weight and food consumption: No data available

Test substance intake: No data available

Reproductive function: estrous cycle: No data available

Reproductive function: sperm measures: No data available

Reproductive performance: No data available

Organ weights: No data available

Gross pathology:No gross pathological changes were observed in offspring of treated rats.

Histopathology:No Soft tissue and Visceral abmormalities were observed in offspring of treated rats.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 241.4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect on survival, clinical sign, Gross pathology and histopathology

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 2241.4 mg/kg when New Zealand female Rabbits were treated with Fluorescein sodium.
Executive summary:

In a Teratogenicity study,New Zealand female Rabbits were treated with Fluorescein sodium in the concentration of 2241.4 mg/kg intravenouslly in 10% water solution (Funduscein) on day 5,6 and 8 day after copulation. No effect was observed on survival and no abortion or miscarriages were observed in treated rats as compared to control. No effect on live-born offspring and stillbirth were observed in treated rabbits as compared to control.  No effect on live-born offspring was observed. At 4 week, 14 offspring (19%) from four mothers subsequently died. The observed effects were due to poor mothers and not due to treatment. One stillbirth and all other offspring were normal and no delayed appearances of birth defects were observed in offspring as compared to control. In addition, no gross pathological and histopathological changes were observed in offspring of treated rabbits as compared to control. Therefore, NOAEL was considered to be 2241.4 mg/kg for F0 and F1 generation when New Zealand female Rabbits were treated with Fluorescein sodium intravenouslly in 10% water solution (Funduscein) on day 5, 6 and 8 day and day 13, 15 and 16 day after copulation.