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EC number: 248-420-5 | CAS number: 27344-06-5
Toxicological information
Developmental toxicity / teratogenicity
Currently viewing:
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
- Principles of method if other than guideline:
- The dose-range finding experiment was performed with 3 groups of treated pregnant female rats and a control group to find appropriate dose for the Prenatal Developmental Toxicity Study
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Disodium 4,4'-bis[[4-anilino-6-[(2-carbamoylethyl)(2-hydroxyethyl)amino]-1,3,5,-triazin-2-yl]amino]stilbene-2,2'-disulphonate
- EC Number:
- 248-420-5
- EC Name:
- Disodium 4,4'-bis[[4-anilino-6-[(2-carbamoylethyl)(2-hydroxyethyl)amino]-1,3,5,-triazin-2-yl]amino]stilbene-2,2'-disulphonate
- Cas Number:
- 27344-06-5
- Molecular formula:
- C42H46N14O10S2.2Na
- IUPAC Name:
- disodium 4,4'-bis[[4-anilino-6-[(2-carbamoylethyl)(2-hydroxyethyl)amino]-1,3,5,-triazin-2-yl]amino]stilbene-2,2'-disulphonate
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- CRL
- Details on test animals or test system and environmental conditions:
- Selection of animal species: laboratory rat has been chosen because our testing laboratory has long experience with this species and because rat is recommended according to the test guideline
Strain: Wistar CRL (SPF quality - guaranteed)
Sex: females (males – only for mating)
Total number of animals: 6 per group
Acclimatization: 13 days
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- The test item concentration at single dose level was adjusted so that the administered volume was constant at all dose levels: 1 ml/100 g body weight.
The animals were without feed two hours before application and two hours after application of the test item. - Details on mating procedure:
- After acclimatization females were mated with males (1 male and 1 female). Control of fertilization was made by the help of the vaginal smears. Vaginal smears were carried out after 24 hours of the first removing to male and then daily at the same time and the presence of sperms were examined. Day 0 of pregnancy was the day on which sperms in vaginal smear were found out.
- Frequency of treatment:
- daily - 7 days per week at the same time (8.00 – 10.00 am)
- Duration of test:
- Exposition lasted from implantation (the 5th day after fertilization) to one day prior to the day of scheduled euthanasia (the 19th day after fertilization).
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 6 females
Male rats serve only for mating (they are not administered by the test item and examined) - Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- - Examination of vaginal smears of females
Each morning in the mating period vaginal smears were prepared from all mated females. These smears were stained and examined microscopically for presence of spermatozoa. Day 0 of pregnancy was the day when sperms were observed.
- Body weight of females:1st, 5th, 8th, 11th, 14th, 17th and 20th day of pregnancy
- Mortality of females: twice daily
- Health condition control of females: daily, before the application of the test item
- Clinical observations of the females: twice a day (except weekend, when clinical observation was performed once a day)
- Haematology examination: blood samples were collected from the orbital plexus by glass micropipette under the light diethyl ether narcosis into the PVC test tubes containing anticoagulation systems.
Basic blood parameters: total erythrocyte count, total leucocyte count, mean corpuscule volume, haematocrit, haemoglobin concentration, total platelet count – 20th day of pregnancy
- Pathological examination of females: 20th day of pregnancy - Ovaries and uterine content:
- Number of implantations, corpora lutea and resorptions
Number of foetuses - Fetal examinations:
- - Pathological examination of foetuses: 20th day of pregnancy
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No serious changes of animal health status and clinical symptoms of intoxication were observed in treated females.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- The body weights of pregnant females at all dose levels were comparable to the control group during whole study.
- Food consumption and compound intake (if feeding study):
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- Haematological examination did not show significant differences among dose levels and control group.
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopic examination was performed in all females (including females without foetuses). No finding related with treatment was noted at necropsy in all treated females.
- Histopathological findings: non-neoplastic:
- not examined
Maternal developmental toxicity
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The numbers of implantations, corpora lutea and resorptions at all dose levels were comparable to the control group.
- Total litter losses by resorption:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No death of foetuses was recorded in any litter.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
- Dose descriptor:
- dose level: dose for selection of maximum tested dose in the main study
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
- pre and post implantation loss
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- not examined
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The total number of live foetuses in group and average number of foetuses per litter were similar or higher at the dose levels compared to the control group.
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- No macroscopic changes of soft tissues and external alteration were found during the pathological examination of the foetuses at all dose levels.
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
Effect levels (fetuses)
- Dose descriptor:
- other: dose for selection of maximum tested dose in the main study
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Remarks on result:
- other: dead foetuses
Fetal abnormalities
- Abnormalities:
- not examined
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table of results
| dose (mg/kg) | notes | ||||
| 0 | 100 | 300 | 1000 | ||
| Number of dams with abortions, early deliveries, stillbirths, resorptions | not examined | not examined | not examined | not examined | |
| Number of dams with dead foetuses | not examined | not examined | not examined | not examined | |
| Number of pregnant females | 5/6 | 6/6 | 6/6 | 5/6 | |
| Number of non-pregnant females | 1/6 | 0/6 | 0/6 | 1/6 | |
| Number of implantations | 16.60 ± 0.89 | 16.67 ± 2.25 | 17.33 ± 1.21 | 16.60 ± 1.82 | |
| Number of resorptions | 0.60 ± 0.89 | 0.83 ± 0.75 | 0.17 ± 0.41 | 1.00 ± 1.22 | |
| Number of corpora lutea | 16.60 ± 0.89 | 17.00 ± 2.10 | 17.67 ± 1.03 | 17.00 ± 2.35 | |
| Pre-implantation loss, number and percent | no effects | no effects | no effects | no effects | |
| post-implantation loss, number and percent | no effects | no effects | no effects | no effects | |
| Body weight (20th day) | 445.16 ± 21.22 | 460.35 ± 26.67 | 453.37 ± 24.86 | 442.50 ± 22.69 | |
| Body weight change | no effects | no effects | no effects | no effects | |
| Absolute weight (g) of the thyroid | not examined | not examined | not examined | not examined | |
| Relative weight (%) of the thyroid | not examined | not examined | not examined | not examined | |
| histopathology of the thyroid | not examined | not examined | not examined | not examined | |
| Results of the thyroid hormone: T3 (ng/mL) | not examined | not examined | not examined | not examined | |
| Results of the thyroid hormone: T4 (µg/dL) | not examined | not examined | not examined | not examined | |
| Results of the thyroid hormone: TSH (ng/mL) | not examined | not examined | not examined | not examined | |
| Mean number (and percent) of live offspring | 16.00 ± 1.58 | 15.83 ± 2.93 | 17.17 ± 1.47 | 15.60 ± 2.41 | Number of foetuses (average per litter; mean ± standard deviation) |
| Mean foetal/pup body weight by sexes combined | not examined | not examined | not examined | not examined | |
| Mean foetal/pup body weight - males | not examined | not examined | not examined | not examined | |
| Mean foetal/pup body weight - females | not examined | not examined | not examined | not examined | |
| Number (and percent) of foetuses and litters with malformation (including runts) and/or variations | not examined | not examined | not examined | not examined | |
| Description and incidences of malformations and main variations | not examined | not examined | not examined | not examined | |
Applicant's summary and conclusion
- Conclusions:
- The oral administration of the test item to pregnant females by gavage from the 5th to the 19th day of pregnancy at the dose levels 100, 300 and 1000 mg/kg/day did not cause mortality of pregnant females.
No adverse changes of health condition and no clinical symptoms of intoxication were found in females at any dose level after administration of the test item.
The haematological examination did not show significant differences among dose levels.
The pathological examination of females and foetuses revealed no serious macroscopic changes.
The reproduction parameters were not changed at any dose levels. - Executive summary:
The oral administration of the test item to pregnant females by gavage from the 5th to the 19th day of pregnancy at the dose levels 100, 300 and 1000 mg/kg/day did not cause mortality of pregnant females.
No adverse changes of health condition and no clinical symptoms of intoxication were found in females at any dose level after administration of the test item.
The haematological examination did not show significant differences among dose levels.
The pathological examinationof females and foetuses revealed no serious macroscopic changes.
The reproduction parameters were not changed at any dose levels.
Based on these findings and the results obtained from studies on other category compounds, the highest tested dose for the main study was selected.
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