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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
1981
Deviations:
yes
Remarks:
No deviations that were deemed to adversely affect the outcome or interpretation of the study occurred.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate
EC Number:
249-616-3
EC Name:
Potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate
Cas Number:
29420-49-3
Molecular formula:
C4HF9O3S.K
IUPAC Name:
potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
- Expiration date of the lot/batch: 31 August, 2003
- Purity test date: 31 August, 2001

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature. Suspensions of the test substance were prepared apprximately every 10 days at the testing facility. Prepared test substance and vehicle formulations were stored at 2 to 8 C.
- Stability under test conditions: Samples of prepared test article were verified analytically
- Solubility and stability of the test substance in the solvent/vehicle: Samples of prepared test article were verified analytically

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test article was suspended in 0.1% carboxymethyl cellulose in deionized water
- Final dilution of a dissolved solid, stock liquid or gel: The test article solutions were prepared so that 0 (vehicle control), 100, 300, and 1000 mg/kg could be dosed via gavage at a volume of 10 mL/kg.
- Final preparation of a solid: The test article was suspended in 0.1% carboxymethyl cellulose in deionized water

FORM AS APPLIED IN THE TEST: The test article was suspended in 0.1% carboxymethyl cellulose in deionized water

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: 70 days
- Weight at study initiation: Females: 220-244 grams, Males: 526-876
- Fasting period before study: None
- Housing: Rats were individually housed in stainless steel, wire-bottomed cages except during the cohabitation period. During cohabitation, each pair of male and female rats was housed in the male rat's cage.
- Diet (e.g. ad libitum): Rats were given ad libitum access to Certified Rodent Diet® #5002 (PMI Nutrition International, St. Louis, Missouri) in individual feeders.
- Water (e.g. ad libitum): Local water that had been processed by passage through a reverse osmosis membrane (R.O. water) was available to the rats ad Iibitum from an automatic watering access system. Chlorine was added to the processed water as a bacteriostat.
- Acclimation period: 5 Days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 13 February, 2001 To: 15 March, 2001

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.1% carboxymethyl cellulose in deionized water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was suspended in 0.1% carboxymethyl cellulose in deionized water

VEHICLE
- Concentration in vehicle: The test article solutions were prepared so that 0 (vehicle control), 100, 300, and 1000 mg/kg could be dosed via gavage at a volume of 10 mL/kg.
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): 49H1332
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Maximum of 5 days
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as Day 0 of pregnancy
Duration of treatment / exposure:
Day of gestation (DG) 6 through DG 20.
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Vehicle control (0.1% CMC in deionized water)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on a range-finding study
- Rationale for animal assignment: Random
- Other:

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Rats were observed for viability at least twice each day of the study.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Rats were examined for clinical observations and general appearance weekly during the acclimation period and on DG 0. Observations for clinical signs of effects of the test substance, abortions, premature deliveries and deaths were also made daily before and approximately 60 +/- 10 minutes after dosage administration and on the day of scheduled sacrifice.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly during the acclimation period, on DG 0, daily during the dosage period and prior to sacrifice.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Feed consumption values were recorded on DGs 0, 6, 9, 12, 15, 18, 20 and 21.

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: Caesarean-sectioned and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. The gravid uterus was excised and weighed. Uteri of apparently nonpregnant rats were examined while being pressed between glass plates to confirm the absence of implantation sites.

OTHER: Rats that died or were sacrificed because of premature delivery were examined for the cause of death on the day the observation was made. The rats were examined for gross lesions. Pregnancy status and uterine contents of female rats were recorded. Gravid uterine weights were recorded unless precluded by autolysis. Delivered pups and fetuses in uteri were examined to the extent possible, using the methods described for term fetuses. Uteri of apparently nonpregnant rats will be examined while being pressed between glass plates to confirm the absence of implantation sites.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included: The number of corpora lutea in each ovary was recorded. The uterus of each rat was excised and examined for pregnancy, number and distribution of implantations, live and dead fetuses and early and late resorptions. An early resorption was defined as one in which organogenesis was not grossly evident. A late resorption was defined as one in which the occurrence of organogenesis was grossly evident. A live fetus was defined as a term fetus that responded to stimuli. Nonresponding term fetuses were considered to be dead (there were no dead fetuses). Dead fetuses and late resorptions were differentiated by the degree of autolysis present; marked to extreme autolysis indicated that the fetus was a late resorption.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter

Approximately one-half of the fetuses in each litter were examined for soft tissue alterations using a variation of the microdissection technique of Staples .These fetuses were fixed in Bouin's solution and the heads were subsequently examined by free-hand sectioning; head sections were retained in alcohol. The decapitated carcasses were discarded. The remaining fetuses (approximately one-half of the fetuses in each litter) were examined for skeletal alterations (bone and cartilage) after staining with alizarin red S. The fetuses were initially fixed in alcohol; skeletal preparations were retained in glycerin with thymol added as a preservative.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No test article-related clinical signs were noted during the study.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two rats in the 1000 mg/kg/day dosage group were found dead. The death of one of these rats was attributed to an intubation accident. No cause of death was determined for the other rat that was found dead in this dosage group, but the death was considered unrelated to the test substance because it was a single event. One rat in each of the 0 (Vehicle) and 300 mg/kg/day dosage groups began delivery before Caesarean sectioning on day 21 of gestation (DG 21) and were sacrificed. All other rats survived until scheduled sacrifice.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight gains were significantly reduced on DGs 6 to 9 and 18 to 21 in the 1000 mg/kg/day dosage group. As a result of these reductions, maternal body weight gains were significantly reduced for the entire gestation period (DGs 0 to 21) and maternal body weights were significantly reduced on DGs 20 and 21 in this dosage group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Absolute (g/day) and relative (g/kg/day) feed consumption values were significantly reduced on DGs 9 to 12 (relative only) and 18 to 21 in the 1000 mg/kg/day dosage group. As a result of these reductions, absolute and relative feed consumption values were significantly reduced in the 1000 mg/kg/day dosage group for the entire dosage period (calculated as DGs 6 to 21).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No treatment-related changes in the number of abortions were noted.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No treatment-related changes in implantations were noted.
Description (incidence and severity):
No total litter loss by resorption was noted.
Early or late resorptions:
no effects observed
Description (incidence and severity):
No treatment-related changes in early or late resorptions were noted.
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead fetuses were noted.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No treatment-related changes in pregnancy duration were noted.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): No treatment-related changes in pregnancy duration were noted.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
No treatment-related changes in the number of pregnant dams were noted.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 300 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
body weight and weight gain

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weights (total, male and female) were statistically significantly reduced in the 1000 mg/kg/day dosage group, compared to the control group value.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Fetal body weights (total, male and female) were significantly reduced in the 1000 mg/kg/day dosage group, compared to the control group value.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No treatment-related changes in the number of live offspring were observed.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No treatment-related changes in the sex ratio were observed.
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
No changes in litter sizes were noted but fetal body weights (total, male and female) were significantly reduced in the 1000 mg/kg/day dosage group, compared to the control group value.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The number of litters with fetuses with alterations numbered 4 (16.7%), 8 (36.4%), 3 (13.0%) and 3 (14.3%), in the 0 (Vehicle), 100, 300 and 1000 mg/kg/day dosage groups, respectively. The numbers of fetuses with any alteration observed were 4 (1.1%), 13 (4.1%), 3 (0.9%) and 3 (1.0%), and the percentages of fetuses with any alteration per litter were 1.2, 4.3, 0.8 and 1.0 in these same respective dosage groups.

No gross external (malformations or variations) were caused by dosages of the test substance as high as 1000 mg/kg/day. There were no dosage-dependent or significant differences in the litter or fetal incidences of any gross external, soft tissue or skeletal alterations. The significant increase in the percentage of fetuses with any alteration in the 100 mg/kg/day dosage groups was not considered treatment-related because it was not dosage-dependent.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The number of litters with fetuses with alterations numbered 4 (16.7%), 8 (36.4%), 3 (13.0%) and 3 (14.3%), in the 0 (Vehicle), 100, 300 and 1000 mg/kg/day dosage groups, respectively. The numbers of fetuses with any alteration observed were 4 (1.1%), 13 (4.1%), 3 (0.9%) and 3 (1.0%), and the percentages of fetuses with any alteration per litter were 1.2, 4.3, 0.8 and 1.0 in these same respective dosage groups.

No gross external, soft tissue or skeletal fetal alterations (malformations or variations) were caused by dosages of the test substance as high as 1000 mg/kg/day. There were no dosage-dependent or significant differences in the litter or fetal incidences of any gross external, soft tissue or skeletal alterations. The significant increase in the percentage of fetuses with any alteration in the 100 mg/kg/day dosage groups was not considered treatment-related because it was not dosage-dependent.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No gross external, soft tissue or skeletal fetal alterations (malformations or variations) were caused by dosages of the test substance as high as 1000 mg/kg/day. There were no dosage-dependent or significant differences in the litter or fetal incidences of any gross external, soft tissue or skeletal alterations. The significant increase in the percentage of fetuses with any alteration in the 100 mg/kg/day dosage groups was not considered treatment-related because it was not dosage-dependent.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 300 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Developmental toxicity at 1000 mg/kg/day cannot be evaluated due to presence of maternal toxicity (significant decrease in maternal body weight gain at 1000 mg/kg/day). The NOAEL for developmental effects is 300 mg/kg/day.

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
Treatment related:
no

Any other information on results incl. tables

Developmental toxicity at 1000 mg/kg/day cannot be evaluated due to presence of maternal toxicity (significant decrease in maternal body weight gain at 1000 mg/kg/day). The NOAEL for developmental effects is 300 mg/kg/day.

Applicant's summary and conclusion

Conclusions:
Developmental toxicity at 1000 mg/kg/day cannot be evaluated due to presence of maternal toxicity (significant decrease in maternal body weight gain at 1000 mg/kg/day). The NOAEL for developmental effects is 300 mg/kg/day.
Executive summary:

The reproductive and developmental toxicity of T-7485 was evaluated in Sprague Dawley rats. This study was performed in compliance with OECD GLP (1997), Japanese MAFF GLP Standards (1984), and US EPA GLP 40 CFR 160 and 792. The study design was based on OECD 414 (1981), US EPA OPPTS 870.3700 (1998), and US EPA TSCA Test Guideline 799.9370 (1997). The test material was prepared in 0.1% carboxymethylcellulose in deionized water (vehicle). Female rats were placed into cohabitation with male rats at a ratio of 1:1. Pregnancy was confirmed by vaginal smear and/or absence of copulatory plug (DG 0). Female rats (25/dose) received 0, 100, 300, or 1000 mg/kg/day of T-7485 via oral gavage at a dose volume of 10 mL/kg on DGs 6 through 20. Clinical observations and body weights were recorded daily. Feed consumption values were recorded on DGs 0, 6, 9, 12, 5, 18, 20, and 21. All surviving rats were euthanized on DG 21. Caesarean-section and gross necropsy was performed. The uterus of each animal was excited and examined for pregnancy, number and distribution of implantations, live and dead fetuses, and early and late resorptions. Fetuses were weighed and examined for sex, gross external alterations, soft tissue alterations, and skeletal alterations. 

Two females treated at 1000 mg/kg/day were found dead on DG 17 and 18, respectively. One of the deaths was attributed to an intubation accident. No cause of death was determined for the other animal, but the death was considered unrelated to test article administration because it was a single event. There were no test article-related, abnormal clinical observations. In the 1000 mg/kg/day dose group, maternal body weight gains were significantly reduced on DGs 6 to 9 and 18 to 21, and thus were also significantly reduced for the entire gestation period (DGs 0 to 21). Gravid uterine weights were slightly reduced in the 1000 mg/kg/day dose group. Food consumption values were significantly reduced in the 1000 mg/kg/day dose group. Body weights, body weight gains, gravid uterine weights, and food consumption were not affected by test article administration in the 100 and 300 mg/kg/day dose groups. Fetal body weights (total, male and female) were significantly reduced in the 1000 mg/kg/day dose group when compared to the control group value. No other litter parameters were affected by test article administration. No gross external, soft tissue, or skeletal fetal alterations were attributed to test article administration.

Developmental toxicity at 1000 mg/kg/day cannot be evaluated due to presence of maternal toxicity (significant decrease in maternal body weight gain at 1000 mg/kg/day). The NOAEL for developmental effects is 300 mg/kg/day.