Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 206-420-2 | CAS number: 338-83-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2018
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- PTPA
- IUPAC Name:
- PTPA
- Details on test material:
- - Name of test material (as cited in study report): (CF3CF2CF2)3N, PTPA, 338-83-0
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 3M Company, Batch 3435912
- Expiration date of the lot/batch: 07 July, 2021
- Purity test date: 12 December, 2017
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability under test conditions: Stable
TREATMENT OF TEST MATERIAL PRIOR TO TESTING : None, dosed neat.
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Deutschland, Sulzfeld, Germany
- Age at study initiation: 11 to 15 weeks old
- Weight at study initiation: between 194 and 266 g
- Fasting period before study: None
- Housing: On arrival and following randomization females were housed individually in Macrolon plastic cages (MIII type, height 18 cm) containing appropriate bedding (Lignocel S 8-15, JRS -
J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles.
- Diet (e.g. ad libitum): Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures.
- Water (e.g. ad libitum): Municipal tap water was freely available to each animal via water bottles.
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 43-54
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 24 March, 2019 To: 11 April, 2019
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test article was dosed neat.
VEHICLE: None - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The purity of the test article was determined via NMR spectormeter using a Bruker Avance 300 digital NMR spectrometer equipped with Bruker 5 mm BBFO 300 MHz Z-gradient high resolution-ATM Probe
- Details on mating procedure:
- Time-mated female Wistar Han Rats were received from Charles River Laboratories Deutschland, Sulzfeld, Germany. The females arrived on Day 0 or Day 1 post-coitum (Day 0 post-coitum is defined as the day of successful mating).
- Duration of treatment / exposure:
- The test item was administered to the animals of Groups 2, 3 and 4 at the appropriate dose volumes (and Elix Water to animals of Group 1) once daily by oral gavage 7 days a week from Day 6 to Day 20 post-coitum, inclusive.
- Frequency of treatment:
- Daily
- Duration of test:
- Day 6 to Day 20 post-coitum, inclusive.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Group 1: Elix water control
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Group 2
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- Group 3
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4
- No. of animals per sex per dose:
- 22 females per dose
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Dose selection rationale: The doses were based on the results of an OECD 421 study conducted on the test article.
- Rationale for animal assignment (if not random): Random
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed
from the cage during observation, unless necessary for identification or confirmation of possible findings.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were performed at least once daily, beginning on Day 2 post-coitum and
lasting up to the day prior to necropsy.
BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually on Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.
FOOD CONSUMPTION: Yes
Food consumption was quantitatively measured for Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum.
WATER CONSUMPTION: Yes
- Time schedule for examinations: Water consumption was monitored on regular basis throughout the study by visual inspection of the water bottles/containers.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Day 21 post-coitum
- Organs examined: number of corpora lutea, organ weights ((gravid) uterus and thyroid gland), uterine contents
Other: The following parameters and end points were evaluated in this study for the F0-generation: mortality/moribundity, clinical signs, body weights, food consumption, thyroid hormone levels (T3, T4, TSH), gross necropsy findings, number of corpora lutea, organ weights ((gravid) uterus and thyroid gland), uterine contents and histopathologic examination (thyroid gland). - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% or 5% levels.
Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible. Inferential statistics were performed according to the matrix below when possible, but excluded semi-quantitative data, and any group with less than 3 observations.
The following pairwise comparisons were made:
Group 2 vs Group 1
Group 3 vs Group 1
Group 4 vs Group 1
Datasets with at least 3 groups were compared using Dunnett-test.
Datasets with at least 3 groups were compared using a Steel-test (many-to-one rank test). Mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and post-implantation loss, and sex distribution were compared using the Mann Whitney test. Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the compound-treated groups to the control group.
An overall Fisher’s exact test was used to compare all groups at the 5% significance level. The above pairwise comparisons were conducted using a two-sided Fisher’s exact test at the 5% significance level if the overall test was significant. No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss. - Indices:
- Number of corpora lutea, the number of live and dead fetuses, early and late resorptions, total implantations, fetal body weights, sex ratio, ano-genital distance.
- Historical control data:
- Results were compared to historical Charles River data.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No adverse clinical signs were noted during the observation period.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean body weights, body weight gain and weight gain corrected for gravid uterus of treated females remained in the same range as controls over the treatment period.
After correction for uterus weight, the body weight of one female at necropsy (No. 80, at 1000 mg/kg/day) appeared to be slightly lower (less than 2%) when compared to its body weight on Day 6 post-coitum. Since a large variation in body weight gain between individual animals was also observed in other groups, this single finding was considered of no toxicological relevance. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption before or after correction for body weight was similar to the control level over the study period.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- Serum levels of TSH, total T3 and T4 were considered to be unaffected by treatment up to 1000 mg/kg/day.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Thyroid weights and thyroid to body weight ratios of treated animals were considered to be similar to those of control animals.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no test item-related gross observations.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no test item-related microscopic observations
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no test item-related microscopic observations
- Other effects:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
- Description (incidence and severity):
- The number of pre- and post-implantation losses in control and test groups were similar and in the range of normal biological variation.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Number of resorptions was unaffected by treatment.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Number of early and late resorptions was unaffected by treatment.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on litter size of any group.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Pregnancy duration was unaffected by treatment.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The number of pregnant femals was not impacted by treatment.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- changes in number of pregnant
- changes in pregnancy duration
- clinical biochemistry
- clinical signs
- dead fetuses
- early or late resorptions
- effects on pregnancy duration
- food consumption and compound intake
- food efficiency
- gross pathology
- histopathology: neoplastic
- histopathology: non-neoplastic
- maternal abnormalities
- mortality
- necropsy findings
- number of abortions
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no toxicologically relevant effects on fetal body weights (both sexes) noted by treatment up to 1000 mg/kg/day.
The statistically significant differences apparent for the mean male fetal weights in Groups 3 and 4 were considered the result of slightly low mean fetal weights in the males of the control group, in comparison with the historical control data, rather than being indicative of a relation to treatment. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on litter size of any group.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The male:female ratio was unaffected by treatment up to 1000 mg/kg/day.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on litter size of any group.
- Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on litter size of any group.
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment related effects on fetal external morphology following treatment up to 1000 mg/kg/day.
Two externally malformed fetuses were observed in this study and in both cases, the lower jaw was affected. Fetus A058-02 at 300 mg/kg/day had a small lower jaw and in control fetus A011-03 the lower jaw was absent. Skeletal examination substantiated these findings, whereby also other skull bones appeared to be affected. The single occurrence and group distribution of these jaw findings did not indicate a test item relationship and were therefore considered spontaneous in origin. External variations were not seen in any group. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related effects on skeletal morphology following treatment up to 1000 mg/kg/day.
Aside from the underlying malformations of the two fetuses with jaw findings (A011-03 and A058-02 of the control and 300 mg/kg/day group, respectively), four different malformations were revealed skeletally in this study. Bent limb bones occurred at 100 mg/kg/day (fetus A039-01), 300 mg/kg/day (fetus A062-02 and A064-10) and 1000 mg/kg/day (fetus A072-10) and was the only malformation that occurred in all test item treated groups. Other malformations noted in treated groups were costal cartilage anomaly at 1000 mg/kg/day (fetus A067-05) and vertebral centra anomaly at 300 mg/kg/day (fetus A058-02). Besides a vertebral anomaly in control fetus A011-01 that also had a costal cartilage anomaly, no other malformations occurred. The single occurrence and group distribution of these malformations did not indicate a dose relationship and all were seen previously in historical controls, therefore they were considered chance findings. Among skeletal variations, two findings showed a remarkable group distribution. Bent ribs occurred at a mean incidence of 9.0%, 21.1%, 11.6% and 30.5% per litter in the control, 100, 300 and 1000 mg/kg/day groups, respectively. The incidences at 100 and 1000 mg/kg/day were statistically significantly increased compared to the control value and the high dose value was even outside the historical control data range (0.8 – 27.4% per litter). However, it is known that bent ribs represent a reversible finding and since no dose relationship could be established, these increases were considered not treatment-related. The other notable variation was the finding of 14 rudimentary ribs, which occurred at an incidence of 41.8%, 66.8%, 61.4% and 51.3% per litter in the control, 100, 300 and 1000 mg/kg/day groups, respectively. The 100 mg/kg/day value was statistically significantly increased compared to the control value, but lower than the historical control maximum value of 72.0% per litter. Therefore, and due to absence of a dose-relationship, this was considered to have occurred by chance. The other variations that were noted occurred in the absence of a dose-related incidence trend, infrequently and/or at frequencies that were within the range of available historical control data. Therefore, they were not considered treatment-related. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related effects on visceral morphology following treatment up to 1000 mg/kg/day.
Visceral malformations occurred in two fetuses of the control group and in one fetus at 1000 mg/kg/day. The fetus at the high dose, A075-04, had a right-sided aortic arch which was also observed in control fetus A014-01 and was therefore considered spontaneous in origin.
The visceral malformation in control fetus A011-03 comprised situs inversus in combination with absence of the lower jaw (see external malformations above).
In addition, three types of visceral variations (small supernumerary liver lobes, absent accessory lung lobe and dilated ureter) were observed among several fetuses in this study. Based on the low incidence of occurrence, their distribution over the dose groups and the fact that the incidence of each finding remained within the range of historical control data, they were considered not to be related to treatment.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
- external malformations
- skeletal malformations
- visceral malformations
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Body Weights (Grams) Summary Parental Generation |
Corrected for gravid uterus |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Post Coitum |
|
|
|
|
|
Day 2 |
Mean |
214 |
217 |
214 |
216 |
|
S.D. |
22.3 |
18.5 |
20.8 |
22.7 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 6 |
Mean |
231 |
234 |
230 |
233 |
|
S.D. |
20.3 |
18.1 |
21.0 |
20.5 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 9 |
Mean |
239 |
242 |
240 |
243 |
|
S.D. |
19.4 |
16.8 |
19.9 |
20.3 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 12 |
Mean |
253 |
254 |
253 |
255 |
|
S.D. |
19.7 |
16.9 |
20.0 |
21.3 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 15 |
Mean |
266 |
267 |
266 |
267 |
|
S.D. |
20.2 |
16.4 |
19.9 |
22.1 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 18 |
Mean |
294 |
296 |
295 |
297 |
|
S.D. |
23.6 |
18.0 |
23.5 |
25.5 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 21 |
Mean |
330 |
332 |
331 |
333 |
|
S.D. |
26.8 |
21.0 |
26.4 |
29.1 |
|
N |
22 |
22 |
22 |
21 |
Body Weights Gain (%) Summary - Parental Generation |
Corrected for gravid uterus |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Post Coitum |
|
|
|
|
|
Day 2 |
Mean |
-7 |
-7 |
-7 |
-8 |
|
S.D. |
2.4 |
2.1 |
2.3 |
2.9 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 6 |
Mean |
0 |
0 |
0 |
0 |
|
S.D. |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 9 |
Mean |
4 |
4 |
4 |
4 |
|
S.D. |
1.4 |
1.7 |
1.6 |
1.5 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 12 |
Mean |
9 |
9 |
10 |
9 |
|
S.D. |
2.4 |
2.2 |
2.2 |
2.8 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 15 |
Mean |
15 |
14 |
16 |
15 |
|
S.D. |
3.1 |
3.0 |
2.8 |
3.9 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 18 |
Mean |
28 |
27 |
28 |
28 |
|
S.D. |
4.4 |
3.3 |
3.3 |
4.2 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Day 21 |
Mean |
43 |
43 |
44 |
43 |
|
S.D. |
6.6 |
4.5 |
4.3 |
5.8 |
|
N |
22 |
22 |
22 |
21 |
Maternal Survival and Pregnancy Status |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
# Females in Study |
22 |
22 |
22 |
22 |
Females Examined at Scheduled Necropsy |
22 |
22 |
22 |
22 |
Nongravid |
0 |
0 |
0 |
1 (4.5%) |
Gravid |
22 (100%) |
22 (100%) |
22 (100%) |
21 (95.5%) |
Gravid with resorptions only |
0 |
0 |
0 |
0 |
Gravid with viable fetuses |
22 (100%) |
22 (100%) |
22 (100%) |
21 (100%) |
|
|
|
|
|
Total Females Gravid |
22 (100%) |
22 (100%) |
22 (100%) |
21 (95.5%) |
Summary of Fetal Data at Necropsy |
|
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Sex: Male |
Total |
134 |
111 |
122 |
116 |
|
Mean |
6.1 |
5.0 |
5.5 |
5.5 |
|
S.D. |
1.8 |
1.65 |
2.39 |
1.72 |
|
|
|
|
|
|
Sex: Female |
Total |
102 |
126 |
116 |
116 |
|
Mean |
4.6 |
5.7 |
5.3 |
5.5 |
|
S.D. |
1.5 |
1.93 |
2.68 |
1.81 |
|
|
|
|
|
|
Viable Fetuses |
Total |
236 |
237 |
238 |
232 |
|
Mean |
10.7 |
10.8 |
10.8 |
11.0 |
|
S.D. |
1.72 |
1.54 |
1.76 |
1.72 |
|
|
|
|
|
|
Dead Fetuses |
Total |
0 |
0 |
0 |
1 |
|
Mean |
0 |
0 |
0 |
0 |
|
S.D. |
0 |
0 |
0 |
0.22 |
|
|
|
|
|
|
Early Resorptions |
Total |
9 |
9 |
11 |
5 |
|
Mean |
0.4 |
0.4 |
0.5 |
0.2 |
|
S.D. |
0.59 |
0.73 |
0.96 |
0.62 |
|
|
|
|
|
|
Late Resorptions |
Total |
0 |
0 |
0 |
0 |
|
Mean |
0 |
0 |
0 |
0 |
|
S.D. |
0 |
0 |
0 |
0 |
|
|
|
|
|
|
Post Implanation Loss |
Total |
9 |
9 |
11 |
6 |
|
Mean |
0.4 |
0.4 |
0.5 |
0.3 |
|
S.D. |
0.59 |
0.73 |
0.96 |
0.64 |
|
|
|
|
|
|
Implantation Sites |
Total |
245 |
246 |
249 |
238 |
|
Mean |
11.1 |
11.2 |
11.3 |
11.3 |
|
S.D. |
1.36 |
1.37 |
1.36 |
1.74 |
|
|
|
|
|
|
Corpora Lutea |
Total |
256 |
261 |
256 |
247 |
|
Mean |
11.6 |
11.9 |
11.6 |
11.8 |
|
S.D. |
1.22 |
1.46 |
1.40 |
1.81 |
|
|
|
|
|
|
Pre Implantation Loss |
Total |
11 |
15 |
7 |
9 |
|
Mean |
0.5 |
0.7 |
0.3 |
0.4 |
|
S.D. |
0.96 |
0.89 |
0.57 |
0.51 |
|
|
|
|
|
|
Fetal Weights in Grams |
Total |
NA |
NA |
NA |
NA |
|
Mean |
5.1 |
5.1 |
5.2 |
5.2 |
|
S.D. |
0.28 |
0.26 |
0.27 |
0.27 |
|
|
|
|
|
|
Number of Gravid Females |
Total |
22 |
22 |
22 |
21 |
|
Mean |
- |
- |
- |
- |
|
S.D. |
- |
- |
- |
- |
None significantly different from control group |
|
|
|
|
|
Summary of Fetal Data at Necropsy (% per litter) |
|
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
CORPORA LUTEA |
Mean |
11.6 |
11.9 |
11.6 |
11.8 |
|
S.D. |
1.22 |
1.46 |
1.40 |
1.81 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
IMPLANTATION SITES |
Mean |
11.1 |
11.2 |
11.3 |
11.3 |
|
S.D. |
1.36 |
1.37 |
1.36 |
1.74 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
VIABLE FETUSES (%) |
Mean |
96.0 |
96.3 |
95.4 |
97.6 |
|
S.D. |
5.84 |
6.63 |
8.63 |
5.44 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
DEAD FETUSES (%) |
Mean |
0.0 |
0.0 |
0.0 |
0.5 |
|
S.D. |
0.0 |
0.0 |
0.0 |
2.18 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
EARLY RESORPTIONS (%) |
Mean |
4 |
3.7 |
4.6 |
1.9 |
|
S.D. |
5.84 |
6.63 |
8.63 |
5.18 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
LATE RESORPTIONS (%) |
Mean |
0.0 |
0.0 |
0.0 |
0.0 |
|
S.D. |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
TOTAL RESORPTIONS (%) |
Mean |
4.0 |
3.7 |
4.6 |
1.9 |
|
S.D. |
5.84 |
6.63 |
8.63 |
5.18 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
PRE-IMPLANTATION LOSS (%) |
Mean |
4.1 |
5.5 |
2.6 |
3.5 |
|
S.D. |
7.78 |
7.37 |
4.60 |
4.25 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
POST-IMPLANTATION LOSS (%) |
Mean |
4.0 |
3.7 |
4.6 |
2.4 |
|
S.D. |
5.84 |
6.63 |
8.63 |
5.44 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
MALES (%) |
Mean |
565.5 |
47.2 |
52.0 |
50.1 |
|
S.D. |
12.53 |
14.36 |
21.75 |
14.46 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
FEMALES (%) |
Mean |
43.5 |
52.8 |
48.0 |
49.9 |
|
S.D. |
12.53 |
14.36 |
21.75 |
14.46 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
MALE FETAL WEIGHTS (g) |
Mean |
5.2 |
5.3 |
5.4* |
5.4* |
|
S.D. |
0.29 |
0.28 |
0.28 |
0.26 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
FEMALE FETAL WEIGHTS (g) |
Mean |
4.9 |
5.0 |
5.1 |
5.1 |
|
S.D. |
0.28 |
0.24 |
0.26 |
0.28 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
COMBINED FETAL WEIGHTS (g) |
Mean |
5.1 |
5.1 |
5.2 |
5.2 |
|
S.D. |
0.28 |
0.26 |
0.27 |
0.27 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
MALE AGD (MM) |
Mean |
2.74 |
2.72 |
2.76 |
2.77 |
|
S.D. |
0.203 |
0.202 |
0.143 |
0.147 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
FEMALE AGD (MM) |
Mean |
1.25 |
1.19 |
1.23 |
1.27 |
|
S.D. |
0.223 |
0.213 |
0.184 |
0.174 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
CORRECTED MALE AGD |
Mean |
1.59 |
1.56 |
1.58 |
1.58 |
|
S.D. |
0.115 |
0.112 |
0.075 |
0.079 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
CORRECTED FEMALE AGD |
Mean |
0.74 |
0.69 |
0.72 |
0.74 |
|
S.D. |
0.132 |
0.124 |
0.112 |
0.102 |
|
N |
22 |
22 |
22 |
21 |
FETAL WEIGHTS COMPARED USING DUNNETT'S TEST * = Significantly different from the control group at 0.05 |
|
|
|
|
|
Summary of Fetuses with Malformations (Absolute No.) |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Number Examined Externally |
236 |
237 |
238 |
232 |
Lower Jaw – Absent or Small |
1 |
0 |
1 |
0 |
|
|
|
|
|
Number Examined Viscerally |
119 |
119 |
119 |
115 |
Aortic arch – right-sided |
1 |
0 |
0 |
1 |
Situs Inversus |
1 |
0 |
0 |
0 |
|
|
|
|
|
Number Examined Skeletally |
118 |
118 |
119 |
117 |
Vertebral anomaly with or without associated rib anomaly |
1 |
0 |
0 |
0 |
Costal cartilage anomaly |
1 |
0 |
0 |
1 |
Bent limb bones |
0 |
1 |
2 |
1 |
Vertebral centra anomaly |
0 |
0 |
1 |
0 |
|
|
|
|
|
Total number with malformations |
|
|
|
|
External: |
1 |
0 |
1 |
0 |
Soft tissue: |
2 |
0 |
0 |
1 |
Skeletal: |
1 |
1 |
3 |
2 |
|
|
|
|
|
Combined: |
3 |
1 |
3 |
3 |
Summary of Litter Proportions of Malformations - % Per Litter |
|
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Number of litters examined externally |
|
22 |
22 |
22 |
21 |
Lower Jaw – absent or small |
Mean |
0.5 |
0.0 |
0.4 |
0.0 |
|
S.D. |
2.37 |
0.00 |
1.78 |
0.00 |
|
|
|
|
|
|
Number of litters examined viscerally |
|
22 |
22 |
22 |
21 |
Aortic Arch – Righ-sided |
Mean |
0.8 |
0.0 |
0.0 |
1.0 |
|
S.D. |
3.55 |
0.00 |
0.00 |
4.36 |
|
|
|
|
|
|
Situs Inversus |
Mean |
0.9 |
0.0 |
0.0 |
0.0 |
|
S.D. |
4.26 |
0.0 |
0.0 |
0.0 |
|
|
|
|
|
|
Number of litters examined skeletally |
|
22 |
22 |
22 |
21 |
Vertebral anomaly with or without associated rib anomaly |
Mean |
0.9 |
0.0 |
0.0 |
0.0 |
|
S.D. |
4.26 |
0.0 |
0.0 |
0.0 |
|
|
|
|
|
|
Costal cartilage anomaly |
Mean |
0.9 |
0.0 |
0.0 |
0.8 |
|
S.D. |
4.26 |
0.0 |
0.0 |
3.64 |
|
|
|
|
|
|
Bent limb bones |
Mean |
0.0 |
0.9 |
1.8 |
1.0 |
|
S.D. |
0.0 |
4.26 |
5.88 |
4.36 |
|
|
|
|
|
|
Vertebral centra anomaly |
Mean |
0.0 |
0.0 |
0.8 |
0.0 |
|
S.D. |
0.0 |
0.0 |
3.55 |
0.0 |
|
|
|
|
|
|
Total Malformations |
|
|
|
|
|
Percent/litter with external malformations |
Mean |
0.5 |
0.0 |
0.4 |
0.0 |
|
S.D. |
2.37 |
0.0 |
1.78 |
0.0 |
|
|
|
|
|
|
Percent/litter with soft tissue malformations |
Mean |
1.7 |
0.0 |
0.0 |
1.0 |
|
S.D. |
5.42 |
0.0 |
0.0 |
4.36 |
|
|
|
|
|
|
Percent/litter with skeletal malformations |
Mean |
0.9 |
0.9 |
2.6 |
1.7 |
|
S.D. |
4.26 |
4.26 |
6.66 |
5.54 |
|
|
|
|
|
|
Total percent/litter with malformations |
Mean |
2.2 |
0.9 |
2.2 |
2.7 |
|
S.D. |
7.37 |
4.26 |
6.03 |
6.80 |
Summary of Fetuses with Variations (Absolute No.) |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Number Examined Externally |
236 |
237 |
238 |
232 |
Number with findings |
0 |
0 |
0 |
0 |
|
|
|
|
|
Number Examined Viscerally |
119 |
119 |
119 |
115 |
LIVER- SMALL SUPERNUMERARY LOBE(S) |
5 |
1 |
2 |
0 |
LUNG- ABSENT ACCESSORY LOBE |
1 |
0 |
0 |
0 |
URETER(S)- DILATED |
0 |
1 |
0 |
0 |
|
|
|
|
|
Number Examined Skeletally |
118 |
118 |
119 |
117 |
14TH RUDIMENTARY RIB(S |
51 |
78 |
74 |
62 |
14TH FULL RIB(S) |
9 |
12 |
8 |
13 |
STERNEBRA(E) MALALIGNED |
9 |
12 |
8 |
13 |
7TH CERVICAL OSSIFICATION SITE(S) |
3 |
7 |
5 |
5 |
BENT RIB(S) |
11 |
24 |
13 |
34 |
REDUCED OSSIFICATION OF THE SKULL |
16 |
13 |
13 |
15 |
PELVIC GIRDLE- CAUDAL SHIFT |
10 |
9 |
7 |
12 |
METACARPAL(S) AND/OR METATARSAL(S) UNOSSIFIED |
5 |
1 |
3 |
2 |
STERNUM- SUPERNUMERARY OSSIFICATION SITE |
1 |
0 |
1 |
0 |
VERTEBRAL CENTRA- REDUCED OSSIFICATION |
0 |
1 |
4 |
1 |
STERNEBRA(E) #5 AND/OR #6 UNOSSIFIED |
0 |
0 |
1 |
0 |
7TH CERVICAL FULL RIB(S) |
1 |
0 |
0 |
0 |
VERTEBRAL ARCHES- REDUCED OSSIFICATION |
1 |
0 |
1 |
0 |
STERNEBRA(E)- BRANCHED |
1 |
1 |
1 |
1 |
METACARPAL(S) AND/OR METATARSAL(S)- MALPOSITIONED
|
0 |
1 |
0 |
0 |
Summary of Fetuses with Variations (Absolute No.) |
|
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Number Examined Externally |
|
22 |
22 |
22 |
21 |
Number with findings |
|
0 |
0 |
0 |
0 |
|
|
|
|
|
|
Number Examined Viscerally |
|
22 |
22 |
22 |
21 |
LIVER- SMALL SUPERNUMERARY LOBE(S) |
Mean |
4.2 |
1.1 |
1.6 |
0.0 |
|
S.D. |
10.14 |
5.33 |
6.09 |
0.0 |
LUNG- ABSENT ACCESSORY LOBE |
Mean |
0.8 |
0.0 |
0.0 |
0.0 |
|
S.D. |
3.55 |
0.0 |
0.0 |
0.0 |
URETER(S)- DILATED |
Mean |
0.0 |
0.9 |
0.0 |
0.0 |
|
S.D. |
0.0 |
4.26 |
0.0 |
0.0 |
|
|
|
|
|
|
Number Examined Skeletally |
|
22 |
22 |
22 |
21 |
14TH RUDIMENTARY RIB(S |
Mean |
41.8 |
66.8** |
61.44 |
51.2 |
|
S.D. |
32.11 |
24.59 |
29.63 |
28.24 |
14TH FULL RIB(S) |
Mean |
8.0 |
9.7 |
6.4 |
11.7 |
|
S.D. |
18.13 |
14.18 |
12.89 |
22.35 |
STERNEBRA(E) MALALIGNED |
Mean |
11.3 |
8.3 |
10.0 |
8.6 |
|
S.D. |
12.87 |
9.41 |
10.84 |
12.62 |
7TH CERVICAL OSSIFICATION SITE(S) |
Mean |
2.2 |
6.4 |
3.9 |
4.3 |
|
S.D. |
7.27 |
12.58 |
8.63 |
9.59 |
BENT RIB(S) |
Mean |
9.0 |
21.1* |
11.6 |
30.5** |
|
S.D. |
18.96 |
27.09 |
14.65 |
32.05 |
REDUCED OSSIFICATION OF THE SKULL |
Mean |
13.8 |
11.0 |
10.9 |
13.5 |
|
S.D. |
24.72 |
15.33 |
20.76 |
20.66 |
PELVIC GIRDLE- CAUDAL SHIFT |
Mean |
9.4 |
7.4 |
6.0 |
11.0 |
|
S.D. |
19.50 |
16.78 |
10.47 |
21.43 |
METACARPAL(S) AND/OR METATARSAL(S) UNOSSIFIED |
Mean |
4.4 |
0.8 |
2.4 |
1.4 |
|
S.D. |
17.26 |
3.55 |
6.27 |
4.30 |
STERNUM- SUPERNUMERARY OSSIFICATION SITE |
Mean |
0.9 |
0.0 |
0.9 |
0.0 |
|
S.D. |
4.26 |
0.0 |
4.26 |
0.0 |
VERTEBRAL CENTRA- REDUCED OSSIFICATION |
Mean |
0.0 |
0.8 |
3.7 |
0.7 |
|
S.D. |
0.0 |
3.55 |
8.65 |
3.12 |
STERNEBRA(E) #5 AND/OR #6 UNOSSIFIED |
Mean |
0.0 |
0.0 |
0.8 |
0.0 |
|
S.D. |
0.0 |
0.0 |
3.55 |
0.0 |
7TH CERVICAL FULL RIB(S) |
Mean |
0.9 |
0.0 |
0.0 |
0.0 |
|
S.D. |
4.26 |
0.0 |
0.0 |
0.0 |
VERTEBRAL ARCHES- REDUCED OSSIFICATION |
Mean |
0.9 |
0.0 |
0.9 |
0.0 |
|
S.D. |
4.26 |
0.0 |
4.26 |
0.0 |
STERNEBRA(E)- BRANCHED |
Mean |
0.6 |
0.8 |
0.9 |
1.2 |
|
S.D. |
3.05 |
3.55 |
4.26 |
5.46 |
METACARPAL(S) AND/OR METATARSAL(S)- MALPOSITIONED
|
Mean |
0.0 |
0.8 |
0.0 |
0.0 |
|
S.D. |
0.0 |
3.55 |
0.0 |
0.0 |
|
|
|
|
|
|
Total Variations |
|
|
|
|
|
PERCENT/LITTER with External Variations |
Mean |
0.0 |
0.0 |
0.0 |
0.0 |
|
S.D. |
0.0 |
0.0 |
0.0 |
0.0 |
|
|
|
|
|
|
PERCENT/LITTER WITH SOFT TISSUE VARIATIONS |
Mean |
5.0 |
2.0 |
1.3 |
0.0 |
|
S.D. |
10.43 |
6.67 |
6.09 |
0.0 |
|
|
|
|
|
|
PERCENT/LITTER WITH SKELETAL VARIATIONS |
Mean |
64.5 |
86.5 |
80.0 |
78.6 |
|
S.D. |
30.9 |
21.2 |
19.77 |
23.64 |
|
|
|
|
|
|
TOTAL PERCENT/LITTER WITH VARIATIONS |
Mean |
69.5 |
88.5 |
81.3 |
78.6 |
|
S.D. |
28.85 |
22.10 |
18.61 |
23.64 |
* = Significantly different from the control group at 0.05 ** = Significantly different from the control group at 0.01 |
|
|
|
|
|
Clinical Biochemistry Summary -Parental Generation |
End of Treatment |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
TSH ulU/mL |
Mean |
0.357 |
0.316 |
0.334 |
0.396 |
|
S.D. |
0.220 |
0.166 |
0.282 |
0.278 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Total T3 ug/dL |
Mean |
59.4 |
55.1 |
61.3 |
55.7 |
|
S.D. |
8.4 |
9.4 |
10.1 |
8.8 |
|
N |
19 |
22 |
21 |
20 |
|
|
|
|
|
|
Total T4 ug/dL |
Mean |
2.58 |
2.4 |
2.32 |
2.55 |
|
S.D. |
0.71 |
0.59 |
0.37 |
0.58 |
|
N |
22 |
22 |
22 |
21 |
Organ Weights (Gram) Summary - Parental Generation |
End of Treatment |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Body Wgt |
Mean |
330 |
332 |
331 |
333 |
|
S.D. |
27 |
21 |
26 |
29 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Thyroids |
Mean |
0.015 |
0.016 |
0.015 |
0.016 |
|
S.D. |
0.004 |
0.004 |
0.003 |
0.003 |
|
N |
22 |
22 |
22 |
21 |
Organ Weight Ratios(%) Summary – Parental Females |
End of Treatment |
0 mg/kg |
100 mg/kg |
300 mg/kg |
1000 mg/kg |
Body W |
Mean |
330 |
332 |
331 |
333 |
|
S.D. |
27 |
21 |
26 |
29 |
|
N |
22 |
22 |
22 |
21 |
|
|
|
|
|
|
Thyroids |
Mean |
0.005 |
0.005 |
0.005 |
0.005 |
|
S.D. |
0.001 |
0.001 |
0.001 |
0.001 |
|
N |
22 |
22 |
22 |
21 |
Historical Control Data Rat: Crl: WI(Han) (Outbred, SPF-quality) |
Mean of Study Means |
Total No. Animals in Control Group: 1097 |
|
|
|
|
|
|
|
Endpoint |
Mean |
S.D. |
Median |
Min |
Max |
P5 |
P95 |
Fetuses |
Litters |
Mean Male Body Weight (g) |
5.4 |
0.11 |
5.4 |
5.0 |
5.5 |
5.2 |
5.5 |
- |
- |
Mean Female Body Weight (g) |
5.1 |
0.12 |
5.1 |
4.7 |
5.3 |
4.9 |
5.3 |
- |
- |
Limb Bone(s) Bent (% Per Litter)1 |
0.3 |
0.71 |
0.0 |
0.0 |
2.3 |
@ |
@ |
5 |
3 |
14thRudimentary Ribs (% per litter) |
51.2 |
11.98 |
53.2 |
19.0 |
72.0 |
23.1 |
71.8 |
3033 |
970 |
Rib(s) – Bent (% per litter) |
13.7 |
6.37 |
12.8 |
0.8 |
27.4 |
2.1 |
25.8 |
757 |
401 |
Liver – Small supernumerary Lobe(s) (% per litter) |
4.6 |
2.8 |
4.8 |
0.0 |
9.6 |
0.0 |
9.1 |
266 |
221 |
Lung – Abnormal Lobation (% per litter) |
0.0 |
0.11 |
0.0 |
0.0 |
0.8 |
0.0 |
0.0 |
1 |
1 |
Ureter(s) – Dialated (% per litter) |
0.5 |
1.32 |
0.0 |
0.0 |
8.5 |
0.0 |
2.3 |
57 |
32 |
@ Insufficient number of data for calculation.1Based on 12 datasets. |
|
|
|
|
|
|
|
|
|
Applicant's summary and conclusion
- Conclusions:
- Based on the results of the study, the prenatal developmental No Observed Adverse Effect Level (NOAEL) is 1000 mg/kg/day.
- Executive summary:
The prenatal developmental toxicity potential of the test article was evaluated in female Wistar Han rats. The study was conducted according to OECD 414 in compliance with OECD GLP regulations. Time-mated female rats (22/dose) were exposed from Day 6 to Day 20 post-coitum, inclusive, via oral gavage to 0 (control), 100, 300, or 1000 mg/kg/day test article. The following parameters and end points were evaluated in this study for the F0-generation: mortality/moribundity, clinical signs, body weights, food consumption, thyroid hormone levels (T3, T4, TSH), gross necropsy findings, number of corpora lutea, organ weights ((gravid) uterus and thyroid gland), uterine contents and histopathologic examination (thyroid gland). In addition, the following parameters were determined for the F1-generation: the number of live and dead fetuses, early and late resorptions, total implantations, fetal body weights, sex ratio, ano-genital distance, external, visceral and skeletal malformations and developmental variations. No maternal toxicity was observed in any dose group. No developmental toxicity was observed in any dose group. Based on the results of the study, the prenatal developmental No Observed Adverse Effect Level (NOAEL) is 1000 mg/kg/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.