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EC number: 211-463-5 | CAS number: 646-06-0
- 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:
- From 27 July 2016 to 26 February 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- other: 40 CFR 799.9370. TSCA Prenatal developmental toxicity
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1,3-dioxolane
- EC Number:
- 211-463-5
- EC Name:
- 1,3-dioxolane
- Cas Number:
- 646-06-0
- Molecular formula:
- C3H6O2
- IUPAC Name:
- 1,3-dioxolane
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: Lambiotte & Cie - 1607011300R
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Remarks:
- Crl:KBL(NZW)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Saint-Constant Québec, Canada
- Age at study initiation: approximately 6 months of age
- Weight at study initiation: 3230.0 g to 4162.0 g
- Fasting period before study: no
- Housing: individually housed in units of six to eight cages
- Diet: approximately 150 g of Certified Rabbit Chow® #5322 (PMI® Nutrition International) was available to each rabbit each day until the first day of dosing, at which time approximately 180 g to 185 g of the same certified feed was offered to each rabbit each day
- Water: ad libitum (local source and passed through a reverse osmosis membrane before use. On the day of arrival, each rabbit was provided a water supplement (Hydrogel™ water pack [Portland, ME]). During the acclimation period, the water supplement was available to each rabbit.
- Acclimation period: up to 4 days and at least 3 days prior to initiation of dosing.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 59°F to 70°F (15°C to 21°C)
- Humidity (%): 30% to 70%.
- Air changes (per hr): minimum of 10 changes per hour of fresh air that had been passed through 99.97% HEPA filters
- Photoperiod (hrs dark / hrs light): 12-hour dark:12-hour light
IN-LIFE DATES: From: 30 July 2016 To: 25 August 2016
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Reverse osmosis (R.O.) membrane-processed deionized water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Test substance dosing formulations was prepared based on Sponsor instructions at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared fresh on the date of dose administration. The dose aliquot containers were maintained at ambient conditions and blanketed with nitrogen with continuous stirring, prior to dose administration. The bottle containing the dosing formulation for each of the test agent groups was not opened until the initiation of dose administration for that group. The dosing formulation was stirred continuously during dosing.
VEHICLE
- Concentration in vehicle: 0, 4, 12, 40 and 100 mg/mL
- Amount of vehicle (if gavage): dose volume of 5mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were performed using a validated analytical procedure. The method number provided by WIL Research was 419.DIW2.01.
On the first and last days of preparation, duplicate 1.0 mL samples were collected from the top, middle and bottom of the formulations for the test substance groups and from the middle of the formulations for the control substance group (Group 1). These samples were submitted for analysis following the first day of preparation. Triplicate samples were also collected in the same manner (duplicate middle samples only for Group 1), were maintained as backup samples and were retained in a refrigerator set to maintain 4°C. On days when only concentration analysis was required, the formulations were only sampled from the middle. All backup samples from the first preparation and the backup samples for Group 2 from the last preparation were shipped for analysis to investigate out of specification results. The remaining backup samples were discarded prior to issue of the final report.
Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 10% of theoretical concentration. Each individual sample concentration result was considered acceptable if it was within or equal to ± 15%. Homogeneity results were considered acceptable if the relative standard deviation (RSD) of the mean value at each sampling location was ≤ 5% for each group.
The analyzed formulations used for dose administration met the protocol-specified acceptance criteria for homogeneity (i.e., the RSD for the mean concentration was ≤ 5%), and concentration acceptability for suspension formulations, i.e., the mean analyzed concentration was 90% to 110% of the target concentration and each individual sample was within ± 15% of the target concentration. No test substance was detected in the analyzed vehicle administered to the control group (Group 1). - Details on mating procedure:
- Female rabbits were naturally bred at the Supplier, by breeder male rabbits of the same source and strain, before shipment to the Testing Facility. The day mating occurred was considered to be DG 0. The rabbits were shipped to the Testing Facility after mating to arrive on DGs 3 and 4 (first shipment) and DGs 2 and 3 (second shipment). The Supplier forwarded breeding records and DG 0 body weights.
- Duration of treatment / exposure:
- DGs 6 through 28
- Frequency of treatment:
- Daily
- Duration of test:
- On DG 29, surviving rabbits were euthanized blind to dose group.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 22
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The inhalation route of exposure could be the likely route of human exposure. The oral route of exposure was selected to achieve significant systemic exposure to 1,3-dioxolane and to satisfy a regulatory request. Dose levels were selected by the Sponsor based on a previous dose range-finding study (Testing Facility Study No. 20096129; Sponsor’s Reference No. 1300R-OECD414-DRF).
- Rationale for animal assignment: Mated female animals were assigned to groups using a computer-based (weight-ordered) randomization procedure, using body weight assessment from DG 0.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily, once in the morning and once in the afternoon
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on the day of arrival daily after arrival at the Testing Facility, daily before dose administration during the dosing period, and on the day of scheduled euthanasia
BODY WEIGHT: Yes
- Time schedule for examinations: recorded on DG 0 (provided by the Supplier), daily after arrival at the Testing Facility, daily during the dose period, and on the day of scheduled euthanasia
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: ovaries and uterus, cervix, esophagus, heart, kidney, liver, lung, spleen, stomach, trachea
OTHER: - 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
- Other: placentae - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter - Statistics:
- Proportions and/or incidences were calculated to summarize categorical data, as appropriate. Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics including number, mean and standard deviation 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. Litter values were used where appropriate. Only body weights of live fetuses were used to determine litter mean fetal body weight. Fetal body weight was analyzed using covariance analysis with live litter size as the covariate. Animal data collected during the
predose period were reported, but were not summarized or analyzed statistically. - Historical control data:
- Historical control data were provided on reproductive indices, material necropsy observations, fetal gross external alterations, fetal soft tissue alterations and fetal skeletal alterations.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 200 and 500 mg/kg/day dose groups, there were increased incidences of thin body condition (2 females in each of the dose groups between DGs 14 to 29) and decreased fecal output (2 females in each of the dose groups between DGs 13 to 20). At 200 mg/kg/day, female #3070 (which aborted) was observed with thin body condition; female #3076 was observed with decreased fecal output; and female #3078 (which was observed with total resorptions) was observed with thin body condition and decreased fecal output. At 500 mg/kg/day, female #3090 (which aborted) and 3102 (which was observed with total resorptions) were observed with thin body condition and decreased fecal output. These females were also observed with a reduction in body weight gain and reduced food consumption.
All other clinical observations were considered unrelated to 1,3-dioxolane because: 1) the incidences were not dose dependent; or 2) the observations occurred in only one or two rabbits. These observations consisted of a scab on the skin; fur loss; ungroomed fur; liquid feces; red aborted material; red liquid material – tissue red; red liquid material; partially missing pinna; and pink aborted material. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One unscheduled euthanasia and an early delivery occurred in the 20 mg/kg/day and 60 mg/kg/day dose groups, respectively. These unscheduled euthanasias were considered not to be test substance related because there was no additional maternal toxicity apparent in these dose groups. Female #5065 at 20 mg/kg/day had a reduction in body weight gain between DGs 20 to 21 and a reduction in food consumption between DGs 13 to 18 and 20 to 21. Female #3050 at 60 mg/kg/day had a reduction in body weight gain between DGs 25 to 28 and a reduction in food consumption between DGs 19 to 27.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Reductions in body weight gain occurred at 200 mg/kg/day at all intervals in comparison with control group values, with the exception of DGs 10 to 13. In the 500 mg/kg/day dose group, there were reductions in body weight gain on DGs 6 to 10, 13 to 16, 16 to 20, 6 to 20, 24 to 29, 20 to 29 and 6 to 29 in comparison with the control group values.
Further, the decrease in body weight gain observed at 500 mg/kg/day between DGs 20 to 29 correlates with the reduced fetal body weight observed in this dose group.
Mean body weight gain was reduced in the 200 and 500 mg/kg/day dose groups (28% and 21% compared to concurrent control, respectively) over the entire dose period (DGs 6 to 29). The reductions in body weight gain correlated with reduced food consumption values observed at 200 and 500 mg/kg/day and are considered to be test substance related.
Although there were test substance related reductions in body weight gain observed in the 200 and 500 mg/kg/day dose groups, the mean body weight values were comparable throughout the dose period.
The corrected maternal body weight values (terminal body weight – gravid uterine weight) were comparable with the control group values at 500 mg/kg/day.
Body weights and body weight gains were unaffected at 20 and 60 mg/kg/day. There was a statistically significant (p≤0.01) body weight loss observed in the 20 mg/kg/day dose group between DGs 16 to 20 in comparison with the control group value. This body weight loss was considered not to be test substance related because it was not dose dependent. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Reductions in food consumption occurred at 200 mg/kg/day on DGs 6 to 20, 20 to 29 and 6 to 29 (12%, 12% and 13% compared to concurrent control, respectively). In the 500 mg/kg/day dose group, mean food consumption was reduced or statistically significantly reduced beginning at the initiation of dose administration and continuing at all intervals, with exception of daily intervals from DGs 21 to 26. In the 200 mg/kg/day dose group, a statistically significant reduction (p≤ 0.01) was also observed for the DGs 20 to 21 interval. A statistically significant reduction (p≤ 0.05) was also observed for the DGs 15 to 16 interval in the 500 mg/kg/day dose group.
There were no test substance related differences in the mean food consumption values at 20 and 60 mg/kg/day as compared to the concurrent control values. There was a statistically significant (p≤0.05) reduction in food consumption observed in the 20 mg/kg/day dose group between DGs 15 to 16 in comparison with the control group value. This reduction in food consumption was considered not to be test substance related because it was not dose dependent. - Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Although not statistically significant, mean gravid uterine weight in the 500 mg/kg/day dose group was slightly reduced at 89% of the control group value. Gravid uterine weights were unaffected at doses up to and including 200 mg/kg/day.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- All does appeared normal at necropsy
Maternal developmental toxicity
- Number of abortions:
- effects observed, treatment-related
- Description (incidence and severity):
- Abortions were observed in one rabbit in each of the 200 and 500 mg/kg/day dose groups. These unscheduled euthanasias were considered to be test substance related because there was additional maternal toxicity observed in each of these dose groups. Female #3070 at 200 mg/kg/day was observed with thin body condition, a reduction in body weight gain and reduced food consumption values basically from the initiation of dose administration until the time the rabbit aborted. Female #3090 at 500 mg/kg/day was observed with thin body condition and decreased fecal output, a reduction in body weight gain between DGs 27 to 28 and a reduction in food consumption at each interval between DGs 6 to 13 and 14 to 24. All other female rabbits
survived until scheduled euthanasia. - Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were two does in each of the 0, 200 and 500 mg/kg/day dose groups observed with litters consisting of only early resorptions (100% resorptions) at the time of Caesarean-sectioning observations. This was considered not to be test substance related because the incidence was similar in each of the groups, including the controls.
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Pregnancy occurred in 21/22 (95.5%), 20/22 (90.9%), 22/22 (100%), 20/22 (90.9%) and
21/21 (100%) does in the 0, 20, 60, 200 and 500 mg/kg/day dose groups, respectively, including
those which were terminated early due to an abortion or an early delivery. - Other effects:
- no effects observed
- Description (incidence and severity):
- All placentae appeared normal.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- mortality
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Average fetal body weights (total, male and female) were statistically significantly reduced (p≤0.01) at 500 mg/kg/day in comparison with the control group values (19%, 19% and 17%, respectively). This reduction in mean fetal body weights in the 500 mg/kg/day dose group correlates with the maternal toxicity observed at this dose.
- Reduction in number of live offspring:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Gross external abnormalities occurred at increased incidences in the 500 mg/kg/day dose group and were considered to be test substance related.
There was a statistically significant increase (p≤ 0.01) in the litter incidence of carpal flexure at 500 mg/kg/day. Carpal flexure occurred in 12 fetuses from 7 litters within the 500 mg/kg/day dose group. Carpal flexure was generally observed in pups with decreased fetal body weights (ranging from 16.0g to 35.8g) in comparison with the mean fetal body weight for the control group (39.9g). Therefore, carpal flexure can be attributed to the reduction in fetal body weight observed at 500 mg/kg/day, which correlates with the maternal toxicity observed at this dose. The increased incidence of this finding was considered to be transient and secondary to the maternal toxicity observed at this dose. All additional external malformations were considered unrelated to 1, 3-dioxolane because the findings were not dose dependent and/or they occurred in
single litters. These malformations consisted of a small lower mandible of the jaw; short snout; anencephaly; cranial meningocele; malrotated hindlimbs; and a herniated umbilicus. No gross external abnormalities (malformations or variations) were caused by doses of the test substance as high as 200 mg/kg/day. - Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Skeletal abnormalities and variations in ossification occurred at increased incidences in the 500 mg/kg/day dose group and were considered to be test substance related.
All skeletal malformations were considered unrelated to 1,3-dioxolane because the findings
were not dose dependent and/or they occurred in one or two fetuses from one or two litters
within the dose groups. These skeletal malformations abnormalities consisted of absent digits;
absent forepaw phalanges; absent metacarpals; missing frontal portion of the skull; absent
interparietal, maxillae, nasals, palatines, parietals, premaxillae; squamosals, supraoccipitals,
zygomatic arches and caudal vertebra; fused caudal vertebrae; and a hemivertebra in the lumbar
vertebrae.
Bent (angulated) hyoid ala(e) occurred in 33 fetuses from 12 litters at 500 mg/kg/day; the litter
incidence of this variation was significantly (p≤ 0.01) increased at this dose in comparison with
the control group value. The increased incidence of this finding was considered to be test
substance related because it was not within the range of Testing Facility control data collected
between 2006 and 2014. In the 500 mg/kg/day dose group, there was also a statistically
significant increase (p≤ 0.01) in the litter incidence of fused sternebrae and an increased incidence of incompletely ossified sternebrae that were considered to be test substance related
because they were dose dependent. These skeletal variations were considered to be related to the reduction in fetal body weights at this dose.
All additional skeletal variations were considered unrelated to the test substance because they
occurred at non-dose dependent incidences, they occurred in a single litter within a dose group,
and/or the fetal and litter incidences were within the ranges observed historically at the Testing
Facility. These skeletal variations consisted of small
forepaw phalanges; misshapen scapula ala and parietal; a fused or misshapen frontal; incomplete
ossification of the frontal, parietal and interparietal bones of the skull; misshapen interparietal,
mandible, supraoccipital and tympanic annulus bones of the skull; holes in the parietal bones of
the skull; presence of the suture bone; incompletely ossified or unossified pubes; nodulated
(thickened) ribs; abnormalities of the sternebrae [asymmetric, bipartite, isolated ossification site,
unossified, and misshapen (irregularly shaped)], supernumerary ribs (cervical short), and
incompletely ossified, misaligned and misshapen caudal vertebrae; unilateral ossification of the
cervical centrum; small lumbar arch; and bipartite sacral centrum.
The 500 mg/kg/day dose group had significant increases (p≤0.05) in the incidence of paired ribs
with associated significant increases and decreases (p≤0.05) in the numbers of thoracic and
lumbar vertebrae, respectively, a common variation observed at maternally toxic doses. In the
500 mg/kg/day dose group, there were also statistically significant decreases (p≤ 0.01) in the
metacarpals and forelimb phalanges in comparison with the control group values.
In the 500 mg/kg/day dose group, there were statistically significant increases (p≤0.05) in the
average number of ossified sternal centra and xiphoid in comparison with the control group
values. These differences were considered not to be test substance related because they were
slight in comparison with the concurrent control group values (i.e., 3% and 7% differences,
respectively).
There were no additional biologically important differences among the dose groups in the
average numbers of ossification sites per fetus for the hyoid, vertebrae (cervical, sacral and
caudal), manubrium, forelimbs (carpals and digits) or hindlimbs (tarsals, metatarsals, digits and
phalanges).
No skeletal fetal abnormalities (malformations or variations) were caused by doses of the test substance as high as 200 mg/kg/day. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All visceral abnormalities were considered unrelated to 1,3-dioxolane because the findings were not dose dependent and/or they occurred in single litters. These visceral abnormalities consisted of a dilated aortic arch; absent or small brain; moderate dilation of the lateral ventricles of the brain; absent or small eyes; hermaphroditism (left testis and right ovary were observed); persistent truncus arteriosus of the great vessels; defect in the ventricular septum of the heart; absent innominate artery; malpositioned intestine; narrow pulmonary trunk; retroesophageal right subclavian artery; and malpositioned origin of the right subclavian artery.
- Details on embryotoxic / teratogenic effects:
- Decreases in fetal body weight, carpal flexure, skeletal variations and delayed skeletal ossification observed at 500 mg/kg/day.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- external malformations
- Remarks on result:
- other:
- Remarks:
- The developmental NOAEL is 200 mg/kg/day due to decreases in fetal body weight, carpal flexure, skeletal variations and delayed skeletal ossification observed at 500 mg/kg/day. The delayed ossification was considered to be related to the reduction in fetal body weight observed in the 500 mg/kg/day dose group. This change in ossification at 500 mg/kg/day was considered not to be adverse because it is a minor, reversible delay in skeletal ossification and was observed in the presence of maternal toxicity.
Fetal abnormalities
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- external: paw
- skeletal: skull
- skeletal: sternum
- other: reversible delay in skeletal ossification
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 500 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 1: Test substance concentration in formulations
Date of Preparation | Mean Concentration, mg/mL (% of Target) | ||||
Group 1 (0 mg/mL) | Group 2 (4 mg/mL) | Group 3 (12 mg/mL) | Group 4 (40 mg/mL) | Group 5 (100 mg/mL) | |
30 Jul 2016 (first preparation) |
ND (NA) |
3.61 (90.3) |
11.1 (92.3) |
37.9 (94.6) |
94.4 (94.4) |
24 Aug 2016 (last preparation) |
ND (NA) |
3.65 (91.1) |
11.8 (98.4) |
40.2 (100) |
106 (106) |
ND = No test substance chromatographic peak detected; NA = Not applicable.
Table 2: Mortality
Dose Level (mg/kg/day) | 20 ( Group 2 ) | 60 ( Group 3 ) | 200 ( Group 4 ) | 500 ( Group 5 ) |
Rabbit Number | 5065 | 3050 | 3070 | 3090 |
Doses Administered | 16 | 22 | 21 | 22 |
Mode of Death | UE | UE – Early Delivery | UE - Abortion | UE - Abortion |
Day of Death | DG 21 | DG 28 | DG 27 | DG 28 |
Clinical Observations |
|
|
|
|
Thin body condition | - | - | DGs 16 to 26 | DGs 16 to 28 |
Decreased fecal output | - | - | - | DGs 16 to 20 |
Ungroomed fur | - | - | - | DGs 19 to 22 |
Red liquid material: red tissue | DG 21 | - | - | - |
Red liquid material | - | - | - | DG 28 |
Aborted material | - | DG 28 | - | - |
Bodyweights |
|
|
|
|
Body weight change (grams) | -7.6% (-281.8g) DGs 20 to 21 | -3.5% (-139.4g) DGs 25 to 28 | -16.6% (-573.3g) DGs 7 to 26 | -4.6% (-178.7g) DGs 27 to 28 |
Food Consumption |
|
|
|
|
Cumulative food consumption | Reduced at each interval between DGs 13 to 18 and 20 to 21 | Reduced at each interval between DGs 19 to 27 | Reduced at all intervals after the initiation of dose administration | Reduced at each interval between DGs 6 to 13 and 14 to 24 |
Necropsy Observations |
|
|
|
|
All tissues appear normal | X | X | X | X |
Uterine Contents |
|
|
|
|
Implantation sites | 9 | 11 | 11 | 11 |
Viable conceptuses | - | - | - | - |
Live fetuses | 8 | 10 | - | - |
Dead fetuses | - | 1 | 11 | 11 |
Early resorptions | - | - | - | - |
Late resorptions | 1 | - | - | - |
X = Procedure conducted, - = Finding not present; DG = Day of presumed gestation; NA = Not applicable; UE = Unscheduled euthanasia
Table 3: Animal accountability
| 0 mg/kg/day | 20 mg/kg/day | 60 mg/kg/day | 200 mg/kg/day | 500 mg/kg/day |
Initial group size | 22 | 22 | 22 | 22 | 22 |
No. of rabbits dosed | 22 | 22 | 22 | 22 | 21 |
No. of early deliveries/abortions during the study | 0 | 0 | 1 | 1 | 1 |
No. of other intercurrent deaths | 0 | 1 | 0 | 0 | 0 |
No. of rabbits not pregnant | 1 | 2 | 0 | 2 | 0 |
No. of rabbits with total resorption | 2 | 0 | 0 | 2 | 2 |
No. of rabbits with live fetuses in utero at term | 19 | 19 | 21 | 17 | 18 |
Table 4: Maternal clinical observations
| Day numbers relative to mating date | ||||
0 mg/kg/day | 20 mg/kg/day | 60 mg/kg/day | 200 mg/kg/day | 500 mg/kg/day | |
Thin | |||||
Number of Observations | - | 10 | - | 23 | 29 |
Number of animals | - | 2 | - | 2 | 2 |
Days from – to | - | 18 29 | - | 14 26 | 14 29 |
Skin, Scab | |||||
Number of Observations | - | - | 1 | - | - |
Number of animals | - | - | 1 | - | - |
Days from – to | - | - | 6 6 | - | - |
Fur, Loss | |||||
Number of Observations | 15 | 6 | 11 | 15 | 12 |
Number of animals | 3 | 1 | 1 | 3 | 2 |
Days from – to | 22 29 | 24 29 | 19 29 | 23 29 | 21 29 |
Fur, Ungroomed | |||||
Number of Observations | - | - | 11 | - | 4 |
Number of animals | - | - | 1 | - | 1 |
Days from – to | - | - | 19 29 | - | 19 22 |
Feces, Liquid | |||||
Number of Observations | - | - | 1 | - | - |
Number of animals | - | - | 1 | - | - |
Days from – to | - | - | 20 20 | - | - |
Feces, Output decreased | |||||
Number of Observations | - | 6 |
| 8 | 11 |
Number of animals | - | 2 |
| 2 | 2 |
Days from – to | - | 17 22 |
| 13 18 | 13 20 |
Material, Liquid, Red | |||||
Number of Observations | 2 | 2 |
| - | 1 |
Number of animals | 1 | 2 |
| - | 1 |
Days from – to | 15 16 | 16 21 |
| - | 28 28 |
Pinna Partly Missing | |||||
Number of Observations | - | - | - | 24 | - |
Number of animals | - | - | - | 1 | - |
Days from – to | - | - | - | 6 29 | - |
Material, Aborted tissue, Pink | |||||
Number of Observations | - | - | 1 | - | - |
Number of animals | - | - | 1 | - | - |
Days from – to | - | - | 28 28 | - | - |
Table 5: Maternal body weights
Day | |||||||||
Group / Sex |
| 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 |
1F |
Mean |
3653 .58 |
3695 .24 |
3719 .47 |
3766 .08 |
3786 .09 |
3805 .76 |
3822 .49 |
3839 .09 |
| SD | 230 .53 | 233 .11 | 240 .00 | 245 .38 | 234 .07 | 241 .34 | 233 .31 | 236 .73 |
| N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 |
2F | Mean | 3558.82 | 3619.12 | 3629.99 | 3657.20 | 3705.10 | 3721.01 | 3741.36 | 3757.23 |
| SD | 173.85 | 181.69 | 178.63 | 175.64 | 184.38 | 197.81 | 191.98 | 196.45 |
| N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 |
| %Diff G1 | -2 59 | -2 06 | -2 41 | -2 89 | -2 14 | -2 23 | -2 12 | -2 13 |
3F | Mean | 3659.47 | 3687.01 | 3698.23 | 3728.42 | 3756.88 | 3775.76 | 3798.74 | 3821.37 |
| SD | 182.17 | 214.70 | 221.64 | 225.03 | 201.70 | 193.19 | 179.84 | 181.86 |
| N | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 |
| %Diff G1 | 0.16 | -0.22 | -0.57 | -1.00 | -0.77 | -0.79 | -0.62 | -0.46 |
4F | Mean | 3653.28 | 3641.72 | 3674.05 | 3700.25 | 3708.61 | 3743.46 | 3764.11 | 3786.57 |
| SD | 205.19 | 181.87 | 163.72 | 175.87 | 186.66 | 193.48 | 179.03 | 187.19 |
| N | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 |
| %Diff G1 | -0.01 | -1.45 | -1.22 | -1.75 | -2.05 | -1.64 | -1.53 | -1.37 |
5F | Mean | 3694.40 | 3705.29 | 3730.50 | 3748.59 | 3761.81 | 3762.71 | 3813.09 | 3827.48 |
| SD | 167.72 | 198.81 | 201.78 | 190.05 | 198.46 | 177.52 | 190.07 | 209.69 |
| N | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 |
| %Diff G1 | 1.12 | 0.27 | 0.30 | -0.46 | -0.64 | -1.13 | -0.25 | -0.30 |
Table 5 (cont): Maternal body weights
Day | |||||||||
Group / Sex |
| 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 |
1F | Mean | 3870.12 | 3901.73 | 3908.47 | 3909.33 | 3924.14 | 3934.40 | 3970.76 | 3961.01 |
| SD | 231.28 | 236.16 | 239.02 | 228.84 | 232.17 | 227.61 | 235.44 | 231.44 |
| N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 |
2F | Mean | 3790.18 | 3794.27 | 3809.99 | 3804.39 | 3811.68 | 3803.07 | 3800.45 | 3807.49 |
| SD | 199.72 | 193.37 | 201.82 | 196.08 | 191.83 | 199.95 | 209.57 | 197.91 |
| N | 19 | 19 | 19 | 19 | 18 | 19 | 19 | 19 |
| %Diff G1 | -2.07 | -2.75 | -2.52 | -2.68 | -2.87 | -3.34 | -4.29 | -3.88 |
3F | Mean | 3860.90 | 3887.44 | 3898.08 | 3902.47 | 3911.68 | 3923.61 | 3924.72 | 3941.54 |
| SD | 196.10 | 214.27 | 210.86 | 215.31 | 205.25 | 212.35 | 207.09 | 200.49 |
| N | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 |
| %Diff G1 | -0.24 | -0.37 | -0.27 | -0.18 | -0.32 | -0.27 | -1.16 | -0.49 |
4F | Mean | 3818.16 | 3830.09 | 3845.67 | 3850.26 | 3863.05 | 3875.31 | 3876.00 | 3887.87 |
| SD | 188.56 | 200.23 | 181.51 | 181.24 | 199.52 | 222.01 | 209.42 | 218.02 |
| N | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 |
| %Diff G1 | -1.34 | -1.84 | -1.61 | -1.51 | -1.56 | -1.50 | -2.39 | -1.85 |
5F | Mean | 3847.66 | 3867.89 | 3882.69 | 3893.92 | 3904.70 | 3919.44 | 3932.02 | 3956.38 |
| SD | 239.00 | 250.81 | 257.60 | 252.94 | 240.51 | 238.59 | 225.90 | 229.34 |
| N | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 |
| %Diff G1 | -0.58 | -0.87 | -0.66 | -0.39 | -0.50 | -0.38 | -0.98 | -0.12 |
Table 5 (cont): Maternal body weights
Day | |||||||||
Group / Sex |
| 22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 |
1F |
Mean | 3984.00 | 3994.59 | 4003.01 | 4014.23 | 4020.17 | 4025.56 | 4036.27 | 4080.64 |
| SD | 229.83 | 237.89 | 232.28 | 233.88 | 227.26 | 218.41 | 213.77 | 219.49 |
| N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 |
2F | Mean | 3812.13 | 3827.63 | 3849.01 | 3862.47 | 3892.46 | 3893.33 | 3910.30 | 3947.47 |
| SD | 214.46 | 223.49 | 227.27 | 223.31 | 207.15 | 223.85 | 234.30 | 248.08 |
| N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 |
| %Diff G1 | -4.31 | -4.18 | -3.85 | -3.78 | -3.18 | -3.28 | -3.12 | -3.26 |
3F | Mean | 3953.52 | 3980.08 | 3983.10 | 3978.50 | 3991.57 | 3992.79 | 4003.25 | 4041.90 |
| SD | 205.85 | 209.47 | 208.42 | 206.68 | 217.15 | 234.28 | 230.62 | 214.73 |
| N | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 |
| %Diff G1 | -0 .77 | -0 .36 | -0 .50 | -0 .89 | -0 .71 | -0 .81 | -0 .82 | -0 .95 |
4F | Mean | 3888.53 | 3890.97 | 3901.65 | 3907.43 | 3924.05 | 3941.74 | 3938.88 | 3960.04 |
| SD | 220.69 | 202.51 | 211.06 | 206.58 | 208.41 | 208.94 | 203.62 | 197.38 |
| N | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 |
| %Diff G1 | -2.40 | -2.59 | -2.53 | -2.66 | -2.39 | -2.08 | -2.41 | -2.96 |
5F | Mean | 3973.82 | 3991.04 | 4013.51 | 4015.06 | 4020.30 | 4024.65 | 4021.90 | 4032.56 |
| SD | 218.22 | 211.94 | 218.98 | 210.98 | 230.61 | 225.34 | 213.75 | 204.42 |
| N | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 |
| %Diff G1 | -0.26 | -0.09 | 0.26 | 0.02 | 0.00 | -0.02 | -0.36 | -1.18 |
Table 6: Maternal body weight gains
Group/ Sex |
| Day | ||||||||
Change 6-10 | Change 10-13 | Change 13-16 | Change 16-20 | Change 6-20 | Change 20-24 | Change 24-29 | Change 20-29 | Change 6-29 | ||
1F | Mean | 132.51 | 53.00 | 69.37 | 62.29 | 317.18 | 32.24 | 77.63 | 109.87 | 427.05 |
SD | 83.69 | 42.55 | 47.10 | 57.42 | 143.55 | 80.78 | 90.69 | 135.56 | 122.36 | |
N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | |
2F | Mean | 146.28 | 52.13 | 52.76 | -9.54a | 241.64 | 48.56 | 98.46 | 147.02 | 388.65 |
SD | 85.14 | 86.22 | 50.43 | 57.32 | 115.59 | 60.50 | 63.96 | 96.44 | 158.63 | |
N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | |
3F | Mean | 97.41 | 64.49 | 76.71 | 26.64 | 265.26 | 58.38 | 58.80 | 117.17 | 382.43 |
SD | 100.98 | 103.00 | 61.56 | 61.42 | 104.99 | 46.76 | 71.77 | 88.97 | 143.46 | |
N | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | |
4F | Mean | 55.34 | 77.96 | 59.10 | 30.33 | 222.72 | 25.65 | 58.39 | 84.04 | 306.76 |
SD | 173.68 | 124.26 | 77.60 | 62.12 | 228.21 | 71.73 | 81.56 | 117.63 | 219.42 | |
N | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | |
5F | Mean | 67.41 | 65.67 | 55.22 | 49.33 | 237.62 | 81.48 | 19.05 | 100.53 | 338.16 |
SD | 97.68 | 122.29 | 117.15 | 81.34 | 128.91 | 49.63 | 66.81 | 88.59 | 148.65 | |
N | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 |
a: significantly different from control group 1 p≤0.01 (Dunnett)
Table 7: Percent body weight gain relative to Group 1 (Control)
| 20 mg/kg/day | 60 mg/kg/day | 200 mg/kg/day | 500 mg/kg/day |
DGs 6 to 10 | +10% | -26% | -58% | -49% |
DGs 6 to 20 | -24% | -16% | -30% | -25% |
DGs 20 to 29 | +34% | +7% | -24% | -9% |
DGs 6 to 29 | -9% | -10% | -28% | -21% |
Table 8: Gravid uterine weights and corrected maternal body weights
Group/ Sex |
| Gravid uterus weight | Day 29 (DTW) | Change from Day 6-29 |
| g | g | g | |
1F | Mean | 556.69 | 3523.95 | -129.64 |
SD | 128.00 | 232.16 | 126.47 | |
N | 19 | 19 | 19 | |
2F | Mean | 541.32 | 3406.15 | -152.66 |
SD | 158.13 | 280.81 | 211.65 | |
N | 19 | 19 | 19 | |
%Diff G1 | -2.76 | -3.34 | 17.76 | |
3F | Mean | 528.16 | 3513.73 | -145.73 |
SD | 160.81 | 271.57 | 190.31 | |
N | 21 | 21 | 21 | |
%Diff G1 | -5.12 | -0.29 | 12.42 | |
4F | Mean | 528.03 | 3432.01 | -221.26 |
SD | 131.06 | 229.08 | 283.55 | |
N | 17 | 17 | 17 | |
%Diff G1 | -5.15 | -2.61 | 70.68 | |
5F | Mean | 498.01 | 3534.55 | -159.85 |
SD | 100.55 | 207.09 | 133.77 | |
N | 18 | 18 | 18 | |
%Diff G1 | -10.54 | 0.30 | 23.31 |
Table 9: Maternal gross pathology observations
| Female | ||||
| 0 mg/kg/day Group 1 | 20 mg/kg/day Group 2 | 60 mg/kg/day Group 3 | 200 mg/kg/day Group 4 | 500 mg/kg/day Group 5 |
Number of animals: | 22 | 22 | 22 | 22 | 21 |
Number of completed animals: | 22 | 22 | 22 | 22 | 21 |
Cervix | |||||
Submitted | 1 | 2 | 0 | 2 | 0 |
No visible lesions | 1 | 2 | - | 2 | - |
Esophagus | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Gallbladder | |||||
Submitted | 1 | 1 | 0 | 0 | 0 |
No visible lesions | 1 | 0 | - | - | - |
Focus; white, multifocal | 0 | 1 | - | - | - |
Heart | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Kidney | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Liver | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Lung | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Ovary | |||||
Submitted | 1 | 2 | 0 | 2 | 0 |
No visible lesions | 1 | 2 | - | 2 | - |
Spleen | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Stomach | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Trachea | |||||
Submitted | 0 | 1 | 1 | 1 | 1 |
No visible lesions | - | 1 | 1 | 1 | 1 |
Uterus | |||||
Submitted | 1 | 2 | 0 | 2 | 0 |
No visible lesions | 1 | 2 | - | 2 | - |
Table 10: Maternal performance
Day(s): 6 to 29 Relative to Mating | ||||||
Sex: Female | 0 mg/kg/day Group 1 | 20 mg/kg/day Group 2 | 60 mg/kg/day Group 3 | 200 mg/kg/day Group 4 | 500 mg/kg/day Group 5 | |
No Pregnant | N-ve N+ve % | 1 21 95.5 | 2 20 90.9 | 0 22 100.0 | 2 20 90.9 | 0 21 100.0 |
Females with live fetuses |
| 19 | 20 | 22 | 17 | 18 |
Females with all dead or resorbed |
| 2 | 0 | 0 | 3 | 3 |
Females euthanized preterminally | N+ve | 0 | 1 | 1 | 1 | 1 |
Pregnant/Early PM | N+ve | 0 | 1 | 1 | 1 | 1 |
Not pregnant/Early PM | N+ve | 0 | 0 | 0 | 0 | 0 |
Females aborted | N+ve | 0 | 0 | 0 | 1 | 1 |
Females delivered | N+ve | 0 | 0 | 1 | 0 | 0 |
Placenta exam Normal | N-ve N+ve | 0 19 | 0 20 | 0 22 | 0 18 | 0 19 |
Table 11: Ovarian and uterine findings
Group/ Sex |
| No. of CL Left | No. of CL Right | No. of Corpora Lutea | Number of Implants | Pre-implantation loss % | Live Male Fetuses % | Live Male Fetuses | Live Female Fetuses | No. of Live Fetuses | No. of Dead Fetuses | Total Fetuses | No. of Resorptions | No. of Early Resorptions | No. of Late Resorptions | Post Implantation Loss % |
1F | Mean | 6.0 | 5.1 | 11.1 | 10.5 | 6.77 | 48.32 | 4.3 | 4.7 | 9.0 | 0.0 | 10.0 | 1.4 | 1.3 | 0.1 | 11.69 |
SD | 1.5 | 1.6 | 2.3 | 3.0 | 15.06 | 12.77 | 2.3 | 2.6 | 4.1 | 0.0 | 3.0 | 3.7 | 3.7 | 0.3 | 29.63 | |
N | 21 | 21 | 21 | 21 | 21 | 19 | 21 | 21 | 21 | 21 | 19 | 21 | 21 | 21 | 21 | |
2F | Mean | 5.7 | 5.5 | 11.3 | 10.5 | 7.29 | 46.77 | 4.7 | 5.4 | 10.1 | 0.0 | 10.1 | 0.4 | 0.1 | 0.4 | 3.90 |
SD | 2.2 | 1.7 | 2.1 | 2.7 | 10.60 | 13.69 | 2.0 | 2.1 | 2.6 | 0.0 | 2.6 | 0.8 | 0.2 | 0.8 | 7.20 | |
N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | |
%Diff G1 | -5.1 | 8.5 | 1.1 | 0.5 | 7.80 | -3.20 | 9.3 | 13.9 | 11.7 | - | 1.1 | -70.5 | -96.1 | 286.8 | -66.64 | |
3F | Mean | 5.6 | 5.2 | 10.9 | 10.4 | 6.69 | 46.77 | 4.4 | 5.2 | 9.7 | 0.0 | 9.7 | 0.7 | 0.6 | 0.1 | 10.50 |
SD | 1.5 | 1.8 | 1.9 | 2.9 | 16.61 | 19.68 | 1.9 | 2.3 | 3.4 | 0.0 | 3.4 | 1.1 | 1.0 | 0.5 | 17.87 | |
N | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | |
%Diff G1 | -7.1 | 2.8 | -2.6 | -0.9 | -1.20 | -3.21 | 2.2 | 11.1 | 6.8 | - | -3.3 | -50.0 | -57.1 | 50.0 | -10.18 | |
4F | Mean | 5.7 | 5.5 | 11.3 | 10.6 | 7.02 | 50.17 | 4.5 | 4.4 | 8.9 | 0.1 | 10.1 | 1.6 | 1.3 | 0.3 | 18.21 |
SD | 2.5 | 1.9 | 2.6 | 3.5 | 18.59 | 12.27 | 2.5 | 2.5 | 4.5 | 0.5 | 3.6 | 2.7 | 2.6 | 0.6 | 31.38 | |
N | 19 | 19 | 19 | 19 | 19 | 17 | 19 | 19 | 19 | 19 | 17 | 19 | 19 | 19 | 19 | |
%Diff G1 | -5.1 | 8.5 | 1.1 | 1.0 | 3.76 | 3.83 | 3.2 | -6.2 | -1.7 | - | 0.6 | 10.5 | -5.3 | 231.6 | 55.73 | |
5F | Mean | 6.0 | 5.2 | 11.2 | 10.9 | 3.00 | 34.99 | 3.2 | 5.5 | 8.7 | 0.1 | 9.7 | 2.1 | 1.5 | 0.6 | 19.70 |
SD | 1.9 | 1.9 | 2.3 | 2.6 | 9.79 | 22.45 | 2.6 | 3.1 | 3.6 | 0.2 | 2.2 | 3.1 | 3.1 | 1.0 | 29.40 | |
N | 20 | 20 | 20 | 20 | 20 | 18 | 20 | 20 | 20 | 20 | 18 | 20 | 20 | 20 | 20 | |
%Diff G1 | -0.8 | 1.1 | 0.1 | 3.6 | -55.67 | -27.59 | -27.3 | 16.7 | -3.8 | - | -2.8 | 47.0 | 12.5 | 530.0 | 68.47 |
Table 12: Mean fetal body weights
Group/ Sex |
| Mean Fetal Weight (M) | Mean Fetal Weight (F) | Mean Fetal Weight (both) |
1F | Mean | 40.475 | 39.372 | 39.914 |
SD | 5.529 | 4.840 | 4.941 | |
N | 19 | 19 | 19 | |
2F | Mean | 40.340 | 38.047 | 38.928 |
SD | 4.193 | 4.528 | 3.873 | |
N | 19 | 19 | 19 | |
%Diff G1 | -0.334 | -3.366 | -2.471 | |
3F | Mean | 40.419 | 38.466 | 39.953 |
SD | 5.894 | 6.339 | 6.448 | |
N | 20 | 20 | 21 | |
%Diff G1 | -0.139 | -2.303 | 0.098 | |
4F | Mean | 38.247 | 37.169 | 37.581 |
SD | 6.437 | 6.448 | 6.064 | |
N | 17 | 17 | 17 | |
%Diff G1 | -5.505 | -5.596 | -5.845 | |
5F | Mean | 32.759a | 32.563a | 32.272a |
SD | 6.236 | 5.493 | 5.472 | |
N | 16 | 18 | 18 | |
%Diff G1 | -19.065 | -17.295 | -19.147 |
a: significantly different from control group 1 p≤0.01 (Dunnett)
Table 13: Fetal abnormalities by finding
|
| 0 mg/kg/day Group 1 | 20 mg/kg/day Group 2 | 60 mg/kg/day Group 3 | 200 mg/kg/day Group 4 | 500 mg/kg/day Group 5 |
| Number of fetuses examined: Number of fetuses evaluated: Number of litters examined: Number of litters evaluated: | 190 190 19 19 | 192 192 19 19 | 203 203 21 21 | 169 171 17 17 | 174 175 18 18 |
Face | ||||||
Jaw, lower (Mandible), Small-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Snout, Short-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Head/neck | ||||||
Head/neck, Anencephaly-malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Head/neck, Cranial meningocele-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Limb | ||||||
Hindlimb, Malrotated-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.6) |
Paw | ||||||
Forepaw, Hyperflexion-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.9) | 12 (6.9) 7 (38.9)** |
Trunk | ||||||
Umbilicus, Herniated-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Aortic arch | ||||||
Aortic arch, Dilated-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Brain | ||||||
Brain, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Brain, Small-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Lateral ventricle, Dilated, Moderate-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.0) 2 (9.5) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Eye | ||||||
Eye, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Eye, Small-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.1) 1 (5.6) |
Gonad | ||||||
Gonad, Hermaphroditism-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.6) |
Great vessels | ||||||
Truncus arteriosus, Persistent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 1 (0.5) 1 (4.8) | 1 (0.6) 1 (5.9) | 0 (0.0) 0 (0.0) |
Heart | ||||||
Ventricular septum, Defect-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 2 (1.0) 2 (10.5) | 1 (0.5) 1 (4.8) | 1 (0.6) 1 (5.9) | 0 (0.0) 0 (0.0) |
Innominate artery | ||||||
Innominate artery, Absent-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.1) 1 (5.6) |
Intestine | ||||||
Intestine, Malpositioned-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Pulmonary trunk | ||||||
Pulmonary trunk, Narrow-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Subclavian artery | ||||||
Subclavian artery, Retroesophageal-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.1) 1 (5.6) |
Subclavian artery origin, Malpositioned-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.1) 1 (5.6) |
Forelimb | ||||||
Digits, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.9) | 2 (1.1) 2 (11.1) |
Forepaw phalanges, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.9) | 2 (1.1) 2 (11.1) |
Forepaw phalanges, Small-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.6) |
Metacarpal, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.9) | 2 (1.1) 2 (11.1) |
Pelvic girdle | ||||||
Pubis, Incomplete ossification-Variation | Fetuses N (%) Litters N (%) | 2 (1.1) 2 (10.5) | 1 (0.5) 1 (5.3) | 2 (1.0) 2 (9.5) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Pubis, Unossified-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Rib | ||||||
Rib, Nodulated-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 3 (1.8) 2 (11.8) | 2 (1.1) 2 (11.1) |
Scapula | ||||||
Scapula ala, Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Skull | ||||||
Frontal, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Frontal, Fused-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.6) |
Frontal, Incomplete ossification-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 3 (1.5) 2 (9.5) | 0 (0.0) 0 (0.0) | 14 (8.0) 2 (11.1) |
Frontal, Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Hyoid ala, Bent-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 33 (19.0) 12 (66.7)** |
Interparietal, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Interparietal, Incomplete ossification-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Interparietal Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Mandible, Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Maxilla, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Nasal, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Palatine, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Parietal, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Parietal, Hole-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 3 (1.5) 3 (14.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Parietal, Incomplete ossification-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.0) 1 (4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Parietal, Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1(4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Premaxilla, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Squamosal, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Supraoccipital, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1(4.8) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Supraoccipital, Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Suture bone, Present-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1(4.8) | 0 (0.0) 0 (0.0) | 3 (1.7) 3 (16.7) |
Tympanic annulus, Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Zygomatic arche, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Sternebra, Asymmetric-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 1 (0.6) 1 (5.9) | 2 (1.1) 1 (5.6) |
Sternebra, Bipartite ossification-Variation | Fetuses N (%) Litters N (%) | 5 (2.6) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.1) 1 (5.6) |
Sternebra, Fused-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 3 (1.6) 2 (10.5) | 3 (1.5) 2 (9.5) | 5 (3.0) 3 (17.6) | 9 (5.2) 6 (33.3)** |
Sternebra, Incomplete ossification-Variation | Fetuses N (%) Litters N (%) | 2 (1.1) 2 (10.5) | 2 (1.0) 2 (10.5) | 1 (0.5) 1 (4.8) | 2 (1.2) 1 (5.9) | 8 (4.6) 4 (22.2) |
Sternebra, Isolated ossification site-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.2) 2 (11.8) | 1 (0.6) 1 (5.6) |
Sternebra, Misshapen-Variation | Fetuses N (%) Litters N (%) | 1 (0.5) 1 (5.3) | 2 (1.0) 1 (5.3) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.9) | 4 (2.3) 2 (11.1) |
Sternebra, Unossified-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Supernumerary rib | ||||||
Cervical, Short-Variation | Fetuses N (%) Litters N (%) | 1 (0.5) 1 (5.3) | 2 (1.0) 1 (5.3) | 2 (1.0) 1 (4.8) | 3 (1.8) 2 (11.8) | 3 (1.7) 3 (16.7) |
Vertebra | ||||||
Caudal vertebra, Absent-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) |
Caudal vertebra, Fused-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.1) 1 (5.6) |
Caudal vertebra, Incomplete ossification-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 3 (1.5) 2 (9.5) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.6) |
Causal vertebra, Misaligned-Variation | Fetuses N (%) Litters N (%) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (4.8) | 0 (0.0) 0 (0.0) | 3 (1.7) 2 (11.1) |
Caudal vertebra, Misshapen-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 1 (0.5) 1 (5.3) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.6) |
Cervical centrum, Unilateral ossification-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 2 (1.1) 1 (5.6) |
Lumbar arch, Small-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.9) | 0 (0.0) 0 (0.0) |
Lumbar vertebra, Hemivertebra-Malformation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.9) | 0 (0.0) 0 (0.0) |
Sacral centrum, Bipartite ossification-Variation | Fetuses N (%) Litters N (%) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 0 (0.0) 0 (0.0) | 1 (0.6) 1 (5.6) |
** p≤0.01
Table 14: Fetal findings by classification - External
Exam Type: External |
| 0 mg/kg/day Group 1 | 20 mg/kg/day Group 2 | 60 mg/kg/day Group 3 | 200 mg/kg/day Group 4 | 500 mg/kg/day Group 5 |
Number of fetuses examined: Number of fetuses evaluated: Number of litters examined: Number of litters evaluated: | 190 190 19 19 | 192 192 19 19 | 203 203 21 21 | 169 171 17 17 | 174 175 18 18 | |
Malformation | Number of Fetuses | 0 | 1 | 2 | 1 | 12 |
Group % of Fetuses | 0.0 | 0.5 | 1.0 | 0.6 | 6.9 | |
Number of Litters (f) | 0 | 1 | 2 | 1 | 7** | |
All classifications | Number of Fetuses | 0 | 1 | 2 | 1 | 12 |
Group % of Fetuses | 0.0 | 0.5 | 1.0 | 0.6 | 6.9 | |
Number of Litters (f) | 0 | 1 | 2 | 1 | 7** |
**: p≤0.01 (Fisher’s Exact)
Table 15: Fetal findings by classification – Fresh visceral
Exam Type: Fresh visceral |
| 0 mg/kg/day Group 1 | 20 mg/kg/day Group 2 | 60 mg/kg/day Group 3 | 200 mg/kg/day Group 4 | 500 mg/kg/day Group 5 |
Number of fetuses examined: Number of fetuses evaluated: Number of litters examined: Number of litters evaluated: | 190 190 19 19 | 192 192 19 19 | 203 203 21 21 | 169 171 17 17 | 174 175 18 18 | |
Variation | Number of Fetuses | 0 | 0 | 2 | 0 | 2 |
Group % of Fetuses | 0.0 | 0.0 | 1.0 | 0.0 | 1.1 | |
Number of Litters (f) | 0 | 0 | 2 | 0 | 1 | |
Malformation | Number of Fetuses | 0 | 3 | 2 | 1 | 5 |
Group % of Fetuses | 0.0 | 1.6 | 1.0 | 0.6 | 2.9 | |
Number of Litters (f) | 0 | 2 | 2 | 1 | 2 | |
All classifications | Number of Fetuses | 0 | 3 | 4 | 1 | 5 |
Group % of Fetuses | 0.0 | 1.6 | 2.0 | 0.6 | 2.9 | |
Number of Litters (f) | 0 | 2 | 3 | 1 | 2 |
Table 16: Fetal findings by classification – Skeletal
Exam Type: Skeletal |
| 0 mg/kg/day Group 1 | 20 mg/kg/day Group 2 | 60 mg/kg/day Group 3 | 200 mg/kg/day Group 4 | 500 mg/kg/day Group 5 |
Number of fetuses examined: Number of fetuses evaluated: Number of litters examined: Number of litters evaluated: | 190 190 19 19 | 192 192 19 19 | 203 203 21 21 | 169 171 17 17 | 174 175 18 18 | |
Variation | Number of Fetuses | 11 | 9 | 12 | 14 | 70 |
Group % of Fetuses | 5.8 | 4.7 | 5.9 | 8.3 | 40.2 | |
Number of Litters (f) | 7 | 6 | 6 | 8 | 15** | |
Malformation | Number of Fetuses | 0 | 1 | 1 | 2 | 4 |
Group % of Fetuses | 0.0 | 0.5 | 0.5 | 1.2 | 2.3 | |
Number of Litters (f) | 0 | 1 | 1 | 1 | 2 | |
All classifications | Number of Fetuses | 11 | 9 | 12 | 15 | 70 |
Group % of Fetuses | 5.8 | 4.7 | 5.9 | 8.9 | 40.2 | |
Number of Litters (f) | 7 | 6 | 6 | 8 | 15** |
**: p≤0.01 (Fisher’s Exact)
Table 17: Ossification of site data
Group/ Sex |
| Hyoid | Cervical Vertebrae | Thoracic Vertebrae | Lumbar Vertebrae | Sacral Vertebrae | Caudal Vertebra | Ribs, Paired | Manubrium | Sternal Centra | Xiphoid | Carpals | Metacarpals | Forelimb Digits | Forelimb Phalanges | Tarsals | Metatarsals | Hindlimb Digits | Hindlimb Phalanges |
1F | Mean | 1.06 | 7.00 | 12.44 | 6.57 | 4.00 | 15.47 | 12.37 | 1.00 | 3.86 | 0.93 | 0.00 | 4.98 | 5.00 | 13.96 | 1.99 | 4.00 | 4.00 | 11.99 |
SD | 0.27 | 0.00 | 0.30 | 0.30 | 0.00 | 0.31 | 0.28 | 0.00 | 0.14 | 0.11 | 0.00 | 0.05 | 0.00 | 0.10 | 0.02 | 0.00 | 0.00 | 0.02 | |
N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | |
2F | Mean | 1.00 | 7.00 | 12.43 | 6.58 | 4.00 | 15.44 | 12.39 | 1.00 | 3.73 | 0.93 | 0.00 | 4.98 | 5.00 | 13.95 | 1.99 | 4.00 | 4.00 | 11.99 |
SD | 0.00 | 0.00 | 0.32 | 0.33 | 0.00 | 0.25 | 0.31 | 0.00 | 0.26 | 0.12 | 0.00 | 0.05 | 0.00 | 0.07 | 0.02 | 0.00 | 0.00 | 0.02 | |
N | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | 19 | |
%Diff G1 | -5.94 | 0.00 | -0.08 | 0.16 | 0.00 | -0.24 | 0.13 | 0.00 | -3.41 | 0.00 | - | 0.00 | 0.00 | -0.04 | 0.00 | 0.00 | 0.00 | 0.00 | |
3F | Mean | 1.04 | 7.00 | 12.53 | 6.48 | 4.00 | 15.49 | 12.50 | 1.00 | 3.88 | 0.94 | 0.00 | 4.96 | 5.00 | 13.97 | 1.99 | 4.00 | 4.00 | 12.00 |
SD | 0.20 | 0.00 | 0.32 | 0.33 | 0.00 | 0.38 | 0.34 | 0.00 | 0.14 | 0.11 | 0.00 | 0.08 | 0.00 | 0.07 | 0.04 | 0.00 | 0.00 | 0.02 | |
N | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | 21 | |
%Diff G1 | -1.91 | 0.00 | 0.74 | -1.40 | 0.00 | 0.11 | 0.98 | 0.00 | 0.60 | 0.70 | - | -0.44 | 0.00 | 0.06 | -0.21 | 0.00 | 0.00 | 0.00 | |
4F | Mean | 0.99 | 7.00 | 12.41 | 6.59 | 4.00 | 15.25 | 12.35 | 1.04 | 3.93 | 0.99 | 0.00 | 4.85 | 5.00 | 13.91 | 1.99 | 4.00 | 4.00 | 11.99 |
SD | 0.05 | 0.00 | 0.34 | 0.34 | 0.00 | 0.43 | 0.33 | 0.17 | 0.12 | 0.02 | 0.00 | 0.22 | 0.00 | 0.13 | 0.03 | 0.00 | 0.00 | 0.02 | |
N | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | |
%Diff G1 | -7.05 | 0.00 | 0.39 | 0.39 | 0.00 | -1.43 | -0.22 | 4.12 | 1.85 | 6.71 | - | -2.65 | 0.00 | -0.33 | -0.33 | 0.00 | 0.00 | -0.01 | |
5F | Mean | 0.99 | 7.00 | 12.73a | 6.28a | 4.00 | 15.36 | 12.68a | 1.00 | 3.97a | 1.00a | 0.00 | 4.41b | 5.00 | 12.84b | 1.98 | 4.00 | 4.00 | 11.94 |
SD | 0.02 | 0.00 | 0.26 | 0.27 | 0.00 | 0.31 | 0.28 | 0.00 | 0.12 | 0.00 | 0.00 | 0.39 | 0.00 | 0.78 | 0.05 | 0.00 | 0.00 | 0.10 | |
N | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | 18 | |
%Diff G1 | -6.46 | 0.00 | 2.38 | -4.42 | 0.00 | -0.73 | 2.50 | 0.00 | 2.96 | 7.34 | - | -11.40 | 0.00 | -8.02 | -0.85 | 0.00 | 0.00 | -0.42 |
a: p≤0.05 (Dunnett)
b: p≤0.01 (Dunnett)
Table 18: Historical control data – Reproductive indices
Period: | January 2006 – July 2014 |
Number of studies: | 19 |
Number of rabbits | |
Tested: | 273 |
Pregnant: | 262 |
Found dead: | 10 |
Aborted: | 10 |
Delivered prematurely: | 1 |
Number of rabbits pregnant at caesarean-sectioning: | 241 |
| Mean or % | Range/Study mean or % |
% pregnant | 95.2 | (80.0-100) |
Average # corpora lutea | 10.7 | (9.2-13.0) |
Average # implantations | 10.0 | (8.5-12.8) |
Average litter size | ||
Average # live fetuses | 9.4 | (8.3-12.0) |
Average # dead fetuses | 0.0 | (0.0-0.2) |
Average # resorptions | 0.6 | (0.0-2.5) |
Average # early resorptions | 0.3 | (0.0-1.0) |
Average # late resorptions | 0.3 | (0-2.0) |
Average % does with any resorptions | 37.3 | (0.0-76.9) |
Average % does with all conceptuses resorbed | 0.0 | - |
Average % does with one or more live fetuses | 100.0 | - |
Average sex ratio (% males/litter) | 48.6 | (32.0-58.9) |
Average fetal body weight (g) | 39.70 | (35.66-44.38) |
Average for males (g) | 37.57 | (35.94-42.67) |
Average for females (g) | 36.69 | (34.12-41.22) |
Average % dead or resorbed conceptuses/litter | 6.3 | (0.0-18.0) |
Table 19: Historical control data – Maternal necropsy observations
Period: | 2006-2014 |
Total no. studies | 19 |
Total no. does: | 273 |
No. pregnant: | 262 |
No. died: | 14 |
No. aborted: | 13 |
No. delivered prematurely: | 1 |
No. does with 100% resorptions: | 0 |
| Range/Study | ||||
N | % | N | % | ||
Gross lesions | |||||
Esophagus | Small amount of red gelatinous material present | 1 | 0.37 | 0-1 | (0-5.0) |
Heart | Pale | 2 | 0.73 | 0-1 | (0-5.0) |
Lungs | All lobes, spongy | 1 | 0.37 | 0-1 | (0-5.0) |
Right bronchi, perforation | 1 | 0.37 | 0-1 | (0-5.0) | |
Stomach | Trichobezoar | 1 | 0.37 | 0-1 | (0-5.0) |
Pup tissue present | 1 | 0.37 | 0-1 | (0-5.0) | |
Cardiac region, mucosal surface, numerous black ulcerations | 1 | 0.37 | 0-1 | (0-5.0) | |
Gallbladder | Numerous white areas or distended tan areas | 3 | 1.10 | 0-2 | (0-7.5) |
Liver | All lobes, pale | 4 | 1.47 | 0-1 | (0-5.0) |
Caudate and right lateral lobes, white area | 1 | 0.37 | 0-1 | (0-5.0) | |
Median lobe, adjacent to gallbladder raised dark area | 1 | 0.37 | 0-1 | (0-5.0) | |
Spleen | Misshapen | 1 | 0.37 | 0-1 | (0-5.0) |
Two accessory spleens | 1 | 0.37 | 0-1 | (0-5.0) | |
Kidneys | Right, misshapen and low set | 1 | 0.37 | 0-1 | (0-5.0) |
Adrenal glands | Left, misshapened round | 1 | 0.37 | 0-1 | (0-5.0) |
Left, absent | 1 | 0.37 | 0-1 | (0-5.0) | |
Uterus | Right horn, reduced to a ligament and ended in blind sac | 1 | 0.37 | 0-1 | (0-5.0) |
Ovaries | Parovarian cysts | 7 | 2.56 | 0.3 | (0-8.75) |
Adipose | All or abdominal, friable | 10 | 3.66 | 0-8 | (0-16.6) |
Table 20: Historical control data – Fetal gross external alterations
Period: | 2006-2014 |
No. of studies: | 18 |
No. litters examined: | 241 |
No. live fetuses examined (Day 29): | 2279 |
| Range/Study | |||||
N | % | N | % | |||
Alteration | ||||||
Head | Meningocele | L | 2 | 0.83 | 0-1 | (0-5.6) |
F | 2 | 0.09 | 0-1 | (0-0.6) | ||
Domed | L | 1 | 0.41 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Eye(s) | Lids open | L | 1 | 0.41 | 0-1 | (0-5.6) |
F | 1 | 0.04 | 0-1 | (0-0.6) | ||
Bulge depressed | L | 2 | 0.83 | 0-1 | (0-5.9) | |
F | 2 | 0.09 | 0-1 | (0-0.6) | ||
Palate | Cleft | L | 1 | 0.41 | 0-1 | (0-5.0) |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Body | Acrania | L | 1 | 0.41 | 0-1 | (0-6.7) |
F | 1 | 0.04 | 0-1 | (0-0.8) | ||
Abdominal distension | L | 1 | 0.41 | 0-1 | (0-4.2) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Forelimb(s) and/or hindlimb(s) | Limb(s): Flexed | L | 4 | 1.66 | 0-1 | (0-6.7) |
F | 4 | 0.18 | 0-1 | (0-0.8) | ||
Limb(s): Rotated | L | 1 | 0.41 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Tail | Short | L | 1 | 0.41 | 0-1 | (0-6.7) |
F | 1 | 0.04 | 0-1 | (0-0.8) |
L: Litter incidence
F: Fetal incidence
Table 21: Historical control data – Fetal soft tissue alterations
Period: | 2006-2014 |
No. of studies: | 14 |
No. litters examined: | 221 |
No. live fetuses examined (Day 29): | 2079 |
| Range/Study | |||||
N | N | N | N | |||
Alteration | ||||||
Eye(s) | Corneal opacity | L | 1 | 0.45 | 0-1 | (0-5.6) |
F | 1 | 0.05 | 0-1 | (0-0.6) | ||
Microphthalmia | L | 2 | 0.90 | 0-1 | (0-5.9) | |
F | 2 | 0.10 | 0-1 | (0-0.6) | ||
Brain | Ventricles, slight dilation | L | 1 | 0.45 | 0-1 | (0-5.0) |
F | 1 | 0.05 | 0-1 | (0-1.0) | ||
Ventricles, extreme dilation | L | 1 | 0.45 | 0-1 | (0-5.0) | |
F | 1 | 0.05 | 0-1 | (0-1.0) | ||
Lungs | One or more lobes, partial or complete agenesis | L | 1 | 0.45 | 0-1 | (0-5.6) |
F | 1 | 0.05 | 0-1 | (0-0.6) | ||
Small | L | 1 | 0.45 | 0-1 | (0-5.9) | |
F | 1 | 0.05 | 0-1 | (0-0.6) | ||
Heart | Interventricular septal defect | L | 3 | 1.36 | 0-1 | (0-5.9) |
F | 3 | 0.14 | 0-1 | (0-0.6) | ||
Vessels | Persistent truncus ateriosis | L | 1 | 0.45 | 0-1 | (0-20.0) |
F | 1 | 0.05 | 0-1 | (0-1.7) | ||
Distended aorta | L | 1 | 0.45 | 0-1 | (0-5.0) | |
F | 1 | 0.05 | 0-1 | (0-0.5) | ||
Constricted pulmonary | L | 1 | 0.45 | 0-1 | (0-5.0) | |
F | 1 | 0.05 | 0-1 | (0-0.5) | ||
Spleen | Small | L | 1 | 0.45 | 0-1 | (0-5.9) |
F | 1 | 0.05 | 0-1 | (0-0.6) | ||
Kidney(s) | Low set | L | 2 | 0.90 | 0-1 | (0-5.9) |
F | 2 | 0.10 | 0-1 | (0-0.6) | ||
Small | L | 1 | 0.45 | 0-1 | (0-5.9) | |
F | 1 | 0.05 | 0-1 | (0-0.6) | ||
Dilated, moderate | L | 1 | 0.45 | 0-1 | (0-5.9) | |
F | 1 | 0.05 | 0-1 | (0-0.6) | ||
Abdominal cavity | Red cloudy fluid | L | 1 | 0.45 | 0-1 | (0-4.2) |
F | 1 | 0.05 | 0-1 | (0-0.5) |
L: Litter incidence
F: Fetal incidence
Table 22: Fetal skeletal alterations
Period: | 2006-2014 |
No. of studies: | 15 |
No. litters examined: | 269 |
No. live fetuses examined (Day 29): | 2476 |
| Range/Study | |||||
N | N | N | N | |||
Alterations | ||||||
Skull | Frontals: interfrontals present | L | 3 | 1.12 | 0-1 | (0-5.6) |
F | 3 | 0.12 | 0-1 | (0-0.6) | ||
Frontals: Contains a hole | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Frontals: Incompletely ossified | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Frontals: Large | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Nasals: Internasals | L | 9 | 3.35 | 0-2 | (0-11.8) | |
F | 10 | 0.40 | 0-3 | (0-1.7) | ||
Nasals: Intranasals | L | 4 | 1.49 | 0-2 | (0-11.8) | |
F | 4 | 0.16 | 0-2 | (0-1.3) | ||
Nasals: Displaced suture | L | 18 | 6.69 | 0-6 | (0-31.6) | |
F | 19 | 0.77 | 0-6 | (0-3.3) | ||
Eye socket: Small | L | 1 | 0.37 | 0-1 | (0-5.6) | |
F | 1 | 0.04 | 0-1 | (0-0.6) | ||
Skull: Incompletely or not ossified | L | 3 | 1.12 | 0-1 | (0-6.7) | |
F | 3 | 0.12 | 0-1 | (0-0.8) | ||
Palate: Incompletely | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Parietal: Contains a hole | L | 3 | 1.12 | 0-2 | (0-10.0) | |
F | 3 | 0.12 | 0-2 | (0-1.0) | ||
Parietal: Large | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Interparietal: Incompletely ossified | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.9) | ||
Interparietal: Large | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Interparietal: Small | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Fontanelle: Anterior, large | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Fontanelle: Posterior, large | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Supraoccipital: Large | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Supraoccipital: Incompletely ossified | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Hyoid | Ala(e), angulated | L | 4 | 1.49 | 0-2 | (0-15.4) |
F | 7 | 0.28 | 0-4 | (0-3.7) | ||
Body, not ossified | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.05) | ||
Vertebrae | Cervical: Arch, misaligned | L | 1 | 0.37 | 0-1 | (0-6.7) |
F | 1 | 0.04 | 0-1 | (0-0.8) | ||
Thoracic: Hemivertebra | L | 2 | 0.74 | 0-1 | (0-5.6) | |
F | 2 | 0.08 | 0-1 | (0-0.6) | ||
Thoracic: Centra, fused | L | 1 | 0.37 | 0-1 | (0-4.2) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Caudal: One or more misaligned | L | 15 | 5.58 | 0-3 | (0-15.8) | |
F | 16 | 0.65 | 0-3 | (0-1.6) | ||
Caudal: Fused | L | 1 | 0.37 | 0-1 | (0-6.7) | |
F | 1 | 0.04 | 0-1 | (0-0.8) | ||
Caudal: Small | L | 1 | 0.37 | 0-1 | (0-5.3) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Caudal: 12 present | L | 1 | 0.37 | 0-1 | (0-6.7) | |
F | 1 | 0.04 | 0-1 | (0-0.8) | ||
Ribs | Two or more, fused | L | 1 | 0.37 | 0-1 | (0-5.6) |
F | 1 | 0.04 | 0-1 | (0-0.6) | ||
One or more, split | L | 1 | 0.37 | 0-1 | (0-5.6) | |
F | 1 | 0.04 | 0-1 | (0-0.6) | ||
One or more, thickened | L | 8 | 2.97 | 0-3 | (0-20.0) | |
F | 8 | 0.32 | 0-3 | (0-2.4) | ||
Flat | L | 1 | 0.37 | 0-1 | (0-6.7) | |
F | 1 | 0.04 | 0-1 | (0-0.8) | ||
Short | L | 1 | 0.37 | 0-1 | (0-5.6) | |
F | 1 | 0.04 | 0-1 | (0-0.6) | ||
T13, Supernumerary | L | 19 | 7.06 | 0-19 | (0-95.0) | |
F | 57 | 2.30 | 0-57 | (0-28.9) | ||
T13, Short | L | 15 | 5.58 | 0-15 | (0-75.0) | |
F | 30 | 1.21 | 0-30 | (0-15.2) | ||
Sternebrae | Two or more, fused | L | 5 | 1.86 | 0-2 | (0-25.0) |
F | 7 | 0.28 | 0-3 | (0-4.1) | ||
One or more, asymmetric | L | 3 | 1.12 | 0-1 | (0-5.6) | |
F | 3 | 0.12 | 0-1 | (0-0.6) | ||
One or more, incompletely or not ossified | L | 15 | 5.58 | 0-1 | (0-50.0) | |
F | 23 | 0.93 | 0-3 | (0-7.6) | ||
Manubrium | Irregularly shaped | L | 1 | 0.37 | 0-1 | (0-6.7) |
F | 1 | 0.04 | 0-1 | (0-0.8) | ||
Pelvis | Pubis, incompletely ossified | L | 4 | 1.49 | 0-2 | (0-10.0) |
F | 4 | 0.16 | 0-2 | (0-1.0) | ||
Pubis, not ossified | L | 2 | 0.74 | 0-2 | (0-10.0) | |
F | 3 | 0.12 | 0-3 | (0-1.5) | ||
Xiphoid | Not ossified | L | 1 | 0.37 | 0-1 | (0-5.0) |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Fused | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) | ||
Forelimb | Metacarpal, not ossified | L | 5 | 1.86 | 0-5 | (0-25.0) |
F | 6 | 0.24 | 0-6 | (0-3.0) | ||
Phalanx, not ossified | L | 1 | 0.37 | 0-1 | (0-5.0) | |
F | 1 | 0.04 | 0-1 | (0-0.5) |
L: Litter incidence
F: Fetal incidence
Applicant's summary and conclusion
- Conclusions:
- The maternal no-observable-adverse effect level (NOAEL) for 1,3-dioxolane is 60 mg/kg/day,
based on mortality, clinical observations (thin body condition and decreased fecal output),
reductions in body weight gain and reductions in food consumption observed at 200 and
500 mg/kg/day during the study. The developmental NOAEL is 200 mg/kg/day due to decreases
in fetal body weight, carpal flexure, skeletal variations and delayed skeletal ossification observed
at 500 mg/kg/day. The delayed ossification was considered to be related to the reduction in fetal
body weight observed in the 500 mg/kg/day dose group. This change in ossification at 500
mg/kg/day was considered not to be adverse because it is a minor, reversible delay in skeletal
ossification and was observed in the presence of maternal toxicity. Reductions in gravid uterine
weights were also observed in the 500 mg/kg/day dose group. The test substance, 1,3-dioxolane, is not a selective developmental toxicant because fetal effects only occurred at the 500 mg/kg/day dose that was toxic to the does. - Executive summary:
The objectives of this study were to detect adverse effects of 1,3-dioxolane on pregnant New Zealand White [Crl:KBL(NZW)] rabbits and development of the embryo and fetus consequent to exposure of the female from implantation to the day prior to termination. This study was designed to evaluate ICH Harmonised Tripartite Guideline stages C to D of the reproductive process.
The following parameters and endpoints were evaluated in this study: viability, clinical signs, maternal body weights, maternal body weight changes, maternal food consumption, ovarian and uterine examinations, gravid uterine weights, fetal examinations (body weight, sex, external, visceral, and skeletal) and gross necropsy findings.
One unscheduled euthanasia and an early delivery occurred in the 20 mg/kg/day and 60 mg/kg/day dose groups, respectively. These unscheduled euthanasias were considered not to be test substance related because there was no additional maternal toxicity apparent in these dose groups.
Abortions were also observed in one rabbit in each of the 200 and 500 mg/kg/day dose groups. These unscheduled euthanasias were considered to be test substance related because there was additional maternal toxicity observed in each of these dose groups, such as thin body condition, decreased fecal output, reduction in body weight gain and reduced food consumption. All other female rabbits survived until scheduled euthanasia.
In the 200 and 500 mg/kg/day dose groups, there were increased incidences of thin body condition (2 females in each of the dose groups between DGs 14 and 29) and decreased fecal output (2 females in each of the dose groups between DGs 13 and 20). At 200 mg/kg/day, female #3070 (which aborted) was observed with thin body condition; female #3076 was observed with decreased fecal output; and female #3078 (which was observed with total resorptions) was observed with thin body condition and decreased fecal output. At 500 mg/kg/day, female #3090 (which aborted) and 3102 (which was observed with total resorptions) were observed with thin body condition and decreased fecal output. These females were also observed with a reduction in body weight gain and reduced food consumption.
Reductions in body weight gain occurred in the 200 mg/kg/day dose group at all intervals in comparison with the control group values, with the exception of DGs 10 to 13. In the 500 mg/kg/day dose group, there were reductions in body weight gain on DGs 6 to 10, 13 to 16, 16 to 20, 6 to 20, 24 to 29, 20 to 29 and 6 to 29 in comparison with the control group values.
Mean body weight gain was reduced in the 200 and 500 mg/kg/day dose groups (28% and 21% compared to concurrent control, respectively) over the entire dose period (DGs 6 to 29). The reductions in body weight gain correlated with reduced food consumption values observed at 200 and 500 mg/kg/day and are considered to be test substance related.
Although not statistically significant, mean gravid uterine weight in the 500 mg/kg/day dose group was slightly reduced at 89% of the control group value. The corrected maternal body weight values were comparable with the control group values at 500 mg/kg/day.
Reductions in food consumption occurred at 200 mg/kg/day on DGs 6 to 20, 20 to 29 and 6 to 29 (12%, 12% and 13% compared to concurrent control, respectively). In the 500 mg/kg/day dose group, mean food consumption were reduced beginning at the initiation of dose administration and continuing at all intervals, with exception of daily intervals from DGs 21 to 26. A statistically significant reduction was observed for the DGs 20 to 21 interval fot the 200 mg/kg/day dose group and the DGs 15 to 16 interval in the 500 mg/kg/day dose group.
There were no necropsy findings observed in the gestating female rabbits.
Average fetal body weights (total, male and female) were statistically significantly reduced at 500 mg/kg/day (19%, 19% and 17% lower than controls, respectively). This reduction in mean fetal body weights in the 500 mg/kg/day dose group correlates with the maternal toxicity observed at this dose.Gross external and skeletal abnormalities and variations in ossification occurred at increased incidences in the 500 mg/kg/day dose group and were considered to be test substance related. These abnormalities included significantly increased numbers of litters with fetuses with carpal flexure at gross examination. Carpal flexure was generally observed in pups with decreased fetal body weights (ranging from 16.0g to 35.8g) in comparison with the mean fetal body weight for the control group (39.9g). Therefore, carpal flexure can be attributed to the reduction in fetal body weight observed at the 500 mg/kg/day dose, which correlates with the maternal toxicity observed at this dose. There was also an increase in the numbers of litters with fetuses with variations in skeletal development. Most common of these skeletal variations were bent hyoid ala, fused sternebrae, and incompletely ossified sternebrae and were likely associated with the reduced fetal weights at this dose. Statistically significant increases in the number of paired ribs
with associated significant increases and decreases in the numbers of thoracic and lumbar vertebrae occurred at 500 mg/kg/day, as well as also statistically significant reductions in the numbers of ossified metacarpals and forelimb phalanges. No gross external, soft tissue or skeletal fetal abnormalities (malformations or variations) were caused by doses of the test substance as high as 200 mg/kg/day.In conclusion, the maternal no-observable-adverse effect level (NOAEL) for 1,3-dioxolane is 60 mg/kg/day, based on mortality, clinical observations (thin body condition and decreased fecal output), reductions in body weight gain and reductions in food consumption observed at 200 and 500 mg/kg/day during the study. The developmental NOAEL is 200 mg/kg/day due to decreases in fetal body weight, carpal flexure, skeletal variations and delayed skeletal ossification observed at 500 mg/kg/day. The delayed ossification was considered to be related to the reduction in fetal body weight observed in the 500 mg/kg/day dose group. This change in ossification at 500 mg/kg/day was considered not to be adverse because it is a minor, reversible delay in skeletal ossification and was observed in the presence of maternal toxicity. Reductions in gravid uterine weights were also observed in the 500 mg/kg/day dose group. The test substance, 1,3-dioxolane, is not a selective developmental toxicant because fetal effects only occurred at the 500 mg/kg/day dose that was toxic to the does.
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