Registration Dossier
Registration Dossier
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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.
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: 247-415-5 | CAS number: 26021-57-8
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 23 July 2004 to 12 April 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 22 January 2001
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3,4-dihydro-2H-1,4-benzoxazin-6-ol
- EC Number:
- 247-415-5
- EC Name:
- 3,4-dihydro-2H-1,4-benzoxazin-6-ol
- Cas Number:
- 26021-57-8
- Molecular formula:
- C8H9NO2
- IUPAC Name:
- 3,4-dihydro-2H-1,4-benzoxazin-6-ol
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: 0508918
- Expiration date of the lot/batch: September 2005.
- Purity test date: 98.3%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at +4°C, protected from light and under nitrogen gas
- Stability under storage conditions: not specified
- Stability under test conditions: Before preparation, the vehicle was degassed by sonication for at least 15 minutes, then saturated
with nitrogen gas and kept under nitrogen atmosphere for 15 minutes.
The test item was administered as a suspension in the vehicle.
The test item was mixed with the required quantity of vehicle in order to achieve the concentrations of 4, 25 and 100 mg/mL and then homogenized using a magnetic stirrer.
The test item dosage forms were prepared under nitrogen atmosphere and stored for up to 9 days at +4°C, protected from light (using a glass beaker covered with aluminium foil) and under nitrogen atmosphere until delivery.
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: Before the start of treatment, the suitability of the proposed preparation procedure was confirmed by the analysis of concentration, homogeneity and stability of dosage forms prepared using this
procedure. These analyses were performed in CIT/Study No. 26976 AHS at concentrations spanning those used in the present study.
During the treatment period, the concentration of dosage forms prepared for use in the study was checked.
- concentration control : The concentration of samples taken from each control and test item dosage form, prepared for use on the first and the last day of the dosing period, was determined according to the analytical method previously validated in CIT/Study No. 26976 AHS.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl CD® (SD) IGS BR, Caesarian Obtained, Barrier Sustained-Virus Antibody Free, (COBS-VAF®).
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories France, L’Arbresle, France
- Age at study initiation: at the beginning of the treatment period, the animals were 10-11 weeks old
- Weight at study initiation: mean body weight of 260 g (range: 220 g to 294 g). The females were sexually mature and primigravid
- Fasting period before study: no data
- Housing: The animal room was disinfected before the arrival of the animals and cleaned regularly thereafter. The animals were individually housed in suspended wire-mesh cages (43.0 x 21.5 x 18.0 cm). A metal tray, containing autoclaved sawdust (SICSA, Alfortville, France), was placed under each cage. The sawdust was changed at least once a week. The cages were placed in numerical order, vertically on the racks.
- Diet (e.g. ad libitum): The animals had free access to A04 C pelleted maintenance diet, batch Nos. 40518 and 40617 (SAFE, Villemoisson, Epinay-sur-Orge, France), which was distributed weekly
- Water (e.g. ad libitum): The animals had free access to bottles containing tap water (filtered with a 0.22 μm filter).
- Acclimation period: a period of 5 days acclimation to the conditions of the study preceded the beginning of the mating period.
- Monitoring of estrous cycle: during the week of mating, the estrous cycle stage was determined periodically from a fresh vaginal lavage (stained with methylene blue).
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air.
The corresponding instrumentation and equipment are checked and calibrated at regular intervals. The temperature and relative humidity are recorded continuously and the records are checked daily and filed.
- Photoperiod (hrs dark / hrs light): 12h/12h (7:00 - 19:00)
IN-LIFE DATES: From: 7 september 2004 To: 6 October 2004
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Before preparation, the vehicle was degassed by sonication for at least 15 minutes, then saturated with nitrogen gas and kept under nitrogen atmosphere for 15 minutes.
The test item was administered as a suspension in the vehicle.
The test item was mixed with the required quantity of vehicle in order to achieve the concentrations of 4, 25 and 100 mg/mL and then homogenized using a magnetic stirrer.
VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was 0.5% carboxymethylcellulose in purified water prepared using:
. purified water, obtained by reverse osmosis using a Milli-Ro 8 plus apparatus (Millipore SA, Saint-Quentin en Yvelines, France),
. carboxymethylcellulose, batch No. 101K0185, supplied by Sigma (Saint-Quentin-Fallavier, France).
- Concentration in vehicle: 250, 400 and 550 mg/kg
- Amount of vehicle (if gavage): 4, 25 and 100 mg/mL - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of samples taken from each control and test item dosage form, prepared for use on the first and the last day of the dosing period, was determined according to the analytical method previously validated in CIT/Study No. 26976 AHS.
- Details on mating procedure:
- - Mating: the females in proestrus were placed overnight in the home cage of singly housed stock males (one female with one male). The males were from the same strain and the same breeder.
Each morning following mating, rats with spermatozoa found in a vaginal smear or sperm plug in situ were considered as pregnant animals. The day where evidence of mating was found was designated as day 0 post-coitum (p.c.).
- Allocation to groups: before day 3 p.c., the animals were allocated to the groups, according to a stratification procedure based on body weight, recorded on day 0 p.c., to ensure a comparatively similar mean body weight among the groups. A larger number of animals than necessary were paired, to permit the selection and/or replacement of individuals before start of treatment. The data on the replaced animals are filed but not presented in the study report. - Duration of treatment / exposure:
- Each animal was given the dosage form once a day, at approximately the same time, from day 6 to day 19 post-coitum, inclusive.
- Frequency of treatment:
- once a day
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 20 mg/kg bw/day
- Dose / conc.:
- 125 mg/kg bw/day
- Dose / conc.:
- 500 mg/kg bw/day
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Rationale for dose-level selection in agreement with the Sponsor
The high dose-level in the present study was set at 500 mg/kg, based on the results of a preliminary study performed at 250, 400 and 550 mg/kg (CIT/Study No. 26999 RSR). In this study, a transient decrease in food consumption and a transient body weight loss were observed at 400 and 550 mg/kg. These body weight losses resulted in a slightly decreased overall body weight gain, when compared to controls (-10%, both dose-levels). Accordingly, the dose-level of 500 mg/kg was expected to be associated with sufficient maternal toxicity, and was selected as a high dose-level for the present study. Low and intermediate dose-levels were set at 20 and 125 mg/kg to assess the dose-relationship of the toxic effects.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
Each animal was checked for mortality or signs of morbidity:
. at least twice a day during treatment period,
. at least once a day on other days.
DETAILED CLINICAL OBSERVATIONS: Yes
From arrival, the animals were observed at least once a day as part of routine examinations.
From the start of the treatment period, each animal was observed at least once a day, at approximately the same time, for the recording of clinical signs.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each female was recorded on days 0, 3, 6, 9, 12, 15, 18 and 20 post-coitum.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption : The quantity of food consumed by each female was recorded for the following intervals:
. days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-20 post-coitum.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day : Hysterectomies
On day 20 p.c., females were sacrificed by inhalation of carbon dioxide gas followed by cervical dislocation, and were submitted for a macroscopic post-mortem examination of the principal thoracic and abdominal organs.
The weight of the gravid uterus of each pregnant female (with at least one live fetus) was recorded.
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
The ovaries and uterus of the females were examined to determine:
. number of corpora lutea,
. number and distribution of dead and live fetuses,
. number and distribution of early and late resorptions,
. number and distribution of uterine scars,
. number and distribution of implantation sites.
The following classification was used to record:
. uterine scar: uterine implantation without implant,
. early resorption: evidence of implant without recognizable embryo,
. late resorption: dead embryo or fetus with external degenerative changes,
. dead fetus: non live fetus with discernible digits.
Uterine horns without visible implantation sites were immersed in an aqueous solution of ammonium sulphide (Salewski) to reveal the presence of uterine scars.
A gross evaluation of placentas was also undertaken. - Fetal examinations:
- These examinations were carried in all the litters (females with at least one live fetus).
The fetal findings were described according to the glossary of the International Federation of Teratology Societies (IFTS) and classified as malformations or variations (Wise, Chahoud):
. malformation refers to a permanent structural change which is likely to adversely affect the survival or health,
. variation refers to a change that occurs within the normal population under investigation and is unlikely to adversely affect the survival or health (this might include a delay in growth, or morphogenesis, that otherwise followed a normal pattern of development).
- External examinations: Yes - Each fetus was submitted for a detailed external examination, which included the observation of all visible structures, surfaces and orifices.
The fetuses were killed by a subcutaneous injection of thiopental sodium.
- Soft tissue examinations: Yes: Approximately half of the fetuses per litter were fixed with Harrisson’s fluid. A detailed soft tissue examination was performed according to a free-hand serial sectioning technique (Wilson technique), which included the observation of all the organs and structures of the head, neck, thorax and abdomen.
- Skeletal examinations: Yes: The remaining fetuses per litter were eviscerated and then fixed with ethyl alcohol. A detailed examination of the skeleton (bone) was performed after staining with alizarin red S (modified Dawson technique). This examination included the observation of all the bone structures of the head, spine, rib cage, pelvis and limbs.
- Head examinations: No
- Sex of fetuses: The sex of each fetus was determined at the time of evisceration or at the time of serial sectioning. - Statistics:
- Mean values were compared by one-way analysis of variance and the Dunnett test (mean values being considered as normally distributed and variances being considered as homogeneous).
Percentage values were compared by the Fisher exact probability test. - Indices:
- Pre- and post-implantation loss, fetal or litter incidence and mean proportion of affected fetuses. Photographs of fetuses were taken to document the findings and archived with the study files
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- A satisfactory agreement was observed between the nominal and actual concentrations of the test item in the administered dosage forms analyzed, since the deviations from nominal concentration were within an acceptable range of ± 9%.
Clinical signs: All females given 500 mg/kg/day and the majority of females given 125 mg/kg/day had orange colored urine generally starting during early- or mid-gestation and lasting until the end of the study. This finding was considered to be evidence of systemic exposure following oral administration of test item. Six females given 500 mg/kg/day experienced excessive salivation, but this clinical sign was observed at a low frequency. - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Net body weight change (body weight change over the dosing period, minus the gravid uterus weight) was statistically and significantly reduced by the test item treatment at 125 and 500 mg/kg/day (-19% p<0.05 and -52% p<0.001, respectively), when compared with the controls. The slight changes observed at 125 mg/kg/day were considered to bear no biological significance as there were no associated significant changes in body weight gain or carcass weight at this dose-level. Accordingly, there were no significant changes in body weight or body weight gain at 20 and 125 mg/kg/day.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- When compared to controls, there was a moderate but statistically significant reduction in mean food consumption at 500 mg/kg/day throughout the dosing period. There were no changes in food intake at 20 and 125 mg/kg.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- At 500 mg/kg/day, the carcass weight, corresponding to maternal body weight on day 20 of gestation minus the gravid uterus weight, was lower (p<0.001, -7.4%) than the control group value.
There was no effect of treatment on the mean gravid uterus weight at any dose-level. - Details on maternal toxic effects:
- The mean number of corpora lutea and implantations, and consequently the pre-implantation loss, were similar for all groups.
There was no effect of treatment on the group mean numbers of dead or live fetuses or on the extent of post-implantation losses.
There was also no effect of treatment on the percentage of male fetuses or on fetal body weight.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 125 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- Given their low incidence and distribution among groups, no external fetal malformations were considered to be related to treatment
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was a single fetus at 20 mg/kg showing various skeletal malformations. This isolated finding was considered to bear no relationship to treatment.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Given their low incidence and their distribution among groups, no soft tissue fetal malformations or variations were considered to be related to treatment. In particular, though there were 2/165, 3/159 and 1/161 fetuses showing a ventricular septal defect respectively at 20, 125 and 500 mg/kg, these slightly high incidences were considered to be fortuitous in the absence of a dose-relationship.
- Description (incidence and severity):
- Slightly high fetal and litter incidences of short 14th ribs (slightly above the upper limit of historical control data, fetal incidence range = 0.0 - 3.7%, litter incidence
range = 0.0 - 11.8%) were observed at 500 mg/kg, and a relationship to treatment with A025 could not be excluded. A slightly high fetal incidence of short 14th rib was also observed at 20 mg/kg, but since this fetal incidence was close to the upper limit of our historical control range, since litter incidence was similar to controls at this dose-level, and since there were no such changes at the higher dose-level of 125 mg/kg, this finding was considered to be unrelated to treatment with A025.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 500 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other:
- Remarks on result:
- other: no effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Lowest effective dose / conc.:
- 500 mg/kg bw/day
- Treatment related:
- no
Any other information on results incl. tables
1.1 CHRONOLOGY OF THE STUDY
The chronology of the study is summarized as follows:
Procedure Date
Study plan approved by:
.StudyDirector 17 December2003
.StudyMonitor 17 December2003
Mating of females(day 0post-coitum)
. First female (experimentalstartingdate) 7 September2004
.Last female 16 September2004
First day of treatment(day 6post-coitum)
.First female 13 September2004
.Last female 22 September2004
Last day of treatment(day 19post-coitum)
.First female 26 September2004
.Last female 5 October2004
Hysterectomies(day 20post-coitum)
.First female 27 September2004
. Last female (experimentalcompletiondate) 6 October2004
1.2 MATERNALDATA
The pregnancy status of the females is summarized in the table below:
Dose-level (mg/kg/day) |
0 |
20 |
125 |
500 |
Number of mated females |
24 |
24 |
24 |
24 |
Number of non-pregnant females |
1 |
0 |
0 |
1 |
Number of females with live fetuses |
23 |
24 |
24 |
23 |
Table: 1
CLINICAL SIGNS (Summary table/Females/Pregnancy period)
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|||
MortalityFINALSACRIFICE |
24 |
24 |
24 |
24 |
|||
Secretion/ExcretionPTYALISM |
0 |
0 |
0 |
6 |
|||
ORANGE COLOURED URINE |
0 |
0 |
22 |
24 |
|||
CHROMODACRYORRHEA |
0 |
0 |
0 |
1 |
|||
Miscellaneous ABNORMALGROWTHOFTEETH(cutregulary) |
1 |
0 |
0 |
0 |
|||
Normal NOREMARKABLEOBSERVATIONS |
23 |
24 |
2 |
0 |
|||
Table: 2
BODY WEIGHT (Mean values/grams/Females/Pregnancy period)
|
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|||
DAY |
0 |
MEAN |
216 d |
222 |
220 |
222 |
||
|
|
S.D. |
14 |
13 |
12 |
11 |
||
|
|
N |
23 |
24 |
24 |
23 |
||
DAY |
3 |
MEAN |
240 d |
244 |
242 |
245 |
||
|
|
S.D. |
15 |
14 |
14 |
12 |
||
|
|
N |
23 |
24 |
24 |
23 |
||
DAY |
6 |
MEAN |
259 d |
261 |
260 |
263 |
||
|
|
S.D. |
15 |
15 |
14 |
10 |
||
|
|
N |
23 |
24 |
24 |
23 |
||
DAY |
9 |
MEAN |
274 d |
275 |
271 |
259* |
||
|
|
S.D. |
19 |
17 |
14 |
20 |
||
|
|
N |
23 |
24 |
24 |
23 |
||
DAY 12 |
MEAN |
296 d |
|
296 |
294 |
280** |
||
|
S.D. |
22 |
|
18 |
16 |
13 |
||
|
N |
23 |
|
24 |
24 |
23 |
||
DAY 15 |
MEAN |
314 d |
|
315 |
311 |
299* |
||
|
S.D. |
24 |
|
21 |
17 |
15 |
||
|
N |
23 |
|
24 |
24 |
23 |
||
DAY 18 |
MEAN |
356 d |
|
354 |
350 |
339 |
||
|
S.D. |
30 |
|
24 |
20 |
18 |
||
|
N |
23 |
|
24 |
24 |
23 |
||
DAY 20 |
MEAN |
393 d |
|
389 |
384 |
372* |
||
|
S.D. |
34 |
|
27 |
23 |
20 |
||
|
N |
23 |
|
24 |
24 |
23 |
||
Statistical key: |
d=ANOVA+ dunnett+test |
* =p<0.05 |
**=p<0.01 |
|
|
|
||
Table: 3
BODY WEIGHT CHANGE (Mean values/grams/Females/Pregnancy period)
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|
DAYS 0 TO 3 |
MEAN |
24 d |
22 |
23 |
22 |
|
S.D. |
4 |
4 |
4 |
6 |
|
N |
23 |
24 |
24 |
23 |
mean percent change |
MEAN% |
11.2 |
10.1 |
10.3 |
10.1 |
DAYS 3 TO 6 |
MEAN |
18 d |
17 |
17 |
18 |
|
S.D. |
5 |
6 |
5 |
6 |
|
N |
23 |
24 |
24 |
23 |
mean percent change |
MEAN% |
7.7 |
7.1 |
7.2 |
7.4 |
DAYS 6 TO 9 |
MEAN |
15 d |
13 |
11 |
-4# |
|
S.D. |
6 |
6 |
5 |
17 |
|
N |
23 |
24 |
24 |
23 |
mean percent change |
MEAN% |
5.7 |
5.1 |
4.2 |
-1.6 |
DAYS 9 TO 12 |
MEAN |
22 d |
21 |
23 |
21 |
|
S.D. |
6 |
5 |
6 |
14 |
|
N |
23 |
24 |
24 |
23 |
mean percent change |
MEAN% |
8.0 |
7.7 |
8.5 |
8.5 |
DAYS 12 TO 15 |
MEAN |
19 d |
19 |
17 |
20 |
|
S.D. |
5 |
5 |
5 |
4 |
|
N |
23 |
24 |
24 |
23 |
mean percent change |
MEAN% |
6.3 |
6.5 |
6.0 |
7.0 |
DAYS 15 TO 18 |
MEAN |
42 d |
39 |
39 |
39 |
|
S.D. |
7 |
6 |
6 |
6 |
|
N |
23 |
24 |
24 |
23 |
mean percent change |
MEAN% |
13.2 |
12.3 |
12.7 |
13.1 |
DAYS 18 TO 20 |
MEAN |
37 d |
35 |
34 |
33 |
|
S.D. |
7 |
7 |
5 |
5 |
|
N |
23 |
24 |
24 |
23 |
meanpercentchange MEAN% |
10.4 |
9.9 |
9.6 |
9.8 |
|
DAYS 6TO20 MEAN |
134 d |
128 |
125 |
109# |
|
|
S.D. |
21 |
16 |
14 |
14 |
|
N |
23 |
24 |
24 |
23 |
mean percent change |
MEAN% |
51.7 |
48.9 |
48.0 |
41.6 |
Statistical key: d=ANOVA+Dunnett-test #=p<0.001
Table: 4
NET BODY WEIGHT CHANGE (Mean values/grams/Females/Pregnancy period)
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
GRAVIDUTERUS MEAN |
83.7 d |
84.3 |
83.5 |
85.1 |
S.D. |
11.1 |
10.6 |
11.6 |
10.1 |
N |
23 |
24 |
24 |
23 |
CARCASS MEAN |
309.4 d |
305.1 |
300.7 |
286.6# |
S.D. |
27.4 |
21.3 |
17.1 |
14.3 |
N |
23 |
24 |
24 |
23 |
NET WEIGHT CHANGE FROM DAY 6 MEAN |
50.5 d |
43.7 |
41.0* |
24.1# |
S.D. |
14.4 |
10.6 |
9.2 |
10.3 |
N |
23 |
24 |
24 |
23 |
Statisticalkey: d=ANOVA+Dunnett-test
* =p<0.05
#=p<0.001
CARCASS WEIGHT = TERMINAL BODY WEIGHT MINUS UTERINE WEIGHT
NET WEIGHT CHANGE FROM DAY 6 = CARCASS WEIGHT MINUS DAY 6 BODY WEIGHT
Table 5
FOOD CONSUMPTION (Mean values/grams per day/Females/Pregnancy period)
Dose:(mg/kg/day) 0 20 125 500
DAYS |
0TO |
3 |
MEAN |
21 d |
22 |
21 |
21 |
|
|
|
S.D. |
2 |
2 |
2 |
2 |
|
|
|
N |
23 |
24 |
24 |
23 |
DAYS |
3TO |
6 |
MEAN |
25 d |
25 |
25 |
25 |
|
|
|
S.D. |
2 |
2 |
2 |
2 |
|
|
|
N |
23 |
24 |
24 |
23 |
DAYS |
6TO |
9 |
MEAN |
26 d |
25 |
24 |
17# |
|
|
|
S.D. |
3 |
2 |
2 |
3 |
|
|
|
N |
23 |
24 |
24 |
23 |
DAYS |
9TO |
12 |
MEAN |
27 d |
26 |
26 |
24# |
|
|
|
S.D. |
3 |
3 |
2 |
2 |
|
|
|
N |
22 |
24 |
24 |
23 |
DAYS12 TO15 |
MEAN |
28 d |
27 |
27 |
25** |
||
|
S.D. |
4 |
3 |
2 |
2 |
||
|
N |
23 |
24 |
24 |
23 |
||
DAYS15 TO18 |
MEAN |
29 d |
28 |
29 |
27* |
||
|
S.D. |
4 |
3 |
2 |
2 |
||
|
N |
23 |
24 |
24 |
23 |
||
DAYS18 TO20 |
MEAN |
29 d |
28 |
28 |
25# |
||
|
S.D. |
4 |
3 |
2 |
2 |
||
|
N |
23 |
24 |
24 |
23 |
||
Statistical key: |
d=ANOVA+Dunnett-test |
* =p<0.05 |
**=p<0.01 #=p<0.001 |
|
|
||
Table 6
SUMMARY OF NECROPSY OBSERVATIONS
Dose:(mg/kg/day) 0 20 125 500
FEMALES N 24 24 24 24
NO REMARKABLE
OBSERVATIONS 24 24 24 24
Table: 7
Hysterectommy DATA (Summary table)
Dose:(mg/kg/day) |
|
0 |
|
20 |
125 |
500 |
Pregnant FemalesAliveatTerm |
N |
|
23 |
24 |
24 |
23 |
withTotalResorptions |
N |
|
0 |
0 |
0 |
0 |
with all Dead Fetuses |
N |
|
0 |
0 |
0 |
0 |
with LiveFetuses |
N |
|
23 |
24 |
24 |
23 |
CorporaLutea TOTAL |
368 |
395 |
385 |
375 |
||
No.peranimal MEAN |
16.0 d |
16.5 |
16.0 |
16.3 |
||
S.D. |
1.7 |
2.2 |
2.3 |
2.0 |
||
ImplantationSites TOTAL |
338 |
351 |
343 |
348 |
||
No.peranimal MEAN |
14.7 d |
14.6 |
14.3 |
15.1 |
||
S.D. |
1.9 |
1.7 |
1.9 |
1.5 |
||
PreimplantationLoss TOTAL |
30 f |
44 |
42 |
27 |
||
% |
8.2 |
11.1 |
10.9 |
7.2 |
||
Fetuses N |
328 |
342 |
333 |
333 |
||
No.peranimal MEAN |
14.3 d |
14.3 |
13.9 |
14.5 |
||
S.D. |
1.8 |
1.8 |
2.1 |
2.0 |
||
Alive % |
100.0 |
100.0 |
100.0 |
100.0 |
||
Dead % |
0.0 |
0.0 |
0.0 |
0.0 |
||
LiveFetuses N |
328 f |
342 |
333 |
333 |
||
% of implantation sites |
97.0 |
97.4 |
97.1 |
95.7 |
||
No.peranimal MEAN |
14.3 d |
14.3 |
13.9 |
14.5 |
||
S.D. |
1.8 |
1.8 |
2.1 |
2.0 |
||
DeadFetuses N |
0 f |
0 |
0 |
0 |
||
% of implantation sites |
0.0 |
0.0 |
0.0 |
0.0 |
||
No.peranimal MEAN |
0.0 |
0.0 |
0.0 |
0.0 |
||
S.D. |
0.0 |
0.0 |
0.0 |
0.0 |
||
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishersexacttest |
|
|
|
||
Table: 7 (continued)
HYSTERECTOMY DATA (Summary table)
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|
Resorptions+Scars |
N |
10 f |
9 |
10 |
15 |
%ofimplantationsites |
|
3.0 |
2.6 |
2.9 |
4.3 |
No. peranimal |
MEAN |
0.4 d |
0.4 |
0.4 |
0.7 |
|
S.D. |
0.8 |
0.9 |
0.7 |
1.1 |
Implant Scars |
N |
0 f |
0 |
0 |
0 |
%ofimplantationsites |
|
0.0 |
0.0 |
0.0 |
0.0 |
No. peranimal |
MEAN |
0.0 |
0.0 |
0.0 |
0.0 |
|
S.D. |
0.0 |
0.0 |
0.0 |
0.0 |
Resorptions: early |
N |
9 f |
7 |
10 |
14 |
%ofimplantationsites |
|
2.7 |
2.0 |
2.9 |
4.0 |
No. peranimal |
MEAN |
0.4 d |
0.3 |
0.4 |
0.6 |
|
S.D. |
0.7 |
0.7 |
0.7 |
1.1 |
Resorptions:late N 1f 2 |
0 |
1 |
|||
%ofimplantationsites 0.3 0.6 |
0.0 |
0.3 |
|||
No.peranimal MEAN |
0.0 d |
0.1 |
0.0 |
0.0 |
|
S.D. |
0.2 |
0.3 |
0.0 |
0.2 |
|
PostimplantationLoss TOTAL |
10 f |
9 |
10 |
15 |
|
% of implantation sites |
3.0 |
2.6 |
2.9 |
4.3 |
|
No.peranimal MEAN |
0.4 d |
0.4 |
0.4 |
0.7 |
|
S.D. |
0.8 |
0.9 |
0.7 |
1.1 |
|
MaleFetuses N |
162 f |
167 |
152 |
170 |
|
% |
49.4 |
48.8 |
45.6 |
51.1 |
|
FemaleFetuses N |
166 f |
175 |
181 |
163 |
|
% |
50.6 |
51.2 |
54.4 |
48.9 |
|
FetalBodyWeight(g) MEAN |
3.64 d |
3.69 |
3.79 |
3.72 |
|
S.D. |
0.21 |
0.13 |
0.23 |
0.34 |
|
MaleFetuses MEAN |
3.73 d |
3.79 |
3.88 |
3.82 |
|
S.D. |
0.24 |
0.16 |
0.23 |
0.36 |
|
FemaleFetuses MEAN |
3.55 d |
3.60 |
3.71 |
3.61 |
|
S.D. |
0.19 |
0.16 |
0.24 |
0.30 |
|
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishersexacttest |
|
|
|
|
Table: 8
SUMMARY OF FETAL EXTERNAL MALFORMATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
|
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
Fetuses Evaluated |
N |
328 |
342 |
333 |
333 |
Live |
N |
328 |
342 |
333 |
333 |
Dead |
N |
0 |
0 |
0 |
0 |
MOUTH, JAW, PALATE
LitterIncidence N |
0 |
1 |
0 |
0 |
FetalIncidence N |
0 |
1 |
0 |
0 |
CLEFT PALATE FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.3 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.3 |
0.0 |
0.0 |
S.D. |
0.0 |
1.3 |
0.0 |
0.0 |
CLEFT LIP FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.3 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.3 |
0.0 |
0.0 |
S.D. |
0.0 |
1.3 |
0.0 |
0.0 |
EYES |
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
FetalIncidence N |
0 |
1 |
0 |
0 |
OPEN EYE FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.3 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.3 |
0.0 |
0.0 |
S.D. |
0.0 |
1.3 |
0.0 |
0.0 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
Table: 8 (continued)
SUMMARY OF FETAL EXTERNAL MALFORMATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
|
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
Fetuses Evaluated |
N |
328 |
342 |
333 |
333 |
Live |
N |
328 |
342 |
333 |
333 |
Dead |
N |
0 |
0 |
0 |
0 |
TRUNK
Litter Incidence |
N |
0 |
0 |
0 |
1 |
Fetal Incidence |
N |
0 |
0 |
0 |
1 |
ANAL ATRESIA Fetal Incidence |
N |
0 f |
0 |
0 |
1 |
|
% |
0.0 |
0.0 |
0.0 |
0.3 |
Litter Incidence |
N |
0 f |
0 |
0 |
1 |
|
% |
0.0 |
0.0 |
0.0 |
4.3 |
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.0 |
0.0 |
0.3 |
|
S.D. |
0.0 |
0.0 |
0.0 |
1.3 |
TAIL |
|
|
|
|
|
Litter Incidence |
N |
0 |
0 |
0 |
1 |
Fetal Incidence |
N |
0 |
0 |
0 |
1 |
THREAD-LIKE TAIL Fetal Incidence |
N |
0 f |
0 |
0 |
1 |
|
% |
0.0 |
0.0 |
0.0 |
0.3 |
Litter Incidence |
N |
0 f |
0 |
0 |
1 |
|
% |
0.0 |
0.0 |
0.0 |
4.3 |
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.0 |
0.0 |
0.3 |
|
S.D. |
0.0 |
0.0 |
0.0 |
1.3 |
CRANIUM
Litter Incidence |
N |
0 |
2 |
0 |
0 |
Fetal Incidence |
N |
0 |
2 |
0 |
0 |
Statistical key: d=ANOVA+Dunnett-test f=Fishers exact test
Table: 8 (continued)
SUMMARY OF FETAL EXTERNAL MALFORMATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
328 |
342 |
333 |
333 |
Live N |
328 |
342 |
333 |
333 |
Dead N |
0 |
0 |
0 |
0 |
EXENCEPHALY FetalIncidence N |
0 f |
2 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
2 |
0 |
0 |
% |
0.0 |
8.3 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
1.8 |
0.0 |
0.0 |
TOTAL FETAL EXTERNAL MALFORMATIONS |
|
|
|
|
FetalIncidence N |
0 f |
2 |
0 |
1 |
% |
0.0 |
0.6 |
0.0 |
0.3 |
LitterIncidence N |
0 f |
2 |
0 |
1 |
% |
0.0 |
8.3 |
0.0 |
4.3 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.3 |
S.D. |
0.0 |
1.8 |
0.0 |
1.3 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
Table: 9
SUMMARY OF FETAL EXTERNAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
|||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
||
Fetuses Evaluated |
N |
328 |
342 |
333 |
333 |
||
Live |
N |
328 |
342 |
333 |
333 |
||
Dead |
N |
0 |
0 |
0 |
0 |
||
TOTAL FETALEXTERNAL Fetal Incidence |
VARIATIONS N |
0 f |
0 |
0 |
0 |
||
|
% |
0.0 |
0.0 |
0.0 |
0.0 |
||
LitterIncidence |
N |
0 f |
0 |
0 |
0 |
||
|
% |
0.0 |
0.0 |
0.0 |
0.0 |
||
AffectedFetuses/Litter |
MEAN% |
0.0 |
0.0 |
0.0 |
0.0 |
||
|
S.D. |
0.0 |
0.0 |
0.0 |
0.0 |
||
Statistical key: f=Fishers exact test
Table: 10
SUMMARY OF FETAL SOFT TISSUE MALFORMATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
160 |
165 |
159 |
161 |
BRAIN |
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
FetalIncidence N |
0 |
1 |
0 |
0 |
HYDROCEPHALY FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
HEART |
|
|
|
|
LitterIncidence N |
0 |
2 |
3 |
1 |
FetalIncidence N |
0 |
2 |
3 |
1 |
VENTRICULAR SEPTUM DEFECT FetalIncidence N |
0 f |
2 |
3 |
1 |
% |
0.0 |
1.2 |
1.9 |
0.6 |
LitterIncidence N |
0 f |
2 |
3 |
1 |
% |
0.0 |
8.3 |
12.5 |
4.3 |
AffectedFetuses/Litter MEAN% |
0.0 d |
1.2 |
2.4 |
0.9 |
S.D. |
0.0 |
4.0 |
6.4 |
4.2 |
LUNGS |
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
FetalIncidence N |
0 |
1 |
0 |
0 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
Table: 10 (continued)
SUMMARY OF FETAL SOFT TISSUE MALFORMATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
160 |
165 |
159 |
161 |
SMALL LUNG FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
DIAPHRAGM |
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
FetalIncidence N |
0 |
1 |
0 |
0 |
DIAPHRAGMATIC HERNIA FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
INTESTINES |
|
|
|
|
LitterIncidence N |
0 |
0 |
0 |
1 |
FetalIncidence N |
0 |
0 |
0 |
1 |
ANAL ATRESIA FetalIncidence N |
0 f |
0 |
0 |
1 |
% |
0.0 |
0.0 |
0.0 |
0.6 |
LitterIncidence N |
0 f |
0 |
0 |
1 |
% |
0.0 |
0.0 |
0.0 |
4.3 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.0 |
0.0 |
0.5 |
S.D. |
0.0 |
0.0 |
0.0 |
2.6 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
Table: 10 (continued)
SUMMARY OF FETAL SOFT TISSUE MALFORMATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
160 |
165 |
159 |
161 |
GONADS |
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
FetalIncidence N |
0 |
1 |
0 |
0 |
SUPERNUMERARY GONAD FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
TOTAL FETALSOFTTISSUEMALFORMATIONS |
|
|
|
|
FetalIncidence N |
0 f |
4 |
3 |
2 |
% |
0.0 |
2.4 |
1.9 |
1.2 |
LitterIncidence N |
0 f |
4 |
3 |
2 |
% |
0.0 |
16.7 |
12.5 |
8.7 |
AffectedFetuses/Litter MEAN% |
0.0 d |
2.2 |
2.4 |
1.4 |
S.D. |
0.0 |
5.1 |
6.4 |
4.8 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
Table: 11
SUMMARY OF FETAL SOFT TISSUE VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
160 |
165 |
159 |
161 |
HEART |
|
|
|
|
LitterIncidence N |
0 |
2 |
0 |
0 |
FetalIncidence N |
0 |
2 |
0 |
0 |
ENLARGED ATRIAL CHAMBER FetalIncidence N |
0 f |
2 |
0 |
0 |
% |
0.0 |
1.2 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
2 |
0 |
0 |
% |
0.0 |
8.3 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
1.2 |
0.0 |
0.0 |
S.D. |
0.0 |
4.0 |
0.0 |
0.0 |
SPLEEN |
|
|
|
|
LitterIncidence N |
1 |
0 |
0 |
0 |
FetalIncidence N |
1 |
0 |
0 |
0 |
SPLENOMEGALY FetalIncidence N |
1 f |
0 |
0 |
0 |
% |
0.6 |
0.0 |
0.0 |
0.0 |
LitterIncidence N |
1 f |
0 |
0 |
0 |
% |
4.3 |
0.0 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.6 d |
0.0 |
0.0 |
0.0 |
S.D. |
3.0 |
0.0 |
0.0 |
0.0 |
STOMACH |
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
FetalIncidence N |
0 |
1 |
0 |
0 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
Table: 11 (continued)
UMMARY OF FETAL SOFT TISSUE VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
160 |
165 |
159 |
161 |
ENLARGED STOMACH FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
KIDNEYS |
|
|
|
|
LitterIncidence N |
4 |
3 |
4 |
3 |
FetalIncidence N |
5 |
4 |
4 |
3 |
DILATED RENAL PELVIS FetalIncidence N |
5 f |
4 |
4 |
3 |
% |
3.1 |
2.4 |
2.5 |
1.9 |
LitterIncidence N |
4 f |
3 |
4 |
3 |
% |
17.4 |
12.5 |
16.7 |
13.0 |
AffectedFetuses/Litter MEAN% |
3.3 d |
2.8 |
2.4 |
2.0 |
S.D. |
8.2 |
8.8 |
5.5 |
5.5 |
URETER |
|
|
|
|
LitterIncidence N |
4 |
1 |
3 |
2 |
FetalIncidence N |
6 |
2 |
3 |
4 |
DILATED URETER FetalIncidence N |
6 f |
2 |
3 |
4 |
% |
3.8 |
1.2 |
1.9 |
2.5 |
LitterIncidence N |
4 f |
1 |
3 |
2 |
% |
17.4 |
4.2 |
12.5 |
8.7 |
AffectedFetuses/Litter MEAN% |
3.5 d |
1.7 |
1.9 |
2.8 |
S.D. |
8.9 |
8.2 |
5.1 |
9.6 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
Table: 11 (continued)
SUMMARY OF FETAL SOFT TISSUE VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
160 |
165 |
159 |
161 |
BLADDER |
|
|
|
|
LitterIncidence N |
0 |
0 |
0 |
2 |
FetalIncidence N |
0 |
0 |
0 |
3 |
DILATED URETHRA FetalIncidence N |
0 f |
0 |
0 |
3 |
% |
0.0 |
0.0 |
0.0 |
1.9 |
LitterIncidence N |
0 f |
0 |
0 |
2 |
% |
0.0 |
0.0 |
0.0 |
8.7 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.0 |
0.0 |
2.0 |
S.D. |
0.0 |
0.0 |
0.0 |
6.5 |
TOTAL FETALSOFTTISSUEVARIATIONS FetalIncidence N |
10 f |
6 |
4 |
5 |
% |
6.3 |
3.6 |
2.5 |
3.1 |
LitterIncidence N |
7 f |
5 |
4 |
3 |
% |
30.4 |
20.8 |
16.7 |
13.0 |
AffectedFetuses/Litter MEAN% |
6.1 d |
4.0 |
2.4 |
3.4 |
S.D. |
11.0 |
9.3 |
5.5 |
9.9 |
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishersexacttest |
|
|
|
Table: 12
SUMMARY OF FETAL SKELETAL MALFORMATIONS
Dose:(mg/kg/day) |
|
0 |
20 |
125 |
500 |
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
THORACIC VERT. |
|
|
|
|
|
Litter Incidence |
N |
0 |
1 |
0 |
0 |
Fetal Incidence |
N |
0 |
1 |
0 |
0 |
THORACIC VERTEBRA(E): FUSED ARCH |
|||||
FetalIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
LitterIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
LUMBAR VERT. |
|
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
|
FetalIncidence N |
0 |
1 |
0 |
0 |
|
SUPERNUMERARY LUMBAR VERTEBRA FetalIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
LitterIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
RIB |
|
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
|
FetalIncidence N |
0 |
1 |
0 |
0 |
|
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishersexacttest |
|
|
|
|
Table: 12 (continued)
SUMMARY OF FETAL SKELETAL MALFORMATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|
LittersEvaluated N |
23 |
24 |
24 |
23 |
|
FetusesEvaluated N |
168 |
177 |
174 |
172 |
|
FUSED RIBS FetalIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
LitterIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
SPINE |
|
|
|
|
|
LitterIncidence N |
0 |
1 |
0 |
0 |
|
FetalIncidence N |
0 |
1 |
0 |
0 |
|
PRESENCEOF 28PRE-SACRALVERTEBRAE |
|
|
|
|
|
Fetal Incidence |
N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
Litter Incidence |
N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
TOTAL FETAL SKELETAL MALFORMATIONS |
|||||
FetalIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
LitterIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishersexacttest |
|
|
|
|
Table: 13
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
|
0 |
20 |
125 |
500 |
|
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
HEAD-SKULL |
|
|
|
|
|
|
Litter Incidence |
N |
10 |
7 |
7 |
2 |
|
Fetal Incidence |
N |
14 |
17 |
8 |
2 |
|
INCOMPLETE OSSIFICATION OF INTERPARIETAL |
||||||
Fetal Incidence |
N |
12 f |
15 |
6 |
2 |
|
|
% |
7.1 |
8.5 |
3.4 |
1.2 |
|
Litter Incidence |
N |
8 f |
7 |
5 |
2 |
|
|
% |
34.8 |
29.2 |
20.8 |
8.7 |
|
AffectedFetuses/Litter |
MEAN% |
6.9 d |
9.1 |
4.0 |
1.3 |
|
|
S.D. |
12.7 |
17.6 |
8.6 |
4.5 |
|
ENLARGED FONTANEL Fetal Incidence |
N |
1 f |
0 |
0 |
0 |
|
|
% |
0.6 |
0.0 |
0.0 |
0.0 |
|
Litter Incidence |
N |
1 f |
0 |
0 |
0 |
|
|
% |
4.3 |
0.0 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.6 d |
0.0 |
0.0 |
0.0 |
|
|
S.D. |
3.0 |
0.0 |
0.0 |
0.0 |
|
INCOMPLETE OSSIFICATION OF PARIETAL |
||||||
FetalIncidence N |
1 f |
5 |
1 |
0 |
||
% |
0.6 |
2.8 |
0.6 |
0.0 |
||
LitterIncidence N |
1 f |
4 |
1 |
0 |
||
% |
4.3 |
16.7 |
4.2 |
0.0 |
||
AffectedFetuses/Litter MEAN% |
0.5 d |
2.9 |
0.5 |
0.0 |
||
S.D. |
2.3 |
6.8 |
2.6 |
0.0 |
||
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
||
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
INCOMPLETE OSSIFICATION OF FRONTAL |
||||||
Fetal Incidence |
N |
1 f |
2 |
0 |
0 |
|
|
% |
0.6 |
1.1 |
0.0 |
0.0 |
|
Litter Incidence |
N |
1 f |
2 |
0 |
0 |
|
|
% |
4.3 |
8.3 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.5 d |
1.0 |
0.0 |
0.0 |
|
|
S.D. |
2.6 |
3.5 |
0.0 |
0.0 |
|
INCOMPLETE OSSIFICATION OF SUPRAOCCIPITAL |
||||||
Fetal Incidence |
N |
1 f |
1 |
2 |
0 |
|
|
% |
0.6 |
0.6 |
1.1 |
0.0 |
|
Litter Incidence |
N |
1 f |
1 |
2 |
0 |
|
|
% |
4.3 |
4.2 |
8.3 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.6 d |
0.5 |
1.3 |
0.0 |
|
|
S.D. |
3.0 |
2.6 |
4.4 |
0.0 |
|
INCOMPLETE OSSIFICATION OF NASAL |
||||||
FetalIncidence N |
0 f |
1 |
0 |
0 |
||
% |
0.0 |
0.6 |
0.0 |
0.0 |
||
LitterIncidence N |
0 f |
1 |
0 |
0 |
||
% |
0.0 |
4.2 |
0.0 |
0.0 |
||
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
||
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
||
UNOSSIFIED SUPRAOCCIPITAL FetalIncidence N |
0 f |
1 |
0 |
0 |
||
% |
0.0 |
0.6 |
0.0 |
0.0 |
||
LitterIncidence N |
0 f |
1 |
0 |
0 |
||
% |
0.0 |
4.2 |
0.0 |
0.0 |
||
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
||
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
||
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
||
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|
LittersEvaluated N |
23 |
24 |
24 |
23 |
|
FetusesEvaluated N |
168 |
177 |
174 |
172 |
|
UNOSSIFIED PARIETAL FetalIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
LitterIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
UNOSSIFIED INTERPARIETAL FetalIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
LitterIncidence N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
HEAD-OTHERS |
|
|
|
|
|
LitterIncidence N |
10 |
14 |
10 |
4 |
|
FetalIncidence N |
19 |
24 |
18 |
5 |
|
INCOMPLETEOSSIFICATIONOFHYOID |
|
|
|
|
|
Fetal Incidence |
N |
10 f |
20 |
15 |
5 |
|
% |
6.0 |
11.3 |
8.6 |
2.9 |
Litter Incidence |
N |
8 f |
12 |
8 |
4 |
|
% |
34.8 |
50.0 |
33.3 |
17.4 |
AffectedFetuses/Litter |
MEAN% |
5.6 d |
11.5 |
8.0 |
2.7 |
|
S.D. |
8.5 |
15.1 |
13.9 |
6.5 |
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|
LittersEvaluated N |
23 |
24 |
24 |
23 |
|
FetusesEvaluated N |
168 |
177 |
174 |
172 |
|
UNOSSIFIED HYOID FetalIncidence N |
9 f |
3 |
3 |
0 |
|
% |
5.4 |
1.7 |
1.7 |
0.0 |
|
LitterIncidence N |
5 f |
2 |
2 |
0 |
|
% |
21.7 |
8.3 |
8.3 |
0.0 |
|
AffectedFetuses/Litter MEAN% |
5.3 d |
2.1 |
1.7 |
0.0 |
|
S.D. |
12.6 |
7.5 |
6.3 |
0.0 |
|
INCOMPLETEOSSIFICATIONOFMAXILLA |
|
|
|
|
|
Fetal Incidence |
N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
Litter Incidence |
N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
INCOMPLETE OSSIFICATION OF PALATE |
|||||
Fetal Incidence |
N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
Litter Incidence |
N |
0 f |
1 |
0 |
0 |
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
CERVICAL VERT. |
|
|
|
|
|
Litter Incidence |
N |
0 |
1 |
0 |
0 |
Fetal Incidence |
N |
0 |
1 |
0 |
0 |
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
CERVICAL VERTEBRA(E): INCOMPLETE OSSIFICATION OF ARCH |
||||||
Fetal Incidence |
N |
0 f |
1 |
0 |
0 |
|
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
Litter Incidence |
N |
0 f |
1 |
0 |
0 |
|
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
THORACIC VERT. |
|
|
|
|
|
|
Litter Incidence |
N |
12 |
9 |
7 |
5 |
|
Fetal Incidence |
N |
25 |
12 |
15 |
12 |
|
THORACIC VERTEBRA(E): INCOMPLETE OSSIFICATION OF CENTRUM |
||||||
Fetal Incidence |
N |
22 f |
10 |
11 |
10 |
|
|
% |
13.1 |
5.6 |
6.3 |
5.8 |
|
Litter Incidence |
N |
10 f |
9 |
5 |
5 |
|
|
% |
43.5 |
37.5 |
20.8 |
21.7 |
|
AffectedFetuses/Litter |
MEAN% |
13.2 d |
5.9 |
6.0 |
5.6 |
|
|
S.D. |
22.3 |
8.3 |
12.7 |
12.7 |
|
THORACIC VERTEBRA(E): BIPARTITE OSSIFICATION OF CENTRUM |
||||||
Fetal Incidence |
N |
3 f |
3 |
3 |
2 |
|
|
% |
1.8 |
1.7 |
1.7 |
1.2 |
|
Litter Incidence |
N |
3 f |
2 |
3 |
1 |
|
|
% |
13.0 |
8.3 |
12.5 |
4.3 |
|
AffectedFetuses/Litter |
MEAN% |
1.7 d |
1.8 |
1.9 |
1.2 |
|
|
S.D. |
4.5 |
6.4 |
5.1 |
6.0 |
|
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
THORACIC VERTEBRA(E): UNOSSIFIED CENTRUM |
||||||
Fetal Incidence |
N |
2 f |
1 |
1 |
0 |
|
|
% |
1.2 |
0.6 |
0.6 |
0.0 |
|
Litter Incidence |
N |
2 f |
1 |
1 |
0 |
|
|
% |
8.7 |
4.2 |
4.2 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
1.1 d |
0.5 |
0.7 |
0.0 |
|
|
S.D. |
3.6 |
2.6 |
3.4 |
0.0 |
|
THORACIC VERTEBRA(E): INCOMPLETE OSSIFICATION OF HEMICENTRUM |
||||||
Fetal Incidence |
N |
0 f |
1 |
0 |
0 |
|
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
Litter Incidence |
N |
0 f |
1 |
0 |
0 |
|
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
LUMBAR VERT. |
|
|
|
|
|
|
Litter Incidence |
N |
1 |
0 |
0 |
0 |
|
Fetal Incidence |
N |
1 |
0 |
0 |
0 |
|
LUMBAR VERTEBRA(E): INCOMPLETE OSSIFICATION OF CENTRUM |
||||||
Fetal Incidence |
N |
1 f |
0 |
0 |
0 |
|
|
% |
0.6 |
0.0 |
0.0 |
0.0 |
|
Litter Incidence |
N |
1 f |
0 |
0 |
0 |
|
|
% |
4.3 |
0.0 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.5 d |
0.0 |
0.0 |
0.0 |
|
|
S.D. |
2.6 |
0.0 |
0.0 |
0.0 |
|
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
|
0 |
20 |
125 |
500 |
|
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
SACRAL VERT. |
|
|
|
|
|
|
Litter Incidence |
N |
1 |
1 |
0 |
0 |
|
Fetal Incidence |
N |
1 |
1 |
0 |
0 |
|
SACRAL VERTEBRA(E): INCOMPLETE OSSIFICATION OF ARCH |
||||||
Fetal Incidence |
N |
1 f |
0 |
0 |
0 |
|
|
% |
0.6 |
0.0 |
0.0 |
0.0 |
|
Litter Incidence |
N |
1 f |
0 |
0 |
0 |
|
|
% |
4.3 |
0.0 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.6 d |
0.0 |
0.0 |
0.0 |
|
|
S.D. |
3.0 |
0.0 |
0.0 |
0.0 |
|
SACRAL VERTEBRA(E): INCOMPLETE OSSIFICATION OF CENTRUM |
||||||
Fetal Incidence |
N |
0 f |
1 |
0 |
0 |
|
|
% |
0.0 |
0.6 |
0.0 |
0.0 |
|
Litter Incidence |
N |
0 f |
1 |
0 |
0 |
|
|
% |
0.0 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
|
|
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
|
CAUDAL VERT. |
|
|
|
|
|
|
Litter Incidence |
N |
3 |
6 |
0 |
1 |
|
Fetal Incidence |
N |
4 |
7 |
0 |
1 |
|
CAUDAL VERTEBRA(E): UNOSSIFIED CENTRUM |
||||||
FetalIncidence N |
3 f |
3 |
0 |
1 |
||
% |
1.8 |
1.7 |
0.0 |
0.6 |
||
LitterIncidence N |
3 f |
2 |
0 |
1 |
||
% |
13.0 |
8.3 |
0.0 |
4.3 |
||
AffectedFetuses/Litter MEAN% |
1.9 d |
1.4 |
0.0 |
0.5 |
||
S.D. |
5.0 |
5.1 |
0.0 |
2.6 |
||
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
||
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
CAUDAL VERTEBRA(E): INCOMPLETE OSSIFICATION OF CENTRUM |
||||||
Fetal Incidence |
N |
2 f |
5 |
0 |
0 |
|
|
% |
1.2 |
2.8 |
0.0 |
0.0 |
|
Litter Incidence |
N |
1 f |
5 |
0 |
0 |
|
|
% |
4.3 |
20.8 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
1.1 d |
2.6 |
0.0 |
0.0 |
|
|
S.D. |
5.2 |
5.3 |
0.0 |
0.0 |
|
STERNEBRA |
|
|
|
|
|
|
Litter Incidence |
N |
23 |
24 |
24 |
23 |
|
Fetal Incidence |
N |
161 |
168 |
161 |
157 |
|
INCOMPLETE OSSIFICATION OF 5th STERNEBRA |
||||||
Fetal Incidence |
N |
118 f |
119 |
131 |
127 |
|
|
% |
70.2 |
67.2 |
75.3 |
73.8 |
|
Litter Incidence |
N |
23 f |
24 |
24 |
23 |
|
|
% |
100.0 |
100.0 |
100.0 |
100.0 |
|
AffectedFetuses/Litter |
MEAN% |
70.0 d |
67.0 |
75.3 |
73.3 |
|
|
S.D. |
23.0 |
19.0 |
22.5 |
27.2 |
|
INCOMPLETE OSSIFICATION OF 6th STERNEBRA |
||||||
FetalIncidence N |
106 f |
103 |
97 |
114 |
||
% |
63.1 |
58.2 |
55.7 |
66.3 |
||
LitterIncidence N |
23 f |
23 |
22 |
22 |
||
% |
100.0 |
95.8 |
91.7 |
95.7 |
||
AffectedFetuses/Litter MEAN% |
63.9 d |
58.6 |
55.0 |
66.4 |
||
S.D. |
23.7 |
28.5 |
29.0 |
28.6 |
||
Statistical key: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
||
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
|
LittersEvaluated N |
23 |
24 |
24 |
23 |
|
FetusesEvaluated N |
168 |
177 |
174 |
172 |
|
UNOSSIFIED 5th STERNEBRA FetalIncidence N |
34 f |
43 |
22 |
21 |
|
% |
20.2 |
24.3 |
12.6 |
12.2 |
|
LitterIncidence N |
15 f |
17 |
12 |
10 |
|
% |
65.2 |
70.8 |
50.0 |
43.5 |
|
AffectedFetuses/Litter MEAN% |
21.0 d |
24.1 |
12.7 |
12.1 |
|
S.D. |
23.5 |
20.6 |
17.0 |
18.2 |
|
UNOSSIFIED 6th STERNEBRA FetalIncidence N |
6 f |
6 |
5 |
7 |
|
% |
3.6 |
3.4 |
2.9 |
4.1 |
|
LitterIncidence N |
2 f |
5 |
2 |
4 |
|
% |
8.7 |
20.8 |
8.3 |
17.4 |
|
AffectedFetuses/Litter MEAN% |
3.7 d |
3.3 |
3.3 |
4.1 |
|
S.D. |
15.1 |
7.2 |
11.5 |
10.5 |
|
INCOMPLETE OSSIFICATION OF 1st TO 4th STERNEBRA(E) |
|||||
Fetal Incidence |
N |
49 f |
32 |
34 |
59 |
|
% |
29.2 |
18.1 |
19.5 |
34.3 |
Litter Incidence |
N |
18 f |
16 |
16 |
17 |
|
% |
78.3 |
66.7 |
66.7 |
73.9 |
AffectedFetuses/Litter |
MEAN% |
28.5 d |
17.8 |
20.1 |
32.5 |
|
S.D. |
21.5 |
17.9 |
21.6 |
29.2 |
BIPARTITE OSSIFICATION OF STERNEBRA(E) |
|||||
FetalIncidence N |
0 f |
2 |
0 |
3 |
|
% |
0.0 |
1.1 |
0.0 |
1.7 |
|
LitterIncidence N |
0 f |
2 |
0 |
2 |
|
% |
0.0 |
8.3 |
0.0 |
8.7 |
|
AffectedFetuses/Litter MEAN% |
0.0 d |
1.0 |
0.0 |
1.6 |
|
S.D. |
0.0 |
3.5 |
0.0 |
5.7 |
|
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
|
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
UNOSSIFIED 1st TO 4th STERNEBRA(E) |
||||||
Fetal Incidence |
N |
1 f |
1 |
0 |
0 |
|
|
% |
0.6 |
0.6 |
0.0 |
0.0 |
|
Litter Incidence |
N |
1 f |
1 |
0 |
0 |
|
|
% |
4.3 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.6 d |
0.5 |
0.0 |
0.0 |
|
|
S.D. |
3.0 |
2.6 |
0.0 |
0.0 |
|
RIB |
|
|
|
|
|
|
Litter Incidence |
N |
5 |
8 |
3 |
6 |
|
Fetal Incidence |
N |
5 |
12 |
5 |
9 |
|
SHORT RIB(S) Fetal Incidence |
N |
2 f |
5 |
2 |
0 |
|
|
% |
1.2 |
2.8 |
1.1 |
0.0 |
|
Litter Incidence |
N |
2 f |
5 |
2 |
0 |
|
|
% |
8.7 |
20.8 |
8.3 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
1.3 d |
2.6 |
1.2 |
0.0 |
|
|
S.D. |
4.2 |
5.1 |
4.0 |
0.0 |
|
SHORT SUPERNUMERARY 14th RIB(S) |
||||||
Fetal Incidence |
N |
3 f |
7 |
3 |
9 |
|
|
% |
1.8 |
4.0 |
1.7 |
5.2 |
|
Litter Incidence |
N |
3 f |
3 |
1 |
6 |
|
|
% |
13.0 |
12.5 |
4.2 |
26.1 |
|
AffectedFetuses/Litter |
MEAN% |
2.0 d |
4.2 |
1.6 |
5.6 |
|
|
S.D. |
5.2 |
14.9 |
7.7 |
11.9 |
|
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
LittersEvaluated N |
23 |
24 |
24 |
23 |
FetusesEvaluated N |
168 |
177 |
174 |
172 |
FULL SUPERNUMERARY 14th RIB(S) FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
INCOMPLETEOSSIFICATIONOFRIB(S) |
|
|
|
|
FetalIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
0.6 |
0.0 |
0.0 |
LitterIncidence N |
0 f |
1 |
0 |
0 |
% |
0.0 |
4.2 |
0.0 |
0.0 |
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
METACARPAL BONE |
|
|
|
|
LitterIncidence N |
12 |
5 |
9 |
5 |
FetalIncidence N |
30 |
12 |
13 |
20 |
UNOSSIFIED 4th METACARPAL(S) FetalIncidence N |
30 f |
12 |
13 |
20 |
% |
17.9 |
6.8 |
7.5 |
11.6 |
LitterIncidence N |
12 f |
5 |
9 |
5 |
% |
52.2 |
20.8 |
37.5 |
21.7 |
AffectedFetuses/Litter MEAN% |
18.2 d |
7.2 |
8.7 |
11.7 |
S.D. |
28.0 |
19.0 |
14.7 |
29.5 |
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
INCOMPLETE OSSIFICATION OF 1st TO 3rd METACARPALS |
||||||
Fetal Incidence |
N |
0 f |
2 |
0 |
0 |
|
|
% |
0.0 |
1.1 |
0.0 |
0.0 |
|
Litter Incidence |
N |
0 f |
2 |
0 |
0 |
|
|
% |
0.0 |
8.3 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.0 d |
1.0 |
0.0 |
0.0 |
|
|
S.D. |
0.0 |
3.5 |
0.0 |
0.0 |
|
METATARSAL BONE |
|
|
|
|
|
|
Litter Incidence |
N |
1 |
1 |
0 |
0 |
|
Fetal Incidence |
N |
1 |
1 |
0 |
0 |
|
INCOMPLETE OSSIFICATION OF METATARSAL(S) |
||||||
Fetal Incidence |
N |
1 f |
1 |
0 |
0 |
|
|
% |
0.6 |
0.6 |
0.0 |
0.0 |
|
Litter Incidence |
N |
1 f |
1 |
0 |
0 |
|
|
% |
4.3 |
4.2 |
0.0 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.6 d |
0.5 |
0.0 |
0.0 |
|
|
S.D. |
3.0 |
2.6 |
0.0 |
0.0 |
|
PELVIS |
|
|
|
|
|
|
Litter Incidence |
N |
2 |
2 |
2 |
1 |
|
Fetal Incidence |
N |
4 |
2 |
2 |
1 |
|
INCOMPLETE OSSIFICATION OF PUBIS |
||||||
FetalIncidence N |
4 f |
1 |
2 |
1 |
||
% |
2.4 |
0.6 |
1.1 |
0.6 |
||
LitterIncidence N |
2 f |
1 |
2 |
1 |
||
% |
8.7 |
4.2 |
8.3 |
4.3 |
||
AffectedFetuses/Litter MEAN% |
2.5 d |
0.6 |
1.3 |
0.7 |
||
S.D. |
9.3 |
2.9 |
4.4 |
3.5 |
||
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
||
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose:(mg/kg/day) |
0 |
20 |
125 |
500 |
||
Litters Evaluated |
N |
23 |
24 |
24 |
23 |
|
Fetuses Evaluated |
N |
168 |
177 |
174 |
172 |
|
INCOMPLETE OSSIFICATION OF ISCHIUM |
||||||
Fetal Incidence |
N |
0 f |
1 |
1 |
0 |
|
|
% |
0.0 |
0.6 |
0.6 |
0.0 |
|
Litter Incidence |
N |
0 f |
1 |
1 |
0 |
|
|
% |
0.0 |
4.2 |
4.2 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.7 |
0.0 |
|
|
S.D. |
0.0 |
2.6 |
3.4 |
0.0 |
|
UNOSSIFIED PUBIS Fetal Incidence |
N |
0 f |
1 |
1 |
0 |
|
|
% |
0.0 |
0.6 |
0.6 |
0.0 |
|
Litter Incidence |
N |
0 f |
1 |
1 |
0 |
|
|
% |
0.0 |
4.2 |
4.2 |
0.0 |
|
AffectedFetuses/Litter |
MEAN% |
0.0 d |
0.5 |
0.7 |
0.0 |
|
|
S.D. |
0.0 |
2.6 |
3.4 |
0.0 |
|
INCOMPLETE OSSIFICATION OF ILIUM |
||||||
FetalIncidence N |
0 f |
1 |
0 |
0 |
||
% |
0.0 |
0.6 |
0.0 |
0.0 |
||
LitterIncidence N |
0 f |
1 |
0 |
0 |
||
% |
0.0 |
4.2 |
0.0 |
0.0 |
||
AffectedFetuses/Litter MEAN% |
0.0 d |
0.5 |
0.0 |
0.0 |
||
S.D. |
0.0 |
2.6 |
0.0 |
0.0 |
||
Statisticalkey: d=ANOVA+Dunnett-test |
f=Fishers exact test |
|
|
|
||
Table: 13 (continued)
SUMMARY OF FETAL SKELETAL VARIATIONS
Dose: (mg/kg/day) |
0 |
20 |
125 |
500 |
||
TOTAL FETALSKELETAL Fetal Incidence |
VARIATIONS N |
163 f |
171 |
164 |
160 |
|
|
% |
97.0 |
96.6 |
94.3 |
93.0 |
|
LitterIncidence |
N |
23 f |
24 |
24 |
23 |
|
|
% |
100.0 |
100.0 |
100.0 |
100.0 |
|
AffectedFetuses/Litter |
MEAN% |
97.3 d |
96.6 |
94.0 |
92.9 |
|
|
S.D. |
7.9 |
8.9 |
12.9 |
15.7 |
|
Statisticalkey: d=ANOVA+Dunnett-test f=Fishersexacttest
Applicant's summary and conclusion
- Conclusions:
- Administration of Hydroxybenzomorpholine (A025) to pregnant female rats during gestation elicited maternal toxicity at 500 mg/kg/day, consisting of reduced body weight gain and food intake. At 125 mg/kg/day, the maternal conditions were generally unaffected by treatment, except the net body weight change which was slightly but statistically significantly decreased from controls. This slight change was considered to bear no biological significance in the absence of associated changes in body weight gain or carcass weight. No effects were noted in the dams at 20 mg/kg/day.
There were no effects of treatment on litter parameters or fetuses, apart from a slightly high incidence of short 14th rib at 500 mg/kg which was conservatively attributed to treatment with A025. In the absence of 14th full rib or abnormal number of pre-sacral vertebrae, these slight changes are readily reversible (Foulon, 2000) and were not considered to be adverse.
The No Observed Adverse Effect Levels (NOAEL) for this study are considered to be:
. maternal toxicity: 125 mg/kg/day,
. developmental toxicity: 500 mg/kg/day. - Executive summary:
The test solutions were prepared under nitrogen and stored for up to 9 days at + 4 °C and under nitrogen until used. Hydroxybenzomorpholine was suspended in 0.5% aqueous carboxymethylcellulose and given at 5 ml/kg. These dose levels were selected on the basis of the
results from a preliminary study where dose-related maternal toxicity was observed at 400 and 550 mg/kg/day.
Each animal was checked at least twice on dosing days and once on other days for clinical signs and death. Body weight was recorded on GD 0, 3, 6, 9 12, 15 18 and 20. Food intake, was recorded over intervals; GD 0-3, 3-6, 6–9, 9-12, 12–15, 15–18, and 18-20.
Post-mortems of all animals were conducted on GD 20. Adrenals, brain, heart, kidneys, liver, Ovaries and intact uterus removed and examined for corpora lutea, implantation sites, the presence of resorption sites (early and late) and foetuses (live, dead and position). Live foetuses
were weighed sexed and checked for gross malformations. Approximately half of the live foetuses where examined for visceral anomalies, and the remaining foetuses were examined for skeletal anomalies.
Results
There were no deaths. Clinical signs were limited to orange-coloured urine in all females at 500 mg/kg/day and most females at 125 mg/kg/day. Presence of coloured urine was considered to be evidence of systemic exposure following oral administration of hydroxybenzomorpholine.
Mean body weight gain was statistically significantly decreased at 500 mg/kg/day (-19%) compared with controls, mainly due to a transient body weight loss at the onset of dosing.
Consequently, mean body weight was lower than for controls over the entire dosing period, and carcass weight (body weight minus gravid uterine weight) was also lower at 500 mg/kg/day.
Group mean food intake at 500 mg/kg/day was slightly but statistically significantly decreased in comparison with controls over the entire dosing period.
Litter parameters including group mean foetal weight were similar in all groups. The incidences of foetuses with a ventricular septal defect, (2/165, 3/159 and 1/161 at 20, 125 and 500 mg/kg, respectively), were not considered to be treatment-related in the absence of any dose-response.
Higher foetal and litter incidences of short supplementary ribs were observed at 500 mg/kg/day.
In comparison with controls, these incidences were not very high, but fell outside the laboratory historical control range
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.
