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EC number: 226-241-3 | CAS number: 5332-73-0
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 04 April 2018 - 04 June 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report Date:
- 2019
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted 22 January 2001
- Deviations:
- no
- Qualifier:
- according to
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- August 1998
- Deviations:
- no
- Qualifier:
- according to
- Guideline:
- other: Japanese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147
- Version / remarks:
- 24 November 2000
- Deviations:
- no
- Qualifier:
- according to
- Guideline:
- other: Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to Regulations (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
- Deviations:
- no
- GLP compliance:
- yes (incl. certificate)
- Limit test:
- no
Test material
Reference
- Name:
- Unnamed
- Type:
- Constituent
- Test material form:
- liquid
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: TE767F05G
- Expiration date of the lot/batch: 05 June 2019
- Purity: 99.7%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature in the dark
- Solubility and stability of the test substance in the solvent/vehicle: stable for 4 hours
- Samples were taken of test item formulations and were analyzed on two occasions for
concentration of Methoxypropylamine (MOPA) at Envigo Analytical Laboratory, Shardlow. The results indicate that the prepared formulations were within 7% of the nominal concentration.
OTHER SPECIFICS: No correction for purity was made.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD (SD) IGS BR
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Age at study initiation: no data
- Weight at study initiation: 199 to 285g
- Fasting period before study: no data
- Housing: The animals were housed in a single air-conditioned room within the Envigo Research Limited, Shardlow, UK Barrier Maintained Rodent Facility.
- Diet: ad libitum; A pelleted diet (Rodent 2018C Teklad Global Certified Diet, Envigo RMS (UK) Limited, Oxon, UK)
- Water: ad libitum; Mains drinking water was supplied from polycarbonate bottles attached to the cage.
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 50 ± 20%
- Air changes (per hr): at least fifteen air changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness.
IN-LIFE DATES: From: 07 April 2018 (first day of treatment) and 26 April 2018 (final day of necropsy).
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Formulations were shown to be stable for four hours. Formulations were therefore prepared daily and dosed within four hours of preparation.
VEHICLE
- Concentration in vehicle: 7.5, 18.75 and 37.5 mg/mL
- Treatment volume: 4 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test item concentration in the test samples was determined by gas chromatography (GC) using an external standard technique. The test item gave a chromatographic profile consisting of a single peak.
The analytical procedure was successfully validated with respect to specificity of chromatographic analysis, linearity of detector response, method accuracy and precision.
The homogeneity and stability was confirmed for test item in Arachis Oil BP formulations at nominal concentrations of 2.5 mg/mL and 100 mg/mL when stored for 4 hours during study number WD30CK.
The mean concentrations of test item in test formulations analyzed for the study were within ± 10% of nominal concentrations, confirming accurate formulation. - Details on mating procedure:
- Animals were delivered in two batches containing females prior to Day 3 of gestation. The day that positive evidence of mating was observed was designated Day 0 of gestation.
- Duration of treatment / exposure:
- between Days 3 and 19 of gestation
- Frequency of treatment:
- daily
- Duration of test:
- from Day 3 to 19 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control group
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Remarks:
- low treatment group
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Remarks:
- Intermediate treatment group
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Remarks:
- high treatment group
- No. of animals per sex per dose:
- 24 females per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were chosen in collaboration with the Sponsor Representative and were based on available toxicity data including a Preliminary Oral (Gavage) Pre-Natal Development Toxicity Study in the Rat (Covance CRS Study Number VF78GT) and a 90 Day Oral (Gavage) Toxicity Study in the Rat (Covance CRS Study Number WD30CK).
- Rationale for animal assignment: The animals were randomly allocated to treatment groups using a randomization procedure based on stratified body weight to ensure similarity between the treatment groups.
Examinations
- Maternal examinations:
- DETAILED CLINICAL OBSERVATIONS: Yes
Following arrival, all animals were examined for overt signs of toxicity, ill-health or behavioral changes once daily during the gestation period. Additionally, during the dosing period, observations were recorded immediately before and soon after dosing and one hour post dosing. All observations were recorded.
BODY WEIGHT: Yes
Individual body weights were recorded on Day 3 (before the start of treatment) and on Days 4, 5, 8, 11, 14 and 17 of gestation. Body weights were also recorded for animals at terminal kill (Day 20).
FOOD CONSUMPTION: Yes
Food consumption was recorded for each individual animal at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.
WATER CONSUMPTION: Yes
Water intake was observed daily by visual inspection of the water bottles for any overt changes.
POST-MORTEM EXAMINATIONS: Yes
All animals were killed by carbon dioxide asphyxiation followed by cervical dislocation on Day 20 of gestation. All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded. - Ovaries and uterine content:
- The ovaries and uteri of pregnant females were removed, examined and the following data recorded:
ii) Number, position and type of intrauterine implantation
iii) Fetal sex
iv) External fetal appearance
v) Fetal weight
vi) Placental weight
vii) Gravid uterus weight
The uteri of any apparently non-pregnant females were immersed in 0.5% ammonium polysulphide solution to reveal evidence of implantation.
Implantation types were divided into:
Early Death: No visible distinction between placental/decidual tissue and embryonic tissue
Late Death: Separate embryonic/fetal and placental tissue visible
Dead Fetus: A fetus that had died shortly before necropsy. These were included as late deaths for reporting purposes.
All implantations and viable fetuses were numbered according to their intrauterine position as follows (as an example):
Left Horn Cervix Right Horn
L1 L2 L3 L4 L5 L6 L7 L8 R1 R2 R3 R4 R5 R6 R7 R8
V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16
V = viable fetus - Fetal examinations:
- The fetuses were killed by subcutaneous injection of a suitable barbiturate agent. Fetuses from each litter were divided into two groups and examined for skeletal alterations and soft tissue alterations. Alternate fetuses were identified using an indelible marker and placed in Bouin’s fixative. Fetuses were subsequently transferred to distilled water and examined for visceral anomalies under a low power binocular microscope and then stored in 10% Buffered Formalin. The remaining fetuses were identified using cardboard tags marked with chinagraph pencil and placed into 70% IMS in distilled water.
The fetuses were subsequently eviscerated, processed and the skeletons stained with alizarin red S before being transferred to 50% glycerol for examination of skeletal development and anomalies and storage. - Statistics:
- Data was assessed using the R Environment for Statistical Computing. Initially, the distribution of the data was assessed by the Shapiro-Wilk normality test, followed by assessment of the homogeneity of the data using Bartlett’s test. Where considered appropriate, parametric analysis of the data was applied incorporating analysis of variance (ANOVA), which if significant, was followed by pair-wise comparisons using Dunnett’s test. Where parametric analysis of the data was considered to be unsuitable, non-parametric analysis of the data was performed incorporating the Kruskal-Wallis test which if significant was followed by the Mann-Whitney "U" test. Dose response relationships were also investigated by linear regression.
Probability values (p) are presented as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 (not significant) - Indices:
- Percentage pre-implantation loss was calculated as:
[(number of corpora lutea-number of implantations)/number of corpora lutea] x 100
Percentage post-implantation loss was calculated as:
[(number of implantations - number of live fetuses)/number of implantations] x 100
Sex ratio was calculated as:
% male fetuses (sex ratio) = (number of male fetuses/total number of fetuses) x 100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Instances of increased salivation were evident in all females treated with 150 mg/kg bw/day between Days 13 and 19 and in two females treated with 75 mg/kg bw/day on Day 19 only.
No such effects were detected in females treated with 30 mg/kg bw/day.
The following observations were noted in a small number of control or treated females and in isolation, these were considered to be incidental and unrelated to the test item. One control female had scattered scabs on one occasion, another control female had red/brown staining around the eyes on one occasion, one female treated with 75 mg/kg bw/day had red/brown staining around the mouth on one occasion, and three females treated with 150 mg/kg bw/day had generalized fur loss between Days 16 and 20, with one of these females also having red/brown staining around the mouth on one occasion. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- There were no unscheduled deaths.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weight and body weight gain, including adjustment for the contribution of the gravid uterus, was unaffected by treatment at 30, 75 or 150 mg/kg bw/day.
Females from all treatment groups showed a statistically significant increase (p<0.05-0.001) in body weight gain between Days 3 and 4 of gestation. An increase in body weight gain is considered not to reflect an adverse effect of treatment and the increase was not dose related and was therefore considered not to be of toxicological significance. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No adverse effect on food consumption was evident in females from any treatment group.
Females treated with 150 mg/kg bw/day exhibited a statistically significant reduction (p<0.01) in food consumption between Days 8 and 11 of gestation. As no such effects were evident before or after this period and all but two individual values for food consumption at this treatment group were within the historical control data range, this reduction was considered not to be of any toxicological significance. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Daily visual inspection of water bottles did not reveal any overt intergroup differences.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Sixteen females treated with 150 mg/kg bw/day had ulceration on the non-glandular region of the stomach. One of these females also had a pale stomach. A further five females from this treatment group had ulceration on both the non-glandular and glandular regions of the stomach. Eleven females treated with 75 mg/kg bw/day had ulceration on the non-glandular region of the stomach and one female treated with 30 mg/kg bw/day had white ridges on the non-glandular region of the stomach.
One female treated with 150 mg/kg bw/day had a mass on the right side of the abdominal cavity. In isolation this was considered to be incidental and unrelated to treatment. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There was no treatment-related effect observed in the pre- and post-implantation loss in all dose groups, when comparing to the control group:
- preimplantation loss: 15.6%, 18.1%, 17.1%, 18.7% at 0, 30, 75 and 150 mg/kg bw/day
- post-implantation loss: 2.3%, 1.3%, 1.5%, 2.7% at 0, 30, 75 and 150 mg/kg bw/day
All data was within the historical control range available for this species and strain. - Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- There were no total litter losses by resorption observed.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on early or late resorptions observed.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on the number of dead fetuses observed.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Cumulative Body Weight Changes were recorded until day 20 of pregnancy, suggesting a duration of 20 days for all females.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- There was no treatment-related, toxicologically relevant effect on the number of pregnant dams per dose group. The number of pregnant females per dose group were 24/24, 24/24, 24/24 and 24/24 at 0,25, 100 and 250 mg/kg bw/day, resp. No historical control data is available for this parameter.
- Details on maternal toxic effects:
- There was no obvious effect of maternal treatment on litter data as assessed by numbers of implantations, in-utero offspring survival (as assessed by the mean numbers of early or late resorptions), live litter size, sex ratio and pre and post-implantation losses at 30, 75 or 150 mg/kg bw/day.
Intergroup differences for mean fetal, litter or placental weights did not indicate any adverse effects of maternal treatment at 30, 75 or 150 mg/kg bw/day.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- clinical signs
- gross pathology
- Remarks on result:
- other: at a lesser extent, also evident in females treated with 75 mg/kg bw/day
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Intergroup differences for mean fetal, litter or placental weights did not indicate any adverse effects of maternal treatment at 30, 75 or 150 mg/kg bw/day.
Male fetal weight and combined fetal weights for litters from females treated with 30 mg/kg bw/day showed a statistically significant increase (p<0.05-0.01) when compared to controls. An increase in fetal weight is generally not considered to represent an adverse effect of treatment and in the absence of a similar effect at the higher dosages, the intergroup differences are considered not to be of toxicological significance. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- There is no treatment-related effect on the number of live offspring.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There was no treatment-related effect observed on sex ratio.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- There was no treatment-related effects observed on litter weight or litter size.
- Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- There was no treatment-related effects observed on postnatal survival.
- External malformations:
- no effects observed
- Description (incidence and severity):
- Neither the type, incidence nor distribution of external finding apparent for fetuses at Day 20 of gestation indicated an adverse effect of maternal treatment on fetal development at 30, 75 or 150 mg/kg bw/day.
A statistically significant increase (p<0.05) in the number of fetuses/litters showing a large placenta was evident at 150 mg/kg bw/day. The group mean value (4.7%) was slightly above the historical control range (0.0 - 4.2%), however, this was considered to be the result of one litter which had five fetuses that had this finding. With this litter excluded, the group mean value was within the historical control range. In the absence of any associated effects, the intergroup difference was considered not to be of toxicological significance. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Skeletal examinations of fetuses on Day 20 of gestation did not indicate any obvious effect of maternal treatment on fetal development at 30, 75 or 150 mg/kg bw/day.
Statistically significant increases (p<0.01) in the number of fetuses/litters showing a ossification centre associated with the first lumbar vertebra, incomplete ossification of the squamosal of the skull and zygomatic process of maxilla of the skull were noted in females treated with 150 mg/kg bw/day. The observations of one variant at a higher incidence compared with controls is not significant when evaluated in isolation. In the absence of a particular pattern of abnormal skeletal development of skeletal structures affecting treated fetuses, the observation of one affected skeletal structure can be considered unlikely to represent true developmental abnormality. This also takes account of these findings being seen regularly on this study type amongst control group fetuses.
A statistically significant increase (p<0.05) in the number of fetuses/litter showing incomplete ossification of the sternebra was evident at 75 mg/kg bw/day. Statistically significant reductions (p<0.05-0.01) in incomplete ossification of the cervical (neural) arch and incomplete ossification of the occipital (supra-occipital) was evident at 30 mg/kg bw/day. In the absence of similar findings at higher dosages or any particular pattern of abnormal skeletal development of skeletal structures affecting treated fetuses, the observation of one affected skeletal structure can be considered unlikely to represent true developmental abnormality. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Visceral examinations of fetuses on Day 20 of gestation did not indicate any obvious effect of maternal treatment on fetal development at 30, 75 or 150 mg/kg bw/day.
A statistically significant increase (p<0.05) in the number of fetuses/litter showing a nonuniform patterning of the rugae was evident at 75 and 30 mg/kg bw/day. In the absence of a similar finding at the highest dosage, the intergroup differences were considered unrelated to treatment. - Details on embryotoxic / teratogenic effects:
- No treatment-related changes were detected in the offspring parameters measured or on embryofetal development. The ‘No Observed Effect Level’ (NOEL) for developmental toxicity was therefore considered to be 150 mg/kg bw/day.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: developmental toxicity
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1 Summary of Female Performance
Category | Number of Females at Dose Level (mg/kg bw/day) | |||
0 (Control) | 30 | 75 | 150 | |
Initial Group Size | 24 | 24 | 24 | 24 |
Pregnant | 24 | 24 | 24 | 24 |
Table 2 Summary Incidence of Daily Clinical Observations
Dose Level (mg/kg bw/day) | Number of Animals | Clinical Observations | Number Showing Effect (Days post coitum affected) |
0 (Control) | 24 | No Abnormalities Detected Scattered Scabs | 22 (0-20) 1 (5) |
|
| Red/Brown Staining around the Eyes | 1 (9) |
30 | 24 | No Abnormalities Detected | 24 (0-20) |
75 | 24 | No Abnormalities Detected Increased Salivation | 21 (0-20) 2 (19) |
|
| Red/Brown Staining Around the Mouth | 1 (19) |
150 | 24 | No Abnormalities Detected Fur Loss (Hind Quarters) | 3 (0-20) 3 (16-20) |
|
| Red/Brown Staining Around the Mouth | 1 (13) |
|
| Increased Salivation | 20 (13-19) |
Table 3 Group Mean Body Weight Values
Dose Level (mg/kg bw/day) |
| 3 | 4 | Body Weight (g) on Day of Gestation 5 8 11 14 | 17 | 20 | |||
0 (Control) | mean sd | 260.7 21.6 | 261.6 20.9 | 267.0 20.2 | 280.6 22.9 | 300.8 23.1 | 320.0 25.0 | 347.4 27.4 | 395.8 33.6 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
30 | mean sd | 258.6 16.2 | 261.3 17.4 | 266.4 17.9 | 280.0 19.5 | 300.1 21.0 | 318.7 23.2 | 349.5 23.8 | 393.9 30.6 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
75 | mean sd | 256.8 15.8 | 261.7 15.5 | 264.7 16.2 | 276.6 16.5 | 295.9 17.3 | 314.8 18.6 | 342.8 22.1 | 388.9 28.7 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
150 | mean sd | 255.8 16.3 | 260.5 16.4 | 264.2 16.9 | 276.1 15.6 | 293.9 17.3 | 312.6 17.7 | 339.6 21.5 | 384.5 26.7 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
Table 4 Group Mean Body Weight Change Values
Dose Level
(mg/kg bw/day) | 3 to 4 |
| Body Weight Change (g) during Days of Gestation 4 to 5 5 to 8 8 to 11 11 to 14 14 to 17 | 17 to 20 | |||||
0 (Control) | mean sd | 0.9 5.6 |
| 5.4 3.7 | 13.6 5.3 | 20.2 4.8 | 19.2 6.1 | 27.4 5.3 | 48.4 8.1 |
| n | 24 |
| 24 | 24 | 24 | 24 | 24 | 24 |
30 | mean sd | 2.8* 3.8 |
| 5.1 3.9 | 13.6 4.6 | 20.1 4.4 | 18.6 6.5 | 30.8 5.3 | 44.4 9.2 |
| n | 24 |
| 24 | 24 | 24 | 24 | 24 | 24 |
75 | mean sd | 4.9*** 2.9 |
| 3.0 3.2 | 11.9 4.4 | 19.3 4.7 | 18.9 5.5 | 28.0 6.6 | 46.1 8.3 |
| n | 24 |
| 24 | 24 | 24 | 24 | 24 | 24 |
150 | mean sd | 4.7* 7.8 |
| 3.7 3.6 | 11.9 4.1 | 17.8 5.5 | 18.7 5.2 | 27.0 8.2 | 44.9 7.7 |
| n | 24 |
| 24 | 24 | 24 | 24 | 24 | 24 |
Dose Level (mg/kg bw/day) |
| 4 | Cumulative Body Weight Change (g) from Day 3 of Gestation 5 8 11 14 17 | 20 | ||||
0 (Control) | mean sd | 0.9 5.6 | 6.3 5.1 | 19.9 7.9 | 40.1 8.6 | 59.3 10.7 | 86.7 13.2 | 135.1 19.3 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
30 | mean sd | 2.8* 3.8 | 7.8 4.5 | 21.4 6.7 | 41.5 8.4 | 60.1 11.5 | 90.9 12.3 | 135.3 19.8 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
75 | mean sd | 4.9*** 2.9 | 7.9 3.2 | 19.8 5.6 | 39.1 6.2 | 58.0 7.9 | 86.0 10.1 | 132.1 16.6 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
150 | mean sd | 4.7* 7.8 | 8.4 8.1 | 20.3 9.1 | 38.1 10.9 | 56.8 12.2 | 83.8 15.8 | 128.7 21.4 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
Table 5 Group Mean Gravid Uterus Weight and Adjusted Body Weight and Body Weight Change Values
Dose Level (mg/kg bw/day) |
| Body Weight (g) on Days of Gestation 3 20 | Body Weight Change (g) during Days of Gestation 3-20 | Gravid Uterus Weight (g) | Adjusted Body Weight (g) Day 20 | Adjusted Body Weight Change (g) 3-20 | |
0 (Control) | mean sd | 260.7 21.6 | 395.8 33.6 | 135.1 19.3 | 80.985 13.696 | 314.8 27.1 | 54.1 11.5 |
| n | 24 | 24 | 24 | 24 | 24 | 24 |
30 | mean sd | 258.6 16.2 | 393.8 30.4 | 135.2 19.5 | 78.509 14.164 | 315.3 25.8 | 56.7 15.9 |
| n | 24 | 24 | 24 | 24 | 24 | 24 |
75 | mean sd | 256.8 15.8 | 388.9 28.7 | 132.1 16.6 | 80.375 12.871 | 308.5 23.0 | 51.8 11.4 |
| n | 24 | 24 | 24 | 24 | 24 | 24 |
150 | mean sd | 255.8 16.3 | 384.5 26.7 | 128.7 21.4 | 77.238 19.951 | 307.3 19.3 | 51.5 12.2 |
| n | 24 | 24 | 24 | 24 | 24 | 24 |
Table 6 Group Mean Food Consumption Values
Dose Level (mg/kg bw/day) |
| Food Consumption (g/rat/day) between Days of Gestation 3 - 5 5 - 8 8 - 11 11 - 14 14-17 17 - 20 | |||||
0 (Control) | mean sd | 21.4 1.8 | 23.0 2.5 | 24.2 2.2 | 24.3 2.4 | 25.3 4.8 | 27.3 4.5 |
| n | 24 | 23 | 24 | 24 | 24 | 24 |
30 | mean sd | 21.0 2.8 | 23.2 3.2 | 23.7 3.0 | 24.4 6.0 | 26.5 5.1 | 26.3 3.4 |
| n | 24 | 24 | 24 | 24 | 24 | 24 |
75 | mean sd | 21.5 3.3 | 24.2 10.0 | 24.1 6.4 | 23.2 2.7 | 26.0 4.9 | 26.2 3.6 |
| n | 24 | 24+ | 23# | 24 | 24 | 24 |
150 | mean sd | 20.6 4.6 | 21.2 2.0 | 21.7** 2.5 | 22.6 1.9 | 24.1 4.9 | 26.0 5.1 |
| n | 24 | 24 | 24 | 24 | 24 | 24 |
+ = Food consumption for Female 61 calculated for Days 5-7 only due to female being present in incorrect cage on Day 8.
# = Data unavailable for Female No. 63, due to erroneous value recorded for food allocated on Day 8.
Table 7 Summary Incidence of Necropsy Findings
|
| Dose Level (mg/kg bw/day) |
| |
0 (Control) | 30 | 75 | 150 | |
TERMINAL DEATH
Number of Animals Examined |
24 |
24 |
24 |
24 |
External: Generalized Fur Loss |
0 |
0 |
0 |
1 |
Mass on Right Side | 0 | 0 | 0 | 1 |
Internal: Stomach – Non-Glandular Region: White Ridges |
0 |
1 |
0 |
0 |
Stomach – Non-Glandular Region: Ulcerated | 0 | 0 | 11 | 16 |
Stomach: Ulcerated | 0 | 0 | 0 | 5 |
Stomach: Pale | 0 | 0 | 0 | 1 |
Outer Right Side of Abdominal Cavity: Mass | 0 | 0 | 0 | 1 |
No Abnormalities Detected
|
24
|
23 |
13
|
3
|
Table 8 Group Mean Litter Data Values
Dose Level (mg/kg bw/day) |
| Number of Corpora Lutea | Number of Implants | Number of Embryonic/Fetal Deaths | Implantation Loss % | Number of Live Implants | % Male Fetuses | Mean Male Fetal Weight (g) | Mean Female Fetal Weight (g) | Mean Fetal Weight (g) | Mean Placental Weight (g) | Litter Weight (g) | Total Placental Weight (g) | |||||
Early | Late | Total | Pre | Post | Male | Female | Total | |||||||||||
0 (Control) | mean sd | 16.3 2.3 | 13.8 2.6 | 0.2 0.5 | 0.1 0.3 | 0.3 0.6 | 15.6 12.3 | 2.3 3.8 | 6.7 2.2 | 6.7 2.0 | 13.4 2.5 | 50.3 13.0 | 3.917 0.315 | 3.742 0.306 | 3.831 0.286 | 0.537 0.065 | 51.054 9.067 | 7.137 1.459 |
| n | 23# | 24 | 24 | 24 | 24 | 23 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 23+ | 24 | 23+ |
30 | mean sd | 15.4 2.4 | 12.8 2.8 | 0.1 0.3 | 0.0 0.2 | 0.2 0.4 | 18.1 13.4 | 1.3 3.0 | 6.3 1.8 | 6.3 2.2 | 12.6 2.9 | 52.1 15.2 | 4.253** 0.546 | 3.906 0.271 | 4.140* 0.569 | 0.571 0.132 | 50.878 9.780 | 6.834 1.202 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 23 | 24 | 24+ | 24 | 24+ |
75 | mean sd | 16.2 2.3 | 13.5 2.5 | 0.2 0.4 | 0.0 0.2 | 0.2 0.4 | 17.1 7.4 | 1.5 3.0 | 7.1 2.7 | 6.2 2.1 | 13.3 2.5 | 53.0 17.2 | 3.961 0.291 | 3.771 0.305 | 3.877 0.279 | 0.540 0.045 | 51.140 8.766 | 7.138 1.334 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
150 | mean sd | 15.3 2.2 | 12.6 3.2 | 0.1 0.4 | 0.0 0.2 | 0.2 0.5 | 18.7 14.7 | 2.7 10.3 | 6.5 2.5 | 5.9 2.5 | 12.4 3.4 | 52.9 14.3 | 4.029 0.264 | 3.781 0.309 | 3.913 0.289 | 0.608 0.165 | 48.735 13.796 | 7.201 1.968 |
| n | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 | 24 |
+ = Placental weights not recorded in error for Female No. 21’s litter and for fetus No. 8 from Female No. 25
# = Data unavailable for Female No. 16
Table 9 Summary Incidence of Fetal External Findings
| External Findings |
| Dose level (mg/kg bw/day) |
|
| ||||||||
0 (Control) | 30 | 75 |
| 150 | |||||||||
| Number of fetuses (litters) examined |
|
| ||||||||||
322 (24) | 303 (24) | 318 (24) |
| 298 (24) | |||||||||
NF | NL | %† | NF | NL | %† | NF | NL | %† | NF | NL | %† | ||
Total Number Affected |
| 4 | 1 | 1.3 | 8 | 5 | 5.9 | 7 | 6 | 2.2 | 15 | 6 | 6.6 |
Small Fetus |
| 4 | 1 | 1.3 | 6 | 4 | 1.8 | 5 | 4 | 1.6 | 8 | 4 | 2.8 |
Pale Fetus |
| 1 | 1 | 0.3 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Large Fetus |
| 0 | 0 | 0.0 | 2 | 1 | 4.2 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Large Placenta |
| 0 | 0 | 0.0 | 2 | 1 | 4.2 | 1 | 1 | 0.3 | 9 | 5 | 4.7* |
Small Placenta |
| 2 | 1 | 0.6 | 1 | 1 | 0.2 | 2 | 2 | 0.7 | 1 | 1 | 0.3 |
Table 10 Summary Incidence of Fetal Visceral Findings
Visceral Findings |
|
|
|
| Dose Level (mg/kg bw/day) |
|
|
|
| ||||
| 0 (Control) |
| 30 | 75 |
|
| 150 |
| |||||
|
|
|
| Number of Fetuses (litters) Examined |
|
|
|
| |||||
| 168 (24) |
|
| 156 (24) | 164 (24) |
|
| 157 (24) |
| ||||
NF |
| NL | %† | NF | NL | %† | NF | NL | %† | NF | NL | %† | |
External Hemorrhage |
0 |
|
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
0 |
0 |
0.0 |
Head Rugae - non-uniform patterning |
2 |
|
2 |
1.0 |
11 |
8 |
6.8* |
8 |
8 |
4.8* |
5 |
2 |
3.9 |
Abdomen Liver - additional lobe between right and left median |
2 |
|
2 |
1.2 |
2 |
1 |
1.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Umbilical artery - left-sided | 0 |
| 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 2 | 2 | 1.2 |
Testis - partially undescended | 4 |
| 3 | 2.4 | 4 | 4 | 2.5 | 1 | 1 | 0.6 | 2 | 2 | 1.2 |
Testis - malrotated | 0 |
| 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.5 |
Ureter - kinked | 15 |
| 10 | 10.0 | 11 | 7 | 7.0 | 12 | 6 | 8.3 | 9 | 7 | 7.3 |
Ureter - dilated | 11 |
| 7 | 7.9 | 3 | 3 | 1.9 | 8 | 4 | 5.9 | 5 | 4 | 4.9 |
Kidney - malpositioned | 0 |
| 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 0 | 0 | 0.0 |
Renal pelvic cavitation - increased | 8 |
| 6 | 4.4 | 8 | 7 | 5.0 | 7 | 5 | 4.5 | 10 | 6 | 7.5 |
Renal papilla - absent | 1 |
| 1 | 0.5 | 2 | 2 | 1.3 | 3 | 2 | 2.3 | 1 | 1 | 1.4 |
Renal medulla - reduced in size | 1 |
| 1 | 0.5 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Thorax Thymus - lobe partially undescended |
5 |
|
4 |
2.8 |
5 |
4 |
2.9 |
3 |
3 |
1.8 |
4 |
4 |
2.2 |
Atrium - enlarged | 4 |
| 4 | 2.3 | 1 | 1 | 0.7 | 2 | 2 | 1.1 | 3 | 3 | 1.6 |
Ventricle - reduced in size | 0 |
| 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
Ventricle - vacuole | 0 |
| 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
Total | 30 |
| 18 | 18.5 | 31 | 14 | 18.9 | 27 | 14 | 17.0 | 30 | 15 | 20.3 |
Table 11 Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
| Dose Level (mg/kg bw/day) |
|
| ||||||||
0 (Control) | 30 | 75 |
| 150 | ||||||||
| Number of Fetuses (litters) Examined |
|
| |||||||||
154 (24) | 147 (24) | 154 (24) |
| 141 (24) | ||||||||
NF | NL | %† | NF | NL | %† | NF | NL | %† | NF | NL | %† | |
Skull Fontanelle (anterior) - large |
2 |
1 |
1.4 |
2 |
2 |
1.1 |
9 |
4 |
5.2 |
1 |
1 |
0.6 |
Nasal - incomplete ossification | 10 | 5 | 6.2 | 6 | 5 | 3.9 | 18 | 9 | 10.5 | 19 | 9 | 12.5 |
Nasal/Frontal - sutural bone | 1 | 1 | 0.7 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Frontal - incomplete ossification | 1 | 1 | 0.7 | 0 | 0 | 0.0 | 5 | 4 | 2.9 | 8 | 5 | 5.1 |
Frontal - unossified area | 1 | 1 | 0.7 | 3 | 2 | 1.9 | 5 | 3 | 3.5 | 3 | 2 | 1.6 |
Parietal - incomplete ossification | 6 | 4 | 3.7 | 3 | 2 | 2.1 | 8 | 6 | 5.0 | 20 | 10 | 14.2 |
Interparietal - incomplete ossification | 29 | 11 | 18.4 | 14 | 8 | 9.1 | 30 | 12 | 18.5 | 38 | 14 | 25.7 |
Occipital (Supra-occipital) - incomplete ossification | 17 | 12 | 11.1 | 6 | 4 | 4.1* | 23 | 10 | 14.2 | 26 | 14 | 18.4 |
Occipital (Supra-occipital) - unossified area(s) | 12 | 8 | 7.2 | 7 | 6 | 4.3 | 8 | 5 | 4.6 | 8 | 7 | 6.5 |
Squamosal - incomplete ossification | 7 | 5 | 4.4 | 8 | 4 | 5.4 | 14 | 7 | 8.1 | 30 | 14 | 20.3** |
Squamosal - unossified area(s) | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 1 | 1 | 0.5 | 1 | 1 | 1.4 |
Jugal - incomplete ossification | 5 | 3 | 3.2 | 4 | 4 | 2.6 | 4 | 4 | 2.5 | 8 | 6 | 6.7 |
Zygomatic process of maxilla - incomplete ossification | 4 | 3 | 2.6 | 7 | 6 | 4.3 | 13 | 9 | 7.6 | 18 | 11 | 12.5** |
Zygomatic process of squamosal - incomplete ossification | 1 | 1 | 0.7 | 0 | 0 | 0.0 | 2 | 2 | 1.1 | 6 | 3 | 4.2 |
Zygomatic process of squamosal - fused to jugal | 1 | 1 | 0.7 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Premaxilla - incomplete ossification | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 3 | 3 | 1.8 | 2 | 1 | 1.4 |
Hyoid - incomplete ossification | 14 | 9 | 8.6 | 17 | 11 | 11.9 | 11 | 8 | 7.0 | 16 | 9 | 10.1 |
Hyoid - not ossified | 14 | 10 | 9.1 | 5 | 5 | 3.6 | 11 | 6 | 6.4 | 14 | 7 | 8.3 |
Presphenoid - incomplete ossification | 1 | 1 | 0.7 | 0 | 0 | 0.0 | 1 | 1 | 0.7 | 2 | 2 | 1.3 |
Presphenoid - not ossified | 0 | 0 | 0.0 | 1 | 1 | 0.7 | 2 | 2 | 1.3 | 0 | 0 | 0.0 |
NOTE: a fetus may appear in more than one category
Skeletal Findings | Dose Level (mg/kg bw/day) |
|
| |||||||||
0 (Control) | 30 | 75 |
| 150 |
| |||||||
Number of Fetuses (litters) Examined |
|
| ||||||||||
154 (24) | 147 (24) | 154 (24) |
| 141 (24) |
| |||||||
NF | NL | %† | NF | NL | %† | NF | NL | %† | NF | NL | %† | |
Vertebral Column Odontoid - ossification present |
0 |
0 |
0.0 |
1 |
1 |
4.2 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
Ventral arch of vertebra 1 - ossification present | 45 | 18 | 31.7 | 49 | 18 | 36.3 | 37 | 16 | 23.9 | 34 | 11 | 22.2 |
Cervical (neural) arch - incomplete ossification | 8 | 7 | 5.1 | 0 | 0 | 0.0** | 10 | 7 | 6.3 | 16 | 9 | 10.1 |
Thoracic centrum - incomplete ossification | 12 | 9 | 8.1 | 3 | 2 | 1.8 | 10 | 5 | 6.3 | 7 | 6 | 5.0 |
Thoracic centrum - not ossified | 3 | 1 | 2.1 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 2 | 2 | 1.3 |
Thoracic centrum - bipartite ossification | 5 | 4 | 3.8 | 2 | 2 | 1.4 | 2 | 2 | 1.1 | 1 | 1 | 0.8 |
Thoracic centrum - dumb-bell-shaped | 20 | 10 | 13.9 | 19 | 11 | 16.2 | 19 | 13 | 11.7 | 21 | 14 | 18.5 |
Thoracic centrum - asymmetrically ossified | 4 | 4 | 3.0 | 1 | 1 | 0.6 | 2 | 2 | 1.1 | 3 | 3 | 2.2 |
Thoracic centrum - misaligned | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Thoracic centrum - hemicentric | 2 | 2 | 1.5 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Thoracic vertebra - absent (arch and centrum) | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Lumbar centrum - incomplete ossification | 3 | 2 | 2.1 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Lumbar centrum - bipartite ossification | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 0 | 0 | 0.0 |
Lumbar centrum - dumb-bell-shaped | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 0 | 0 | 0.0 |
Lumbar centrum - asymmetrically ossified | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 0 | 0 | 0.0 |
Sacral centrum - incomplete ossification | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 0 | 0 | 0.0 |
Sacral centrum - bipartite ossification | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.8 | 0 | 0 | 0.0 |
Sacral (neural) arch - incomplete ossification | 25 | 11 | 15.9 | 22 | 9 | 15.3 | 31 | 13 | 19.9 | 39 | 14 | 26.5 |
Sacral (neural) arch - not ossified | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.6 | 0 | 0 | 0.0 |
Caudal vertebrae - less than 4 ossified | 28 | 14 | 18.0 | 24 | 12 | 14.8 | 47 | 13 | 28.0 | 51 | 15 | 32.8 |
Number of pre-sacral vertebrae = 25/27 | 1 | 1 | 0.8 | 1 | 1 | 0.7 | 1 | 1 | 0.8 | 1 | 1 | 2.1 |
Skeletal Findings | Dose Level (mg/kg bw/day) |
| ||||||||||
0 (Control) | 30 | 75 |
| 150 | ||||||||
Number of Fetuses (litters) Examined |
| |||||||||||
154 (24) | 147 (24) | 154 (24) |
| 141 (24) | ||||||||
NF | NL | %† | NF | NL | %† | NF | NL | %† | NF | NL | %† | |
Ribs Ossification centre - associated with 7th cervical vertebra |
0 |
0 |
0.0 |
1 |
1 |
0.8 |
0 |
0 |
0.0 |
2 |
2 |
1.4 |
14th rib - extra - associated with 1st lumbar vertebra | 0 | 0 | 0.0 | 1 | 1 | 0.7 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Ossification centre - associated with 1st lumbar vertebra | 2 | 2 | 1.5 | 8 | 4 | 5.5 | 4 | 3 | 2.5 | 18 | 11 | 14.1** |
One or more ribs - wavy | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 2 | 1 | 1.0 |
One or more ribs - thickened | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 2 | 1 | 1.0 |
Rib - short | 3 | 1 | 1.8 | 1 | 1 | 0.7 | 2 | 2 | 1.5 | 0 | 0 | 0.0 |
Rib - fused | 2 | 2 | 1.5 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Rib - incomplete ossification | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.5 |
Rib - interrupted ossification | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Rib - not ossified | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Rib - absent | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Rib - no articulation point | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
Rib - bifurcated | 1 | 1 | 0.8 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 |
Costal cartilage - misaligned | 3 | 2 | 2.0 | 2 | 2 | 1.2 | 3 | 3 | 1.6 | 1 | 1 | 0.7 |
Costal cartilage - not fused to sternebra | 14 | 9 | 8.7 | 11 | 9 | 7.5 | 12 | 7 | 7.9 | 14 | 7 | 11.1 |
Sternebrae Sternebra - incomplete ossification |
4 |
2 |
2.7 |
0 |
0 |
0.0 |
11 |
8 |
6.2* |
4 |
3 |
2.7 |
Sternebra - not ossified | 3 | 1 | 2.1 | 0 | 0 | 0.0 | 1 | 1 | 0.7 | 0 | 0 | 0.0 |
Sternebra - bipartite ossification | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.7 |
Sternebra - misaligned | 2 | 2 | 1.3 | 4 | 4 | 2.4 | 6 | 5 | 3.3 | 8 | 6 | 4.9 |
Sternum - split | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.7 | 0 | 0 | 0.0 |
Skeletal Findings | Dose Level (mg/kg bw/day) |
|
| |||||||||
0 (Control) | 30 | 75 |
| 150 |
| |||||||
Number of Fetuses (litters) Examined |
|
| ||||||||||
154 (24) | 147 (24) | 154 (24) |
141 (24)
| |||||||||
NF | NL | %† | NF | NL | %† | NF | NL | %† | NF | NL | %† | |
Sternebrae (continued) Xiphoid cartilage - split |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Xiphoid cartilage - partially split | 14 | 11 | 9.9 | 9 | 8 | 5.7 | 8 | 8 | 5.1 | 14 | 11 | 10.1 |
Pectoral Girdle Scapula - misshapen |
1 |
1 |
0.6 |
5 |
5 |
6.6 |
2 |
2 |
1.0 |
4 |
2 |
2.6 |
Pelvic Girdle Ischium - not ossified |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Ischium - incomplete ossification | 1 | 1 | 0.7 | 1 | 1 | 0.7 | 4 | 2 | 2.6 | 2 | 2 | 1.2 |
Pubis - not ossified | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 3 | 3 | 1.8 | 1 | 1 | 0.7 |
Pubis - incomplete ossification | 8 | 3 | 5.4 | 8 | 5 | 5.8 | 11 | 8 | 7.0 | 13 | 8 | 9.3 |
Forelimbs Metacarpal - not ossified |
51 |
20 |
31.8 |
41 |
15 |
27.0 |
65 |
19 |
42.2 |
57 |
17 |
37.7 |
Metacarpal - incomplete ossification | 0 | 0 | 0.0 | 1 | 1 | 0.7 | 4 | 3 | 2.9 | 3 | 3 | 1.9 |
Forepaw phalanges - 1 or more - ossified | 14 | 10 | 10.5 | 13 | 9 | 12.8 | 10 | 5 | 6.5 | 10 | 5 | 7.0 |
Humerus - incomplete ossification | 2 | 2 | 1.3 | 1 | 1 | 0.7 | 2 | 2 | 1.7 | 7 | 5 | 5.6 |
Humerus - hole | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 1 | 1 | 0.6 | 0 | 0 | 0.0 |
Hindlimbs Metatarsal - 1st - ossified |
0 |
0 |
0.0 |
1 |
1 |
4.2 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Metatarsal - not ossified | 0 | 0 | 0.0 | 0 | 0 | 0.0 | 1 | 1 | 0.7 | 0 | 0 | 0.0 |
Metatarsal - incomplete ossification | 3 | 2 | 2.2 | 0 | 0 | 0.0 | 5 | 4 | 2.9 | 2 | 2 | 1.3 |
Femur - incomplete ossification | 12 | 7 | 7.7 | 2 | 2 | 1.4 | 9 | 6 | 5.9 | 7 | 6 | 4.6 |
Total | 132 | 24 | 86.6 | 118 | 24 | 81.4 | 130 | 24 | 82.7 | 126 | 24 | 90.2 |
Applicant's summary and conclusion
- Conclusions:
- The oral administration of the test substance to pregnant rats by oral gavage during gestation at dose levels of 30, 75 and 150 mg/kg bw/day, resulted in treatment-related macroscopic abnormalities detected in females treated with 150 and 75 mg/kg bw/day. The macroscopic findings detected were considered to be the result of localized irritation from the test item formulations and are not considered to reflect systemic toxicity. The ‘No Observed Adverse Effect Level’ (NOAEL) for the pregnant female was therefore considered to be 150 mg/kg bw/day.
No treatment-related changes were detected in the offspring parameters measured or on embryofetal development. The ‘No Observed Effect Level’ (NOEL) for developmental toxicity was therefore considered to be 150 mg/kg bw/day.
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