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Registration Dossier
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EC number: 257-077-0 | CAS number: 51240-95-0
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Experimental Starting Date: 04 August 2015 Experimental Completion Date: 01 December 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1,1,3,3-tetramethylbutyl peroxyneodecanoate
- EC Number:
- 257-077-0
- EC Name:
- 1,1,3,3-tetramethylbutyl peroxyneodecanoate
- Cas Number:
- 51240-95-0
- Molecular formula:
- C18H36O3
- IUPAC Name:
- 2,4,4-trimethylpentan-2-yl 2,2,3,5-tetramethylhexaneperoxoate; 2,4,4-trimethylpentan-2-yl 2,2-diethylhexaneperoxoate; 2,4,4-trimethylpentan-2-yl 2,2-dimethyloctaneperoxoate; 2,4,4-trimethylpentan-2-yl 2,4-dimethyl-2-(propan-2-yl)pentaneperoxoate; 2,4,4-trimethylpentan-2-yl 2-ethyl-2,5-dimethylhexaneperoxoate
- Test material form:
- liquid
- Remarks:
- clear, colorless
Constituent 1
- Specific details on test material used for the study:
- Information as provided by the Sponsor.
Identification : 1,1,3,3-tetramethylbutyl peroxyneodecanoate (CAS# 51240-95-0)
Physical State/Appearance:Clear colorless liquid
Chemical Name:1,1,3,3-Tetramethylbutyl peroxyneodecanoate
Chemical Formula:C18H36O3
Purity:69.2%
Batch Number:1503447025
Label : TRIGONOX 423-C70 1,1,3,3-tetramethylbutyl peroxyneodecanoate 1kg Below -15°C Batch/lot: 1503447025 Expiry Date 14 June 2015
Date Received : 17 June 2015
Storage Conditions : Stored at approximately -20 °C, used/formulated under ambient conditions
Expiry Date : 15 April 2016
No correction for purity was made.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Age at study initiation: Females prior to Day 3 of gestation
- Weight at study initiation: 187 - 285g
- Fasting period before study: No
- Housing: Individually in solid-floor polypropylene cages with stainless steel mesh lids furnished with softwood flakes (Datesand Ltd., Cheshire, UK).
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20%
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From 04 August to 01 December 2015
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Oral gavage
- Concentration in vehicle: 0, 7.5, 43.8, 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken of each test item formulation and were analyzed for concentration of 1,1,3,3-tetramethylbutyl peroxyneodecanoate (CAS# 51240-95-0) at Harlan Laboratories Ltd., Shardlow.
Stock solutions of the test item in acetonitrile were prepared for external standard calibration at a concetration of 1 mg/mL. Aliqupots of stock standard solutions were used to prepare working standard solutions in aceytonitrile with concentration of 0.1 mg/mL. On each occasion standard solutions derived from two standard stock solutions were used for calculation.
The fomulations received were extracted with acetonitrile. An aliquot of the test item formulation was accurately weighed into a volumetric flask and brought to volume with acetonitrile, ultra sonicated and centrifuged for 10 minutes. Where necessary sample solutions were further diluted with acetonitrile to achieve working concentrations. The test item concentration in the test samples was determined by gas chromatography (GC) using the external standard technique.
The accuracy and linearity determinations were determined under study number 41501125.
The formulations were found to comprise test item in the range of 98% to 103% and, thus, the required content limit of ±10% with reference to the nominal content was met. The results obtained during study number 41501125 indicate the accurate use of the test item in Arachis Oil BP as vehicle during this stiudy. The formulations were found to be homogeneoulsy prepared and sufficient formulation stability under storage conditions was proven.
The detection system was found to have acceptable linearity. The analytical system had acceptable recoveries of test item in vehicle. The method of analysis was validated and proven to be suitable for use. - Details on mating procedure:
- The experimental animals were obtained time-mated from the supplier.
- Duration of treatment / exposure:
- The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, between Days 5 and 19 of gestation inclusive at dose levels 30, 175 or 1000 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Arachis oil BP) to serve as a control.
- Frequency of treatment:
- Daily
- Duration of test:
- Experimental Starting Date: 04 August 2015
Experimental Completion Date: 01 December 2015
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Control - 0 mg/mL
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- Remarks:
- Low - 7.5 mg/mL
- Dose / conc.:
- 175 mg/kg bw/day (actual dose received)
- Remarks:
- Intermediate - 43.8 mg/mL
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- High - 250 mg/mL
- No. of animals per sex per dose:
- 24 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: 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:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Yes
- Cage side observations checked in Table 2 and Appendix 1 were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Yes
BODY WEIGHT: Yes
- Time schedule for examinations: Yes
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION: Yes
- Time schedule for examinations: Visual inspection
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Ovaries and uteri
i) Number of corpora lutea
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 - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Other:
- Dead fetus
All implantations and viable fetuses were numbered according to their intrauterine position. - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [ half per litter ]
- Skeletal examinations: Yes: [ half per litter ]
- Head examinations: Yes: [all per litter] - Statistics:
- Female body weight change, food consumption and gravid uterus weight: Shapiro Wilk normality test and Bartlett’s test for homogeneity of variance and one way analysis of variance, followed by Dunnett’s multiple comparison test or, if unequal variances were observed, on alternative multiple comparison test.
Most caesarean necropsy parameters and fetal parameters: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.
Fetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis non-parametric analysis of variance and Mann-Whitney ‘U’ test.
Probability values (p) are presented as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 (not significant)
Computerized sysyems used:
R Environment for Statistical Computing - Historical control data:
- Historical control data used for comparison purposes for fetal examination findings and uterus weights.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical observations for any of the animals throughout the study.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- There were no unscheduled deaths during the study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At all dose levels, females showed a dose-related reduction in group mean body weight gains over Days 5 to 6 of gestation with most animals from the 1000 mg/kg bw/day showing actual body weight losses. Subsequent recovery was evident for females receiving 30 or 175 mg/kg bw/day with periodic body weight gains for these animals remaining comparable with controls from Day 6 of gestation. Females treated with 1000 mg/kg bw/day also showed improvement in body weight performance following the initial affect such that body weight gains over Days 7 to 14 of gestation were comparable with controls; however, further reduction in body weight gain was observed over Days 14 to 17 of gestation resulting in lower cumulative body weight gains for these animals throughout the treatment period. The overall body weight gain for these females was approximately 21% lower than controls with body weight gain adjusted for gravid uterus contribution also being markedly lower than controls. The effect on body weight development for the 1000 mg/kg bw/day females was considered to be of toxicological significance.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- There was marked reduction in food consumption at the start of dosing for females given 1000 mg/kg bw/day. Gradual improvement was apparent, however, dietary intake for these animals remained statistically significantly lower than controls up to Day 17 of gestation. Taken together with the effect on body weight development at this dose level, this observation was considered to be of toxicological significance.
There was no effect of treatment on food intake at 30 or 175 mg/kg bw/day. - Food efficiency:
- not specified
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Group mean gravid uterus weight for females treated with 1000 mg/kg bw/day was also slightly lower than controls; however, it is worth noting that whilst 4/24 control females showed gravid uterus weights slightly above the historical data ranges the corresponding values for most females treated with 1000 mg/kg bw/day were within these ranges. Group mean body weight gain when adjusted for contribution from gravid uterus for these females was also markedly lower than controls and with most individual values below the historical control data ranges, this finding was deemed to be of toxicological relevance.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- For all dose groups, there were no statistically significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external or visceral abnormalities. At 1000 mg/kg bw/day, a number of skeletal anomalies achieved statistical significance. These included incomplete ossification of occipital (supra-occipital) region, thoracic centrum and sternbrae, no ossification of metacarpal, and caudal vertebrae - less than 4 ossified. These observations are minor variants and although group mean values were outside the historical background data ranges, they were deemed likely due to a slightly slower fetal growth rate resulting from maternal toxicity rather than an indication of a direct effect of the test item on fetal development. Any other skeletal findings at all dose levels were considered to be within normal biological variation.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There was considered to be no detrimental 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 post-implantation losses at 30, 175 or 1000 mg/kg bw/day.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- The number of late deaths for the 1000 mg/kg bw/day dose group was slightly higher than controls but the intergroup difference did not achieve statistical significance and with one litter (Female 86) from this dose group showing four late deaths this observation was deemed unlikely to be of any toxicological significance.
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- All animals (24) in all dose groups, including control, became pregnant.
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- The oral administration of 1,1,3,3-tetramethylbutyl peroxyneodecanoate (CAS# 51240-95-0) to pregnant rats by gavage during gestation Days 5 to 19, at dose levels of 30, 175 or 1000 mg/kg bw/day resulted in an adverse effect on body weight gain and food consumption at the high dose level. Although some improvement was evident, cumulative body weight gains for females treated with 1000 mg/kg bw/day remained lower than controls throughout the dosing period with body weight gain adjusted for the contribution of gravid uterus also being markedly lower than controls. Taking into consideration the overall results, the No Observed Adverse Effect Level’ (NOAEL) for the pregnant female was considered to be 175 mg/kg bw/day within the confines of this type of study.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- <= 175 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
Maternal abnormalities
- Abnormalities:
- not specified
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, group mean fetal weights were marginally lower than controls which resulted in slightly lower litter weight for this dose group. These findings were deemed likely due to maternal toxicity rather than a direct effect of treatment on fetal growth and development
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): At 1000 mg/kg bw/day, group mean fetal weights were marginally but statistically significantly lower than controls (p<0.001 for males, p<0.01 for females and p<0.001 for combined) resulting in statistically significantly lower litter weight (p<0.01). - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- There was considered to be no detrimental effect of maternal treatment on litter data as assessed by live litter size.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There was considered to be no detrimental effect of maternal treatment on litter data as assessed by sex ratio.
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, group mean fetal weights were marginally but statistically significantly lower than controls (p<0.001 for males, p<0.01 for females and p<0.001 for combined) resulting in statistically significantly lower litter weight (p<0.01).
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, the number of small fetuses was slightly higher than controls, however, the mean percentage affected remained within the historical control data ranges and as such this finding was considered to be of no toxicological significance. Of other external findings, neither the type, incidence nor distribution indicated any obvious effect of maternal treatment on fetal development at any dose level
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Skeletal Examination of fetuses/litters revealed a number of statistically significant anomalies in relation to controls (p<0.01). At 1000 mg/kg bw/day, these included incomplete ossification of occipital (supra-occipital) region (p<0.01), thoracic centrum (p<0.01) and sternbrae (p<0.05), no ossification of metacarpal (p<0.05), and caudal vertebrae - less than 4 ossified (p<0.001); group mean values for these anomalies were above the historical control data ranges and as such these intergroup differences were deemed to be treatment-related. These resulted in a higher percentage of the fetuses affected for the 1000 mg/kg bw/day dose group (p<0.01).
Fetuses/litters from 175 mg/kg bw/day dose group also showed statistically significantly higher incomplete ossification of thoracic centrum (p<0.05) although group mean value remained within the background data ranges and as such this observation was considered to be within normal biological variation.
Additionally, the skeletal anomaly of thoracic centrum – dumb bell shaped was statistically significantly higher for fetuses/litters from the 175 and 1000 mg/kg bw/day dose group when compared with controls (p<0.01); a dose-relationship was apparent but group mean values were within the background data ranges and as such these observations were considered to be incidental. Other statistically significant intergroup differences included interparietal (unossified areas) for the 30 and 175 mg/kg bw/day dose groups (p<0.05), incomplete ossification of hyoid and ossification of ventral arch for the 1000 mg/kg bw/day dose group (p<0.01) but corresponding mean values were lower than controls and these findings were considered to be incidental. Any other intergroup differences did not achieve statistical significance and group mean values were usually within the background data ranges. - Visceral malformations:
- no effects observed
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One fetus from a control litter appeared to be a conjoined twin showing a number of malformations including additional tail and forelimb, malpositioned and bulging eyes, open eye macroglossia, malpositioned pinnae, encephalocoele and full body oedema; these findings were deemed incidental.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- <= 175 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- skeletal malformations
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- <= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- skeletal malformations
Fetal abnormalities
open allclose all
- Abnormalities:
- not specified
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: skull
- skeletal: forelimb
- skeletal: sternum
- skeletal: vertebra
- Description (incidence and severity):
- Skeletal Examination of fetuses/litters revealed a number of statistically significant anomalies in relation to controls (p<0.01). At 1000 mg/kg bw/day, these included incomplete ossification of occipital (supra-occipital) region (p<0.01), thoracic centrum (p<0.01) and sternbrae (p<0.05), no ossification of metacarpal (p<0.05), and caudal vertebrae - less than 4 ossified (p<0.001); group mean values for these anomalies were above the historical control data ranges and as such these intergroup differences were deemed to be treatment-related. These resulted in a higher percentage of the fetuses affected for the 1000 mg/kg bw/day dose group (p<0.01).
Additionally, the skeletal anomaly of thoracic centrum – dumb bell shaped was statistically significantly higher for fetuses/litters from the 175 and 1000 mg/kg bw/day dose group when compared with controls (p<0.01); a dose-relationship was apparent but group mean values were within the background data ranges and as such these observations were considered to be incidental. Other statistically significant intergroup differences included interparietal (unossified areas) for the 30 and 175 mg/kg bw/day dose groups (p<0.05), incomplete ossification of hyoid and ossification of ventral arch for the 1000 mg/kg bw/day dose group (p<0.01) but corresponding mean values were lower than controls and these findings were considered to be incidental. Any other intergroup differences did not achieve statistical significance and group mean values were usually within the background data ranges.
Overall developmental toxicity
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 175 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table1 Summary of Female Performance
Category |
Number of Females at Dose Level (mg/kg bw/day) |
|||
0 (Control) |
30 |
175 |
1000 |
|
Initial Group Size |
24 |
24 |
24 |
24 |
Pregnant |
24 |
24 |
24 |
24 |
Table2 Summary Incidence of Daily Clinical Observations
Dose Level (mg/kg bw/day) |
Number of Animals |
Clinical Observations |
0 (Control) |
24 |
No Abnormalities Detected |
30 |
24 |
No Abnormalities Detected |
175 |
24 |
No Abnormalities Detected |
1000 |
24 |
No Abnormalities Detected |
Table 3 Group Mean Body Weight Values
Dose Level (mg/kg bw/day) |
|
Body Weight (g) at Day of Gestation |
||||||||
3 |
5 |
6 |
7 |
8 |
11 |
14 |
17 |
20 |
||
0 (Control) |
mean |
232.8 |
243.8 |
248.9 |
253.8 |
257.3 |
275.7 |
295.1 |
326.0 |
367.4 |
sd |
22.0 |
24.3 |
24.6 |
24.8 |
25.7 |
26.2 |
28.8 |
32.7 |
36.0 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
30 |
mean |
235.2 |
247.9 |
250.8 |
255.9 |
261.0 |
279.3 |
299.0 |
328.3 |
373.0 |
sd |
19.2 |
22.3 |
20.7 |
21.4 |
20.7 |
21.5 |
22.8 |
26.6 |
27.7 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
175 |
mean |
235.4 |
249.9 |
251.5 |
257.5 |
263.5 |
281.5 |
301.7 |
331.5 |
375.5 |
sd |
16.9 |
17.6 |
18.8 |
17.4 |
17.4 |
19.6 |
20.8 |
23.3 |
24.5 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
1000 |
mean |
234.0 |
248.8 |
243.7 |
245.3 |
252.8 |
270.4 |
287.9 |
305.8* |
346.4* |
sd |
21.0 |
20.9 |
20.0 |
18.9 |
20.1 |
23.5 |
24.1 |
25.9 |
30.5 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
Table 4 Group Mean Body Weight Change Values
Dose Level (mg/kg bw/day) |
|
Body Weight Change (g) during Days of Gestation |
|||||||||||||
3 to 5 |
5 to 6 |
6 to 7 |
7 to 8 |
8 to 11 |
11 to 14 |
14 to 17 |
17 to 20 |
||||||||
0 (Control) |
mean |
11.0 |
5.1 |
5.0 |
3.5 |
18.4 |
19.4 |
30.9 |
41.4 |
||||||
sd |
7.6 |
5.3 |
2.7 |
3.8 |
4.2 |
3.7 |
6.1 |
6.0 |
|||||||
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|||||||
30 |
mean |
12.7 |
2.9 |
5.1 |
5.1 |
18.3 |
19.7 |
29.3 |
44.8 |
||||||
sd |
6.6 |
5.7 |
4.2 |
4.8 |
3.0 |
3.5 |
6.8 |
5.8 |
|||||||
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|||||||
175 |
mean |
14.5 |
1.6 |
6.0 |
6.0 |
18.0 |
20.1 |
29.8 |
44.0 |
||||||
sd |
5.2 |
6.8 |
5.6 |
5.1 |
5.7 |
3.6 |
4.1 |
4.9 |
|||||||
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|||||||
1000 |
mean |
14.8 |
-5.1*** |
1.6* |
7.5 |
17.6 |
17.5 |
17.9*** |
40.6 |
||||||
sd |
5.2 |
4.9 |
4.7 |
5.9 |
7.6 |
6.0 |
6.4 |
11.3 |
|||||||
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|||||||
Dose Level (mg/kg bw/day) |
|
Cumulative Body Weight Change (g) from Day 5 of Gestation |
||||||
6 |
7 |
8 |
11 |
14 |
17 |
20 |
||
0 (Control) |
mean |
5.1 |
10.0 |
13.5 |
31.9 |
51.3 |
82.2 |
123.6 |
sd |
5.3 |
6.3 |
7.4 |
7.9 |
9.5 |
13.2 |
16.5 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
30 |
mean |
2.9 |
8.0 |
13.1 |
31.4 |
51.1 |
80.4 |
125.1 |
sd |
5.7 |
6.3 |
6.1 |
6.4 |
7.8 |
11.6 |
14.2 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
175 |
mean |
1.6 |
7.6 |
13.6 |
31.6 |
51.8 |
81.6 |
125.6 |
sd |
6.8 |
5.1 |
5.6 |
7.7 |
9.3 |
11.0 |
13.5 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
1000 |
mean |
-5.1*** |
-3.5*** |
4.0*** |
21.6*** |
39.1*** |
57.0*** |
97.6*** |
sd |
4.9 |
6.6 |
7.1 |
10.7 |
12.3 |
15.9 |
20.6 |
|
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 |
Body Weight Change (g) during Days of Gestation |
Gravid Uterus Weight |
Adjusted |
Adjusted |
|
5 |
20 |
5-20 |
|||||
0 (Control) |
mean |
243.8 |
367.4 |
123.6 |
83.113 |
284.3 |
40.5 |
sd |
24.3 |
36.0 |
16.5 |
11.341 |
29.7 |
12.5 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
30 |
mean |
247.9 |
373.0 |
125.1 |
84.197 |
288.8 |
40.9 |
sd |
22.3 |
27.7 |
14.2 |
9.787 |
27.1 |
12.4 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
175 |
mean |
249.9 |
375.5 |
125.6 |
83.782 |
291.8 |
41.8 |
sd |
17.6 |
24.5 |
13.5 |
6.764 |
22.8 |
12.3 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
1000 |
mean |
248.8 |
346.4 |
97.6 |
73.972** |
272.4 |
23.7*** |
sd |
20.9 |
30.5 |
20.6 |
11.928 |
21.6 |
13.9 |
|
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 |
21.3 |
21.7 |
23.5 |
24.3 |
23.5 |
25.9 |
sd |
2.8 |
2.8 |
2.8 |
2.5 |
3.0 |
3.2 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
30 |
mean |
22.1 |
22.1 |
24.1 |
24.6 |
23.1 |
26.4 |
sd |
3.7 |
1.8 |
2.0 |
2.3 |
2.5 |
2.8 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
175 |
mean |
22.1 |
21.8 |
23.4 |
24.7 |
23.6 |
26.9 |
sd |
2.9 |
2.6 |
3.5 |
2.8 |
2.9 |
3.2 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
1000 |
mean |
22.5 |
13.1*** |
19.8*** |
21.7** |
18.8*** |
25.1 |
sd |
2.6 |
2.7 |
3.5 |
3.2 |
3.0 |
4.5 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
Table 7 Summary Incidence of Necropsy Findings
|
Dose Level (mg/kg bw/day) |
|||
0 (Control) |
30 |
175 |
1000 |
|
TERMINAL DEATH |
|
|
|
|
Number of animals examined |
24 |
24 |
24 |
24 |
Uterus: filled with yellow color fluid |
0 |
0 |
0 |
1 |
No abnormalities detected |
24 |
24 |
24 |
23 |
Table 8 Group Mean Litter DataValues
Dose Level (mg/kg bw/day) |
|
Number of Corpora Lutea |
Number of Implants |
Number of Embryonic/Fetal Deaths |
Implantation Loss |
Number of Live Implants |
% |
Mean Male Fetal Weight (g) |
Mean Female Fetal Weight (g) |
Mean Fetal Weight (g) |
MeanPlacentalWeight |
Litter Weight (g) |
TotalPlacentalWeight |
|||||
Early |
Late |
Total |
Pre |
Post |
Male |
Female |
Total |
|||||||||||
0 (Control) |
mean |
13.8 |
13.5 |
0.0 |
0.1 |
0.2 |
2.1 |
1.1 |
6.9 |
6.5 |
13.4 |
52.0 |
4.062 |
3.881 |
3.982 |
0.581 |
53.128 |
7.717 |
sd |
2.1 |
2.0 |
0.2 |
0.3 |
0.4 |
3.8 |
2.5 |
2.2 |
2.4 |
1.9 |
15.0 |
0.224 |
0.212 |
0.208 |
0.064 |
7.286 |
1.128 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
30 |
mean |
14.1 |
13.8 |
0.3 |
0.0 |
0.3 |
2.8 |
2.4 |
6.8 |
6.6 |
13.4 |
50.7 |
4.187 |
4.008 |
4.095 |
0.582 |
54.687 |
7.798 |
sd |
1.4 |
1.8 |
0.6 |
0.2 |
0.6 |
6.7 |
4.1 |
2.1 |
2.1 |
1.8 |
14.7 |
0.316 |
0.344 |
0.314 |
0.071 |
6.547 |
1.341 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
175 |
mean |
14.0 |
13.7 |
0.2 |
0.1 |
0.3 |
1.7 |
2.1 |
6.6 |
6.8 |
13.5 |
49.7 |
4.113 |
3.899 |
4.014 |
0.554 |
53.839 |
7.415 |
sd |
1.5 |
1.3 |
0.5 |
0.4 |
0.6 |
3.9 |
4.2 |
1.6 |
2.1 |
1.1 |
13.7 |
0.212 |
0.222 |
0.196 |
0.069 |
5.135 |
0.964 |
|
n |
23 |
23 |
24 |
24 |
24 |
23 |
23 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
1000 |
mean |
13.6 |
13.3 |
0.1 |
0.4 |
0.5 |
2.1 |
4.1 |
7.0 |
5.7 |
12.8 |
55.5 |
3.744*** |
3.602** |
3.683*** |
0.544 |
46.796** |
6.887* |
sd |
2.2 |
2.1 |
0.3 |
0.9 |
0.9 |
4.2 |
7.1 |
2.1 |
2.1 |
2.2 |
13.7 |
0.289 |
0.321 |
0.294 |
0.065 |
8.099 |
1.207 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
Table 9 Summary Incidence of Fetal External Findings
External Findings |
Dose level (mg/kg bw/day) |
||||||||||||||||||||||||
0 (Control) |
30 |
175 |
1000 |
||||||||||||||||||||||
Number of fetuses (litters) examined |
|||||||||||||||||||||||||
321 (24) |
322 (24) |
323 (24) |
306 (24) |
||||||||||||||||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
||||||||||||||
Total Number Affected |
3 |
3 |
1.1 |
4 |
4 |
1.2 |
3 |
2 |
0.9 |
6 |
6 |
1.9 |
|||||||||||||
Additional Tail |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Additional Forelimb |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Eyes malpositioned |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Full Body Odema |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Open Eye Macroglossia |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Encephalocoele |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Malpositioned Pinnae |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Bulging Eyes |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Small |
1 |
1 |
0.3 |
1 |
1 |
0.3 |
2 |
1 |
0.6 |
5 |
5 |
1.6 |
|||||||||||||
Hematoma - Left Hind Limb |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Hematoma - Above Tail |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Thread Like Tail |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Hematoma - Right Side of Head |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
|||||||||||||
Hematoma - Back |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
1 |
1 |
0.3 |
|||||||||||||
Hematoma - Top of Head |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
|||||||||||||
Pale |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
|||||||||||||
Table 10 Summary Incidence of Fetal Visceral Findings
Visceral Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
167 (24) |
167 (24) |
168 (24) |
158 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
External/General |
|
|
|
|
|
|
|
|
|
|
|
|
Hemorrhage |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Head |
|
|
|
|
|
|
|
|
|
|
|
|
Tongue - short |
0 |
0 |
0.0 |
2 |
2 |
1.1 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Rugae - non-uniform patterning |
15 |
13 |
8.9 |
15 |
9 |
10.0 |
9 |
7 |
5.2 |
6 |
6 |
3.8 |
Micropthalmia |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Anopthalmia |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Brain - lateral ventricle - enlarged |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Brain - third ventricle - enlarged |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Abdomen |
|
|
|
|
|
|
|
|
|
|
|
|
Liver - additional lobe between right and left median |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
2 |
2 |
1.0 |
0 |
0 |
0.0 |
Liver - papillary process - reduced in size |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Spleen - reduced in size |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Umbilical artery - left-sided |
1 |
1 |
0.7 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
2 |
2 |
1.2 |
Testis - partially undescended |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
Ureter - kinked |
34 |
14 |
20.7 |
29 |
18 |
18.2 |
15 |
8 |
9.4 |
19 |
9 |
11.5 |
Ureter - dilated |
30 |
12 |
18.4 |
20 |
13 |
12.9 |
15 |
7 |
9.2 |
12 |
8 |
7.2 |
Renal pelvis cavitation - increased |
13 |
8 |
7.9 |
20 |
10 |
12.1 |
8 |
6 |
5.0 |
15 |
6 |
9.2 |
Renal papilla - absent |
1 |
1 |
0.6 |
3 |
3 |
1.8 |
2 |
2 |
1.1 |
1 |
1 |
0.6 |
l
Table10(continued) Summary Incidence of Fetal Visceral Findings
Visceral Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
167 (24) |
167 (24) |
168 (24) |
158 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Thorax |
|
|
|
|
|
|
|
|
|
|
|
|
Thymus - lobe partially undescended |
4 |
4 |
2.3 |
2 |
2 |
1.1 |
10 |
8 |
6.1 |
11 |
9 |
7.1 |
Lungs - irregular surface throughout |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Right subclavian artery - retro-oesophageal |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Atrium - enlarged |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Ventricular septal defect |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Total |
54 |
22 |
32.6 |
50 |
22 |
31.0 |
37 |
19 |
22.3 |
41 |
17 |
25.5 |
Table 11 Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
154 (24) |
155 (24) |
155 (24) |
148 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Skull |
|
|
|
|
|
|
|
|
|
|
|
|
Nasal - incomplete ossification |
14 |
8 |
9.2 |
7 |
6 |
4.6 |
12 |
6 |
7.6 |
21 |
11 |
13.8 |
Frontal - incomplete ossification |
3 |
3 |
1.7 |
3 |
3 |
2.0 |
1 |
1 |
0.7 |
3 |
3 |
1.8 |
Frontal - unossified area |
4 |
2 |
2.9 |
0 |
0 |
0.0 |
3 |
3 |
1.9 |
0 |
0 |
0.0 |
Frontal - misshapen |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Intraorbital process of frontal - incomplete ossification |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Parietal - incomplete ossification |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Parietal - unossified area(s) |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
Parietal - absent |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Interparietal - incomplete ossification |
7 |
6 |
4.2 |
18 |
9 |
11.7 |
12 |
8 |
7.9 |
2 |
2 |
1.6 |
Interparietal - unossified area(s) |
5 |
5 |
3.6 |
0 |
0 |
0.0* |
0 |
0 |
0.0* |
1 |
1 |
0.5 |
Interparietal - absent |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Occipital (Supra-occipital) - incomplete ossification |
7 |
5 |
4.1 |
17 |
10 |
10.5 |
6 |
6 |
4.1 |
35 |
14 |
23.3** |
Occipital (Supra-occipital) - unossified area(s) |
7 |
5 |
4.3 |
15 |
10 |
9.7 |
6 |
5 |
3.6 |
13 |
10 |
8.1 |
Occipital - absent |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Squamosal - incomplete ossification |
6 |
5 |
3.5 |
14 |
7 |
8.6 |
7 |
7 |
4.5 |
8 |
5 |
5.2 |
a
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
154 (24) |
155 (24) |
155 (24) |
148 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Skull (continued) |
|
|
|
|
|
|
|
|
|
|
|
|
Squamosal - unossified area(s) |
7 |
5 |
5.6 |
3 |
3 |
2.0 |
1 |
1 |
0.7 |
5 |
5 |
3.5 |
Squamosal - misshapen |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Jugal - incomplete ossification |
1 |
1 |
0.5 |
4 |
3 |
2.6 |
2 |
2 |
1.4 |
0 |
0 |
0.0 |
Zygomatic process of maxilla - incomplete ossification |
6 |
4 |
3.8 |
6 |
4 |
3.9 |
4 |
2 |
2.6 |
0 |
0 |
0.0 |
Zygomatic process of squamosal - incomplete ossification |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Premaxilla - incomplete ossification |
2 |
2 |
1.1 |
2 |
1 |
1.4 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Hyoid - incomplete ossification |
18 |
12 |
11.1 |
14 |
8 |
9.3 |
6 |
5 |
3.8 |
1 |
1 |
0.6** |
Hyoid - not ossified |
7 |
6 |
4.6 |
3 |
3 |
2.1 |
4 |
4 |
2.5 |
0 |
0 |
0.0 |
Presphenoid - incomplete ossification |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
2 |
2 |
1.4 |
0 |
0 |
0.0 |
Presphenoid - misshapen |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Basisphenoid - incomplete ossification |
1 |
1 |
0.6 |
3 |
3 |
1.8 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
Basisphenoid - misshapen |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
a
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
154 (24) |
155 (24) |
155 (24) |
148 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Vertebral Column |
|
|
|
|
|
|
|
|
|
|
|
|
Odontoid - ossification present |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Ventral arch of vertebra 1 - ossification present |
27 |
17 |
18.0 |
44 |
12 |
28.9 |
34 |
16 |
22.0 |
11 |
5 |
6.7** |
Cervical (neural) arch - incomplete ossification |
5 |
4 |
2.9 |
7 |
5 |
4.4 |
1 |
1 |
0.7 |
2 |
2 |
1.3 |
Thoracic centrum - incomplete ossification |
0 |
0 |
0.0 |
2 |
2 |
1.2 |
4 |
4 |
2.6* |
12 |
7 |
7.8** |
Thoracic centrum - not ossified |
1 |
1 |
0.6 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
Thoracic centrum - bipartite ossification |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
2 |
2 |
1.4 |
2 |
1 |
1.0 |
Thoracic centrum - dumb-bell-shaped |
5 |
4 |
2.9 |
11 |
10 |
6.7 |
17 |
13 |
11.1** |
22 |
12 |
14.3** |
Thoracic centrum - asymmetrically ossified |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
3 |
3 |
1.9 |
4 |
4 |
2.5 |
Lumbar centrum - absent |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Lumbar centrum - bipartite ossification |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Lumbar centrum - dumb-bell-shaped |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
Lumbar vertebra - absent (arches and centrum) |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Sacral (neural) arch - incomplete ossification |
6 |
6 |
3.7 |
12 |
7 |
7.5 |
7 |
5 |
4.5 |
4 |
3 |
2.4 |
Sacral (neural) arch - not ossified |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Sacral vertebrae - absent (arches and centrum) |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
a
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
154 (24) |
155 (24) |
155 (24) |
148 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Vertebral Column (continued) |
|
|
|
|
|
|
|
|
|
|
|
|
Number of pre-sacral vertebrae = 25/27 |
0 |
0 |
0.0 |
2 |
2 |
1.3 |
0 |
0 |
0.0 |
2 |
2 |
1.2 |
Caudal vertebrae - less than 4 ossified |
25 |
12 |
15.8 |
31 |
14 |
19.1 |
34 |
17 |
21.8 |
79 |
21 |
51.4*** |
Caudal vertebrae - all absent |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Conjoined twin fetuses |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Ribs |
|
|
|
|
|
|
|
|
|
|
|
|
Ossification centre - associated with 7th cervical vertebra |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
Ossification centre - associated with 1st lumbar vertebra |
4 |
1 |
2.4 |
3 |
2 |
1.8 |
1 |
1 |
0.8 |
7 |
5 |
4.7 |
One or more ribs - thickened |
1 |
1 |
1.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Rib - short |
6 |
2 |
3.8 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
2 |
2 |
1.3 |
Rib - rudimentary |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Costal cartilage - misaligned |
4 |
4 |
2.9 |
3 |
3 |
1.7 |
2 |
2 |
1.3 |
4 |
4 |
3.4 |
Costal cartilage - not fused to sternebra |
18 |
10 |
12.0 |
21 |
12 |
13.1 |
16 |
10 |
10.2 |
33 |
16 |
23.6 |
a
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
154 (24) |
155 (24) |
155 (24) |
148 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Sternebrae |
|
|
|
|
|
|
|
|
|
|
|
|
Sternebra - incomplete ossification |
2 |
2 |
1.2 |
1 |
1 |
0.6 |
5 |
5 |
3.1 |
8 |
8 |
5.3* |
Sternebra - not ossified |
1 |
1 |
0.6 |
3 |
1 |
1.8 |
1 |
1 |
0.7 |
2 |
2 |
1.2 |
Sternebra - bipartite ossification |
1 |
1 |
0.6 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
2 |
1 |
1.4 |
Sternebra - misaligned |
2 |
2 |
1.1 |
0 |
0 |
0.0 |
4 |
4 |
2.6 |
9 |
6 |
6.2 |
Xiphoid cartilage - partially split |
2 |
2 |
1.4 |
1 |
1 |
0.8 |
6 |
5 |
3.7 |
9 |
8 |
5.9 |
Pectoral Girdle |
|
|
|
|
|
|
|
|
|
|
|
|
Scapula - misshapen |
2 |
2 |
1.2 |
2 |
1 |
1.0 |
9 |
6 |
5.8 |
12 |
7 |
7.4 |
Pelvic Girdle |
|
|
|
|
|
|
|
|
|
|
|
|
Ischium - incomplete ossification |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Pubis - not ossified |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Pubis - incomplete ossification |
2 |
2 |
1.1 |
5 |
4 |
3.2 |
3 |
3 |
2.0 |
5 |
5 |
3.3 |
a
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
30 |
175 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
154 (24) |
155 (24) |
155 (24) |
148 (24) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Forelimbs |
|
|
|
|
|
|
|
|
|
|
|
|
Metacarpal - not ossified |
23 |
11 |
14.2 |
42 |
14 |
26.2 |
20 |
12 |
13.1 |
52 |
18 |
34.7* |
Metacarpal - incomplete ossification |
0 |
0 |
0.0 |
2 |
2 |
1.4 |
2 |
2 |
1.4 |
0 |
0 |
0.0 |
Forepaw phalanges - 1 or more - ossified |
26 |
9 |
17.3 |
33 |
11 |
21.0 |
36 |
11 |
22.0 |
30 |
12 |
20.7 |
Humerus - incomplete ossification |
0 |
0 |
0.0 |
4 |
3 |
2.5 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Humerus - hole |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Humerus - short |
2 |
1 |
1.2 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Hindlimbs |
|
|
|
|
|
|
|
|
|
|
|
|
Metatarsal - incomplete ossification |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
5 |
2 |
3.0 |
Femur - incomplete ossification |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Total |
117 |
24 |
75.9 |
126 |
24 |
80.5 |
122 |
24 |
78.5 |
136 |
24 |
91.2** |
NOTE: a fetus may appear in more than one category
Number of dams with abortions, early deliveries, stillbirths, resorptions, and/or dead foetuses
Dose level |
0 mg/kg (control) |
30 mg/kg |
175 mg/kg |
1000 mg/kg |
Abortions |
0 |
0 |
0 |
0 |
Early deliveries |
0 |
0 |
0 |
0 |
Still births |
0 |
0 |
0 |
0 |
Resorptions/ dead fetuses |
4/24 |
7/24 |
5/24 |
9/24 |
Pre-and post-implantation (fetus) loss, number and percent
Dose level |
Number pre-implantation |
Number post implantation |
Percentage live offspring# |
0 mg/kg (control) |
332-325=7 |
325-321=4 |
13.4/13.5*100=99.26% |
30 mg/kg |
339-330=9 |
330-322=8 |
13.4/13.8*100=97.1% |
175 mg/kg |
322-316=6 |
316-309=7 |
13.5/13.7*100=98.54% |
1000 mg/kg |
326-319=7 |
319-306=13 |
12.8/13.3*100=96.24% |
Applicant's summary and conclusion
- Conclusions:
- The oral administration of 1,1,3,3-tetramethylbutyl peroxyneodecanoate (CAS# 51240-95-0) to pregnant rats by gavage during gestation Days 5 to 19, at dose levels of 30, 175 or 1000 mg/kg bw/day resulted in an adverse effect on body weight gain and food consumption at the high dose level. Although some improvement was evident, cumulative body weight gains for females treated with 1000 mg/kg bw/day remained lower than controls throughout the dosing period with body weight gain adjusted for the contribution of gravid uterus also being markedly lower than controls. Taking into consideration the overall results, the No Observed Adverse Effect Level’ (NOAEL) for the pregnant female was considered to be 175 mg/kg bw/day within the confines of this type of study.
At 1000 mg/kg bw/day, fetal and litter weights were marginally lower than control with skeletal examination identifying a number of treatment-related variants. These observations were, however, considered to be due to maternal toxicity which results in slight reduction in fetal growth rather than an indication of a direct effect of the test item on fetal growth and development. The ‘No Observed Adverse Effect Level’ (NOAEL) for developmental toxicity was therefore considered to be 1000 mg/kg bw/day whilst the ‘No Observed Effect Level’ (NOEL) for developmental toxicity was deemed to be 175 mg/kg bw/day within the confines of this type of study. - Executive summary:
The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD®(SD) IGS BR strain rats, between Days 5 and 19 of gestation inclusive at dose levels 30, 175 or 1000 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Arachis oil BP) to serve as a control.
Clinical signs, body weight change, food and water consumptions were monitored during the study.
All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, fetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter was examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.
There were no unscheduled deaths during the study. There were no clinical signs for any of the animals throughout the study. At all dose levels, females showed a dose-related reduction in group mean body weight gains over Days 5 to 6 of gestation with most animals from the 1000 mg/kg bw/day showing actual body weight losses. Subsequent recovery was evident for females receiving 30 or 175 mg/kg bw/day with periodic body weight gains for these animals remaining comparable with controls from Day 6 of gestation. Females treated with 1000 mg/kg bw/day also showed improvement in body weight performance such that body weight gains over Days 7 to 14 of gestation were comparable with controls; however, further reduction in body weight gain was observed over Days 14 to 17 of gestation resulting in lower cumulative body weight gains for these animals throughout the treatment period. The overall body weight gain for these females was approximately 21% lower than controls with body weight gain adjusted for gravid uterus contribution also being markedly lower than controls. The effect on body weight development for the 1000 mg/kg bw/day females was considered to be adverse. There was marked reduction in food consumption at the start of dosing for females given 1000 mg/kg bw/day. Gradual improvement was apparent, however, dietary intake for these animals remained statistically significantly lower than controls up to Day 17 of gestation. Taken together with the effect on body weight development at this dose level, this observation was considered adverse. There was no effect of treatment on food intake at 30 or 175 mg/kg bw/day. Daily visual inspection of water bottles did not reveal any treatment-related intergroup differences. There were no treatment-related macroscopic findings at terminal necropsy. Treatment with the test item at 30, 175 or 1000 mg/kg bw/day did not result in any treatment-related effects on in utero survival. Sex ratios were also similar across all dose groups including controls. At 1000 mg/kg bw/day, group mean fetal weights were marginally lower than controls which resulted in slightly lower litter weight for this dose group. These findings were deemed likely due to maternal toxicity rather than a direct effect of treatment on fetal growth and development. Group mean total placental weight for the dams treated with 1000 mg/kg bw/day was also slightly lower than controls which was also considered to be due to maternal toxicity. For all dose groups, there were no statistically significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external or visceral abnormalities. At 1000 mg/kg bw/day, a number of skeletal anomalies achieved statistical significance. These included incomplete ossification of occipital (supra-occipital) region, thoracic centrum and sternbrae, no ossification of metacarpal, and caudal vertebrae - less than 4 ossified. These observations are minor variants and although group mean values were outside the historical background data ranges, they were considered to be due to a slower fetal growth rate resulting from maternal toxicity rather than an indication of a direct effect of the test item on fetal development. Any other skeletal findings at all dose levels were considered to be within normal biological variation.
The oral administration of 1,1,3,3-tetramethylbutyl peroxyneodecanoate (CAS# 51240-95-0) to pregnant rats by gavage during gestation Days 5 to 19, at dose levels of 30, 175 or 1000 mg/kg bw/day resulted in an adverse effect on body weight gain and food consumption at the high dose level. Although some improvement was evident, cumulative body weight gains for females treated with 1000 mg/kg bw/day remained lower than controls throughout the dosing period with body weight gain adjusted for the contribution of gravid uterus also being markedly lower than controls. Taking into consideration the overall results, the NOAEL for the pregnant female was considered to be 175 mg/kg bw/day. At 1000 mg/kg bw/day, fetal and litter weights were marginally lower than control with skeletal examination identifying a number of treatment-related variants. These were however considered to be due to maternal toxicity which resulted in reduced fetal growth rather than an indication of a direct effect of the test item on fetal growth and development. The NOAEL for developmental toxicity was therefore considered to be 175 mg/kg bw/day; findings were noted in the presence of clear maternal toxicity.
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