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EC number: 207-330-6 | CAS number: 462-95-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 14 November 2017 - 07 September 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
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
- Justification for study design:
- The purpose of this study was a screening test for reproductive/developmental effects, with administration of the test item, Ethylal, by oral gavage administration to Sprague Dawley Rats for at least four weeks.
The doses used in this study (0, 300, 600 and 1000 mg/kg/day) were selected in conjunction with the Sponsor. Dose levels were selected following the completion of the preliminary toxicity study (Envigo Study number: WG36YM).
In that study, dose levels of 300, 600 and 1000 mg/kg/day were well tolerated with no clinical signs or abnormal macroscopic findings and there were no adverse effects on food intake or body weight gain. There were initial post dosed signs of decreased activity in all animals receiving 1000 mg/kg/day, and unsteady gait in all males and 2/3 females at this dose level. Decreased activity, unsteady gait and piloerection was observed in one male receiving 1000 mg/kg/day on Day 2, after which no post dose signs were observed.
Based on the data generated on WG36YM and as the LD50 had been reported as 3536 mg/kg bw, a high dose level of 1000 mg/kg/day was selected for use on this study. The intermediate and low dose remained at 600 and 300 mg/kg/day to allow for assessment of a dose response.
Test material
- Reference substance name:
- Diethoxymethane
- EC Number:
- 207-330-6
- EC Name:
- Diethoxymethane
- Cas Number:
- 462-95-3
- Molecular formula:
- C5H12O2
- IUPAC Name:
- diethoxymethane
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- Colourless liquid.
Batch number: 1709141400R
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The rat was chosen as the test species because of the requirement for a rodent species by regulatory agencies. The Sprague Dawley [Crl:CD(SD)] strain was used because of the historical control data available at this laboratory.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: Males 71 to 77 days old. Females 85 to 91 days old.
- Weight at study initiation: Males 336 to 418 g. Females 264 to 321 g.
- Housing: On arrival and non-selective allocation to cages.
- Diet: SDS VRF1 Certified pelleted diet. ad libitum
- Water: Potable water from the public supply via polycarbonate bottles with sipper tubes; ad libitum
- Acclimation period: Males: eight days prior to the commencement of treatment. Females: 22 days prior to the commencement of treatment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): and Humidity (%): Monitored and maintained within the range of 20-24ºC and 40-70%.
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): Artificial lighting, 12 hours light : 12 hours dark.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The required amount of test item was mixed with a small quantity of the vehicle. Approximately 20% of the final volume of vehicle was gradually added. The formulation was quantitatively transferred and diluted to final volume and magnetically stirred in a sealed container of appropriate size ensuring there is no head space.
Frequency of preparation: Weekly.
Storage of formulation Refrigerated: (2-8°C) in amber glass. - Details on mating procedure:
- Pairing commenced - After a minimum of two weeks of treatment.
Male/female ratio - 1:1 from within the same treatment groups.
Duration of pairing - Up to two weeks.
Daily checks for evidence of mating - Ejected copulation plugs in cage tray and sperm in the vaginal smear.
Day 0 of gestation - When positive evidence of mating was detected.
Male/female separation Day - when mating evidence was detected.
Pre-coital interval - Calculated for each female as the time between first pairing and evidence of mating. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analytical procedure was successfully validated for Ethylal in corn oil with respect to the specificity of chromatographic analysis, limit of detection and quantification, the linearity of detector response, precision of injection, method accuracy and precision, standard solution stability and extracted sample solution stability.
The mean concentrations of Ethylal in test formulations analyzed for the study were within +10/-15% of nominal concentrations, confirming accurate formulation. With the exception of Week 4 Group 2, which was confirmed at -20.8%. The difference from mean and coefficient of variation remained within 5%, confirming precise analysis.
(Table 2) - Duration of treatment / exposure:
- Males: Two weeks pre-pairing up to necropsy after minimum of four weeks.
Females: Two weeks before pairing, then throughout pairing and gestation until Day 12 of lactation.
Animals of the F1 generation were not dosed. - Frequency of treatment:
- Once daily at approximately the same time each day.
- Details on study schedule:
- - parental animals not mated until 2 weeks after selection
- Age at mating of the mated animals in the study: Males 78 to 84 days old. Females 92 to 98 days old.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Control - corn oil
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 600 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
based on preliminary toxicity study.
- Animal allocation: On arrival and non-selective allocation to cages. Estrous cycles were evaluated pre-treatment. After 14 days evaluation, animals that failed to exhibit typical 4-5 days cycles were not allocated to the study. On Day 1 of study all animals were weighed and body weights were reviewed by Study Management before dosing commenced to ensure variations in body weight of animals did not exceed ±20% of the mean for each sex. - Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: A viability check was performed near the start and end of each working day. Animals were killed for reasons of animal welfare where necessary. A complete necropsy was performed in all cases.
CLINICAL OBSERVATIONS: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate. During the acclimatization period, observations of the animals and their cages were recorded at least once per day.
A detailed physical examination was performed on each animal to monitor general health according to the following schedule:
F0 - males Weekly
F0 - females Week 1 and 2 - weekly
Gestation phase - Days 0, 7, 14 and 20
Lactation phase - Days 1, 6 and 13
BODY WEIGHT:
The weight of animals was recorded as follows:
F0 males - Weekly during acclimatization (not reported)
Before dosing on the day that treatment commenced (Day 1), and weekly thereafter.
On the day of necropsy.
F0 females - Weekly during acclimatization (not reported)
Before dosing on the day that treatment commenced (Day 1) and weekly before pairing.
Days 0, 7, 14 and 20 after mating.
Day 1, 4, 7 and 13 of lactation.
On the day of necropsy.
FOOD CONSUMPTION:
The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded as follows:
F0 animals: Weekly before pairing, from the day that treatment commenced.
Food consumption was not recorded for males and females during the period when paired for mating (Days 15 to 22), but recommenced for males in Week 4.
For females after mating food consumption was recorded as follows:
Days 0-6, 7-13 and 14-19 after mating
Days 1-3, 4-6 and 7-12 of lactation.
From these records the mean daily consumption per animal (g/animal/day) was calculated for each phase.
SIGNS ASSOCIATED WITH DOSING
Detailed observations were recorded at the following times in relation to dose administration and according to the following schedule:
F0 males: Week 1 - daily
Week 2 onwards - twice each week
F0 females: Week 1 - daily
Week 2 - twice
Gestation phase - Days 0, 7, 14 and 20
Lactation phase - Days 1, 6 and 12
Detailed observations were recorded at the following times in relation to dose administration:
Pre-dose observation
One to two hours after completion of dosing all groups
As late as possible in the working day. - Oestrous cyclicity (parental animals):
- Dry and wet smears were taken as follows:
Dry smears: For 15 days before pairing using cotton swabs.
Wet smears: Using pipette lavage during the following phases:
For 14 days before treatment (all females including spares); animals that failed to exhibit 4-5 day cycles were not allocated to study.
After pairing until mating.
For four days before scheduled termination. - Sperm parameters (parental animals):
- Parameters examined in male parental generations: testis weight, epididymis weight, sperm morphology
- Litter observations:
- From Day 20 after mating, females were inspected three times daily for evidence of parturition. The progress and completion of parturition was monitored, numbers of live and dead offspring were recorded and any difficulties observed were recorded.
Records Made During Littering Phase:
Clinical observations - Examined at approximately 24 hours after birth (Day 1 of age) and then daily thereafter for evidence of ill health or reaction to maternal treatment; these were on an individual offspring basis or for the litter as a whole, as appropriate.
Litter size - Daily records were maintained of mortality and consequent changes in litter size from Days 1-13 of age.
Sex ratio of each litter - Recorded on Days 1, 4, 7 and 13 of age.
Individual offspring body weights - Days 1, 4, 7, 11 and 13 of age.
Ano-genital distance - Day 1 - all F1 offspring.
Nipple/areolae count - Day 13 of age - male offspring. - Postmortem examinations (parental animals):
- Abnormalities, Epididymides (caput, corpus and cauda), Ovaries, pituitary, prostate, seminal vesicles, testes, thyroids, uterus with cervix and oviducts.
For females the following were recorded:
Each uterine horn, number of implantation sites was counted and confirmed if none were visible at visual inspection.
The organs weighed, tissue samples fixed and sections examined microscopically are detailed below in table 1 for F0 animals: - Postmortem examinations (offspring):
- Premature deaths: Where possible, a fresh external macroscopic examination with an assessment of stomach for milk content. Abnormal pups were retained.
F1 offspring on Day 4 of age: Blood sampling required.
All animals were subject to an external macroscopic examination; particular attention was paid to the external genitalia.
F1 offspring on Day 13 of age: Blood sampling required.
All animals were subject to an external macroscopic examination; particular attention was paid to the external genitalia.
Thyroid glands were preserved from two offspring per litter, one male and one female in each litter, where possible. - Statistics:
- A parametric analysis was performed if Bartlett's test for variance homogeneity was not significant at the 1% level.
If the F1 approximate test was significant, suggesting that the dose response was not monotone, Dunnett's test was performed instead.
A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. For pretreatment data, Kruskal-Wallis’ test was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using Wilcoxon rank sum tests were made.
If the H1 approximate test was significant, suggesting that the dose-response was not monotone, Steel's test was performed instead.
For live birth and viability indices dichotomized to 1 when 100% and 0 otherwise, if the Cochran-Armitage test was significant at the 5% level, then the direction of the trend was established and one-tailed step-down testing in this direction was performed. If the Cochran-Armitage test was not significant at the 5% level, then a Chi-square test was applied. If the Chi-square test was significant at the 5% level, the treatment groups were compared using pairwise comparisons of each dose group against the Control using Fisher’s exact tests; otherwise, no further comparisons were made.
For gestation length an exact two-tailed Linear-by-linear test, with equally spaced scores, was applied to all groups.
For estrous cycles an exact one-tailed (upper-tail) Linear-by-linear test was applied to all groups, using scores appropriate to the severity of the observation assuming 4 day cycles to be normal.
For organ weight data, analysis of covariance was performed using terminal body weight as covariate, unless non-parametric methods were applied. - Reproductive indices:
- Estrous Cycle, Pre-Coital Interval, Mating Performance and Fertility, Gestation Length and Index,
- Offspring viability indices:
- Litter Size, Survival Indices, sex ratio
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- See tables 1-3
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One group 2 female (Animal No. 134) was found dead on Day 23 of gestation. The animal did not have any adverse clinical signs prior to death, and there were no findings at macroscopic examination, but the female gave birth to 6 pups which were killed for welfare reasons.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The overall bodyweight gain (Day 1-29) and bodyweight change during treatment was statistically significantly lower in males that received 1000 mg/kg/day when compared with Controls, this was predominantly due to statistically significantly reduced weight gain in the first week of treatment.
The overall body weight gain during lactation (Days 1-13) in all females treated with Ethylal, was statistically significantly lower when compared with the Controls this was predominantly due to minor weight loss on Days 1-4 at 300 or 1000 mg/kg/day and statistically significantly reduced weight gain on Days 7-13 of lactation at all doses. However, there was no dose response.
See tables 4-6 - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food intake was marginally but statistically significantly reduced during Days 1-8 prior to pairing for females receiving 1000 mg/kg/day when compared with Controls. However, food intake was statistically significantly higher for females receiving Ethylal during Day 14-20 of gestation and lower for females receiving 600 or 1000 mg/kg/day during Days 7-13 of lactation, but a dose response was not apparent.
See tables 7-9 - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Tables 24-25
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- See tables 10-11
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
See table 26 for thyroid hormone (T4) results.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive function (oestrous cycle)
- reproductive performance
Target system / organ toxicity (P0)
open allclose all
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- male reproductive system
- Organ:
- testes
- other: epididymides
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- female reproductive system
- Organ:
- ovary
- uterus
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- See table 19
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Anogenital distance (AGD):
- no effects observed
- Nipple retention in male pups:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- See table 26 for thyroid hormone (T4) results.
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- clinical signs
- mortality
- body weight and weight gain
- haematology
- gross pathology
- histopathology: non-neoplastic
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- endocrine system
- Organ:
- thyroid gland
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Treatment related:
- no
Any other information on results incl. tables
|
Control |
Ethylal |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
300 |
600 |
1000 |
Table 1: Clinical signs – group distribution of observations for males and for females before pairing (F0)
|
|
|
Number of animals affected |
|||||||
Category |
Observation |
Group/Sex : Initial no : |
1M 10 |
2M 10 |
3M 10 |
4M 10 |
1F 10 |
2F 10 |
3F 10 |
4F 10 |
Behavior |
Aggressive |
|
0 |
0 |
1 |
2 |
0 |
0 |
0 |
0 |
|
Grinding teeth |
|
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
Vocalization |
|
0 |
0 |
0 |
2 |
0 |
0 |
0 |
0 |
Body Temperature |
Abnormally cold to touch |
|
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
Breathing |
Irregular |
|
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
Coat |
Hair loss, Dorsal surface |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
Hair loss, Forelimbs |
|
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
Ungroomed |
|
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Eyes |
Pale, Bilateral |
|
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
Muscle reaction |
Abnormal gait, Uncoordinated |
|
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
|
Impaired locomotion, Other |
|
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
Table 1 (cont): Clinical signs – group distribution of observations for males and for females before pairing (F0)
|
|
|
Number of animals affected |
|||||||
Category |
Observation |
Group/Sex : Initial no : |
1M 10 |
2M 10 |
3M 10 |
4M 10 |
1F 10 |
2F 10 |
3F 10 |
4F 10 |
Reason for dispatch |
Loss of or limited locomotion |
|
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
Skin |
Cut, Lower ventral surface |
|
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
|
Encrustation, Dorsal surface |
|
0 |
0 |
0 |
0 |
0 |
2 |
0 |
0 |
|
Encrustation, Forelimb - left |
|
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
Encrustation, Lower ventral surface |
|
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
|
Encrustation, Upper dorsal surface |
|
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
Skin color |
Reddening, Hindlimbs |
|
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Staining |
Abnormal color, Brown, Eye - left |
|
0 |
0 |
2 |
1 |
0 |
0 |
0 |
0 |
|
Abnormal color, Brown, Head |
|
0 |
0 |
0 |
0 |
0 |
0 |
1 |
1 |
|
Abnormal color, Brown, Muzzle |
|
1 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
|
Abnormal color, Red, Muzzle |
|
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Staining |
Chromodacryorrhea |
|
0 |
0 |
1 |
1 |
0 |
0 |
0 |
0 |
Table 2: Clinical signs – group distribution of observations for females during gestation (F0)
|
|
|
Number of animals affected |
|||
Category |
Observation |
Group/Sex : Initial no : |
1F 10 |
2F 9 |
3F 10 |
4F 10 |
Behavior |
Decreased activity |
|
0 |
0 |
2 |
0 |
Breathing |
Irregular |
|
0 |
0 |
1 |
0 |
|
Slow |
|
0 |
0 |
1 |
0 |
Build (Deformity) |
Prominent area, Ventral surface |
|
1 |
0 |
0 |
1 |
Coat |
Hair loss, Dorsal surface |
|
0 |
0 |
0 |
1 |
|
Hair loss, Forelimbs |
|
0 |
0 |
0 |
6 |
|
Hair loss, Ventral surface |
|
0 |
0 |
0 |
1 |
|
Piloerection |
|
0 |
0 |
2 |
0 |
Eyes |
Dark, Bilateral |
|
0 |
0 |
1 |
0 |
|
Dull, Bilateral |
|
0 |
0 |
1 |
0 |
Reason for dispatch |
General poor clinical condition |
|
0 |
0 |
2 |
0 |
Table 2 (cont): Clinical signs – group distribution of observations for females during gestation (F0)
|
|
|
Number of animals affected |
|||
Category |
Observation |
Group/Sex : Initial no : |
1F 10 |
2F 9 |
3F |
4F 10 |
Skin |
Encrustation, Dorsal surface |
|
0 |
1 |
0 |
0 |
|
Encrustation, Ears |
|
0 |
1 |
0 |
0 |
|
Encrustation, Forelimb digit(s) |
|
0 |
0 |
1 |
0 |
|
Encrustation, Upper dorsal surface |
|
0 |
0 |
0 |
2 |
Skin color |
Pallor, Whole body |
|
0 |
0 |
2 |
0 |
Staining |
Abnormal color, Brown, Ears |
|
1 |
0 |
1 |
0 |
|
Abnormal color, Brown, Head |
|
2 |
4 |
2 |
4 |
|
Abnormal color, Brown, Upper dorsal surface |
|
6 |
3 |
1 |
1 |
|
Chromodacryorrhea |
|
2 |
0 |
2 |
0 |
Table 3: Clinical signs – group distribution of observations for females during lactation (F0)
|
|
|
Number of animals affected |
|||
Category |
Observation |
Group/Sex : Initial no : |
1F 10 |
2F 8 |
3F 8 |
4F |
Behavior |
Vocalization |
|
0 |
0 |
0 |
1 |
Build (Deformity) |
Partially absent appendage, Ear - right |
|
0 |
1 |
0 |
0 |
|
Prominent area, Ventral surface |
|
7 |
6 |
8 |
8 |
Coat |
Hair loss, Dorsal surface |
|
0 |
0 |
0 |
1 |
|
Hair loss, Forelimbs |
|
0 |
2 |
1 |
5 |
|
Hair loss, Hindlimbs |
|
0 |
1 |
1 |
3 |
|
Hair loss, Ventral surface |
|
0 |
1 |
1 |
1 |
Staining |
Abnormal color, Brown, Ears |
|
0 |
0 |
1 |
0 |
|
Abnormal color, Brown, Head |
|
1 |
2 |
2 |
2 |
|
Abnormal color, Brown, Upper dorsal surface |
|
8 |
4 |
4 |
3 |
Table 4: Body weight and body weight change – group mean values (g) for males and for females before pairing (F0)
Group /Sex |
|
Day 1 |
8 |
15 |
22 |
29 |
Change 1-8 |
Change 8-15 |
Change 15-22 |
Change 22-29 |
Change 1-29 |
Statistics test |
|
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
1M |
Mean |
373 |
399 |
422 |
434 |
461 |
26 |
22 |
13 |
26 |
87 |
|
SD |
24.5 |
32.7 |
36.6 |
40.5 |
43.4 |
9.8 |
6.0 |
6.9 |
5.0 |
20.9 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
2M |
Mean |
378 |
405 |
430 |
446 |
473 |
28 |
25 |
16 |
27 |
96 |
|
SD |
17.3 |
22.1 |
23.3 |
26.7 |
30.4 |
5.6 |
4.6 |
5.6 |
5.2 |
15.0 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
3M |
Mean |
370 |
394 |
416 |
428 |
453 |
24 |
22 |
12 |
25 |
82 |
|
SD |
17.0 |
21.1 |
26.2 |
25.2 |
26.4 |
8.0 |
6.6 |
4.5 |
5.2 |
13.8 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
4M |
Mean |
373 |
390 |
409 |
418 |
438 |
16** |
19 |
9 |
20* |
65** |
|
SD |
19.2 |
19.2 |
21.0 |
21.0 |
20.7 |
6.3 |
8.4 |
4.8 |
6.5 |
12.0 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Table 4 (cont): Body weight and body weight change – group mean values (g) for males and for females before pairing (F0)
Group /Sex |
|
Day 1 |
8 |
15 |
Change 1-8 |
Change 8-15 |
Change 1-15 |
Statistics test |
|
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
1F |
Mean |
290 |
293 |
294 |
3 |
1 |
5 |
|
SD |
16.7 |
16.5 |
18.5 |
3.6 |
8.1 |
9.3 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
2F |
Mean |
291 |
292 |
301 |
1 |
9 |
11 |
|
SD |
10.0 |
9.9 |
9.4 |
7.5 |
6.8 |
8.4 |
|
N |
10 |
10 |
9 |
10 |
9 |
9 |
3F |
Mean |
294 |
296 |
305 |
2 |
9 |
11 |
|
SD |
16.3 |
16.7 |
17.8 |
4.2 |
6.1 |
5.8 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
4F |
Mean |
296 |
296 |
301 |
1 |
4 |
5 |
|
SD |
12.3 |
11.4 |
10.4 |
4.0 |
7.3 |
8.5 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
Table 5: Body weight and body weight change – group mean values (g) for females during gestation (F0)
Group /Sex |
|
Day 0 |
7 |
14 |
20 |
Change 0-7 |
Change 7-14 |
Change 14-20 |
Change 0-20 |
Statistics test |
|
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
1F |
Mean |
304 |
328 |
360 |
441 |
24 |
33 |
80 |
137 |
|
SD |
16.3 |
15.0 |
12.0 |
12.8 |
8.0 |
6.9 |
12.4 |
15.5 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
2F |
Mean |
305 |
334 |
369 |
456 |
29 |
36 |
87 |
151 |
|
SD |
13.6 |
7.6 |
11.1 |
14.0 |
9.1 |
8.5 |
9.4 |
14.3 |
|
N |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
9 |
3F |
Mean |
308 |
334 |
366 |
448 |
26 |
32 |
82 |
140 |
|
SD |
17.5 |
21.0 |
20.5 |
26.7 |
9.4 |
7.8 |
11.5 |
18.8 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
4F |
Mean |
300 |
328 |
367 |
448 |
28 |
39 |
81 |
148 |
|
SD |
13.5 |
8.7 |
13.6 |
20.9 |
9.7 |
8.3 |
10.8 |
16.5 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Table 6: Body weight and body weight change – group mean values (g) for females during lactation (F0)
Group /Sex |
|
Day 1 |
4 |
7 |
13 |
Change 1-4 |
Change 4-7 |
Change 7-13 |
Change 1-13 |
Statistics test |
|
Wi |
Wi |
Wi |
Wi |
Sh |
Wi |
Wi |
Wi |
1F |
Mean |
339 |
341 |
358 |
382 |
2 |
17 |
25 |
44 |
|
SD |
14.3 |
16.6 |
15.8 |
16.0 |
6.9 |
9.3 |
8.2 |
13.3 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
2F |
Mean |
346 |
344 |
360 |
369 |
-2 |
15 |
9* |
23* |
|
SD |
12.4 |
5.7 |
8.4 |
8.0 |
11.3 |
4.3 |
8.9 |
14.8 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
3F |
Mean |
345 |
351 |
360 |
374 |
6 |
9 |
14* |
29* |
|
SD |
22.1 |
22.8 |
21.9 |
15.8 |
8.9 |
7.5 |
9.8 |
12.1 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
4F |
Mean |
347 |
345 |
358 |
376 |
-2 |
13 |
18** |
29* |
|
SD |
18.8 |
18.3 |
15.8 |
13.7 |
24.4 |
8.9 |
6.3 |
18.4 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Table 7: Food consumption – group mean values (g/animal/day) for males and for females before pairing (F0)
Group /Sex |
|
Day 1-8 |
8-15 |
15-22 |
22-29 |
Statistics test |
|
Wi |
Wi |
|
Wi |
1M |
Mean |
22 |
20 |
# |
20 |
|
SD |
1.3 |
1.3 |
|
1.0 |
|
N |
3 |
3 |
|
3 |
2M |
Mean |
23 |
21 |
# |
22 |
|
SD |
1.2 |
0.9 |
|
1.1 |
|
N |
3 |
3 |
|
3 |
3M |
Mean |
22 |
20 |
# |
21 |
|
SD |
1.2 |
1.1 |
|
1.2 |
|
N |
3 |
3 |
|
3 |
4M |
Mean |
20 |
20 |
# |
21 |
|
SD |
1.2 |
0.9 |
|
1.0 |
|
N |
3 |
3 |
|
3 |
# - Food consumption not recorded whilst paired for mating
Table 7 (cont): Food consumption – group mean values (g/animal/day) for males and for females before pairing (F0)
Group /Sex |
|
Day 1-8 |
8-15 |
Statistics test |
|
Wi |
Wi |
1F |
Mean |
15 |
14 |
|
SD |
0.7 |
1.0 |
|
N |
3 |
3 |
2F |
Mean |
14 |
15 |
|
SD |
0.7 |
0.7 |
|
N |
3 |
3 |
3F |
Mean |
15 |
15 |
|
SD |
0.6 |
0.1 |
|
N |
3 |
3 |
4F |
Mean |
14* |
14 |
|
SD |
0.4 |
0.6 |
|
N |
3 |
3 |
Table 8: Food consumption – group mean values (g/animal/day) for females during gestation (F0)
Group /Sex |
|
Day 1-7 |
7-14 |
14-20 |
Statistics test |
|
Wi |
Wi |
Wi |
1F |
Mean |
19 |
21 |
22 |
|
SD |
1.7 |
3.7 |
3.9 |
|
N |
10 |
10 |
10 |
2F |
Mean |
19 |
20 |
25* |
|
SD |
1.1 |
4.8 |
2.0 |
|
N |
9 |
8 |
9 |
3F |
Mean |
19 |
21 |
24* |
|
SD |
1.9 |
2.1 |
1.5 |
|
N |
10 |
10 |
10 |
4F |
Mean |
19 |
22 |
26** |
|
SD |
1.7 |
1.7 |
2.5 |
|
N |
10 |
10 |
10 |
Table 9: Food consumption – group mean values (g/animal/day) for females during lactation (F0)
Group /Sex |
|
Day 1-4 |
4-7 |
7-13 |
Statistics test |
|
Wi |
Wi |
Wi |
1F |
Mean |
30 |
51 |
70 |
|
SD |
5.0 |
4.3 |
4.1 |
|
N |
10 |
10 |
10 |
2F |
Mean |
35 |
50 |
66 |
|
SD |
3.7 |
5.0 |
3.1 |
|
N |
8 |
8 |
8 |
3F |
Mean |
32 |
48 |
64* |
|
SD |
6.1 |
5.7 |
8.5 |
|
N |
8 |
8 |
8 |
4F |
Mean |
30 |
46 |
63* |
|
SD |
9.4 |
7.1 |
5.4 |
|
N |
10 |
10 |
10 |
Table 10: Estrous cycles – group values before treatment (F0)
Group |
Number of Animals |
|
4 day |
Regular cycles
4/5 days |
5 day |
Irregular cycle* |
Extended estrus** |
Acyclicy*** |
1 |
10 |
N (%) |
9 (90) |
1 (10) |
0
|
0
|
0
|
0
|
2 |
10 |
N (%) |
8 (80) |
1 (10) |
1 (10) |
0
|
0
|
0
|
3 |
10 |
N (%) |
7 (70) |
1 (10) |
2 (20) |
0
|
0
|
0
|
4 |
10 |
N (%) |
9 (90) |
1 (10) |
0
|
0
|
0
|
0
|
* At least one cycle of two, three or six to ten days
** At least four consecutive days of estrus
*** At least ten days without estrus
Table 11: Estrous cycles – group values during treatment (F0)
Group |
Number of Animals |
|
4 day |
Regular cycles
4/5 days |
5 day |
Irregular cycle* |
Extended estrus** |
Acyclic*** |
Statistics test |
Lt |
|
|
|
|
|
|
|
1 |
10 |
N (%) |
9 (90) |
1 (10) |
0
|
0
|
0
|
0
|
2 |
10 |
N (%) |
8 (80) |
1 (10) |
0
|
1 (10) |
0
|
0
|
3 |
10 |
N (%) |
8 (80) |
0
|
1 (10) |
1 (10) |
0
|
0
|
4 |
10 |
N (%) |
6 (60) |
2 (20) |
0
|
1 (10) |
1 (10) |
0
|
Table 12: Pre-coital interval – group values (F0)
|
Pre-coital interval (days) |
|||||
Group |
Number of animals |
|
1-4 |
5-8 |
9-12 |
13-14 |
1 |
10 |
N (%) |
10 (100) |
0 |
0 |
0 |
2 |
9 |
N (%) |
9 (100) |
0 |
0 |
0 |
3 |
10 |
N (%) |
10 (100) |
0 |
0 |
0 |
4 |
10 |
N (%) |
10 (100) |
0 |
0 |
0 |
Table 13: Mating performance and fertility – group values (F0)
Group and sex |
Number paired |
Number mating |
Number achieving pregnancy |
Percentage mating |
Conception rate (%) |
Fertility index (%) |
1M |
10 |
10 |
10 |
100 |
100 |
100 |
2M |
9 |
9 |
9 |
100 |
100 |
100 |
3M |
10 |
10 |
10 |
100 |
100 |
100 |
4M |
10 |
10 |
10 |
100 |
100 |
100 |
|
|
|
|
|
|
|
1F |
10 |
10 |
10 |
100 |
100 |
100 |
2F |
9 |
9 |
9 |
100 |
100 |
100 |
3F |
10 |
10 |
10 |
100 |
100 |
100 |
4F |
10 |
10 |
10 |
100 |
100 |
100 |
Table 14: Gestation length and gestation index – group values (F0)
|
Gestation length (days) |
|
||||||
Group |
Number of pregnant animals |
|
22 |
22.5 |
23 |
23.5 |
Number of liver litters born |
Gestation index (%) |
Statistics test |
|
|
Lt |
|
CA |
|||
1 |
10 |
N (%) |
1 (10) |
6 (60) |
3 (30) |
0
|
10
|
100
|
2 |
9 |
N (%) |
0
|
2 (22) |
7 (78) |
0
|
8A
|
89
|
3 |
10B |
N (%) |
2 (22) |
4 (44) |
2 (22) |
1 (11) |
8A
|
80
|
4 |
10 |
N (%) |
0
|
5 (50) |
4 (40) |
1 (10) |
10
|
100
|
A Excludes one female which did not produce a complete live litter
B Percentage distribution of gestation lengths calculated from nine animals - one pregnant female failed to litter, killed for welfare reasons on Day 24 of gestation
Table 15: Litter size – group mean values (F1)
Group /Sex |
|
Implantations |
Total @ |
Live on Day Before bleed 1 |
4 |
After bleed 4 |
13 |
Statistics test |
|
Wi |
Wi |
Wi |
Wi |
|
|
1F |
Mean |
15.6 |
14.4 |
14.0 |
13.9 |
12.5 |
12.5 |
|
SD |
2.55 |
2.41 |
2.21 |
2.18 |
1.78 |
1.78 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
2F |
Mean |
17.0 |
15.8 |
15.0 |
15.0 |
13.3 |
13.3 |
|
SD |
1.41 |
1.28 |
1.60 |
1.60 |
1.91 |
1.91 |
|
N |
9 |
8 |
8 |
8 |
8 |
8 |
3F |
Mean |
15.5 |
14.9 |
13.5 |
13.3 |
11.9 |
11.9 |
|
SD |
3.03 |
3.48 |
3.21 |
3.15 |
2.42 |
2.42 |
|
N |
10 |
8 |
8 |
8 |
8 |
8 |
4F |
Mean |
16.2 |
14.8 |
13.4 |
13.1 |
11.6 |
11.6 |
|
SD |
2.35 |
2.74 |
2.50 |
2.64 |
2.07 |
2.07 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
@ - Includes offspring that died prior to the designated Day 1 of age
Table 16: Offspring survival indices – group mean values (F1)
Group /Sex |
|
Post implantation survival index (%) |
Live birth index (%) |
Viability index (%) Day 4 |
Lactation index (%) Day 13 |
Statistics test |
|
Wi |
Ch |
Ch |
|
1F |
Mean |
92.2 |
97.5 |
99.3 |
100.0 |
|
SD |
8.04 |
4.30 |
2.11 |
0.00 |
|
N |
10 |
10 |
10 |
10 |
|
N<100% |
6 |
3 |
1 |
0 |
2F |
Mean |
94.1 |
95.1 |
100.0 |
100.0 |
|
SD |
4.55 |
4.42 |
0.00 |
0.0 |
|
N |
8 |
8 |
8 |
8 |
|
N<100% |
6 |
5 |
0 |
0 |
3F |
Mean |
93.8 |
91.1 |
98.3 |
100.0 |
|
SD |
8.89 |
11.31 |
3.20 |
0.00 |
|
N |
8 |
8 |
8 |
8 |
|
N<100% |
3 |
4 |
2 |
0 |
4F |
Mean |
91.1 |
91.2 |
97.5 |
100.0 |
|
SD |
9.41 |
10.25 |
4.17 |
0.00 |
|
N |
10 |
10 |
10 |
10 |
|
N<100% |
7 |
6 |
3 |
0 |
The following data were used for the statistics tests, animal indices for post implantation survival index and animal indices dichotomized to 1 when 100% and 0 otherwise for live birth and viability indices.
Table 17: Offspring sex ratio – group mean values
Group /Sex |
|
Total @ |
Live (before bleed) on Day |
Live (after bleed) on Day |
||||||||||||
M |
F |
%M |
1 M |
F |
%M |
4 M |
F |
%M |
4 M |
F |
%M |
13 M |
F |
%M |
||
Statistic test |
|
|
Wi |
|
|
Wi |
|
|
Wi |
|
|
|
|
|
|
|
1F |
Mean |
8.5 |
5.7 |
59.7 |
8.3 |
5.7 |
59.1 |
8.2 |
5.7 |
58.8 |
8.2 |
4.3 |
64.9 |
8.2 |
4.3 |
64.9 |
|
SD |
2.32 |
1.95 |
12.33 |
2.26 |
1.95 |
12.27 |
2.30 |
1.95 |
12.49 |
2.30 |
1.42 |
12.17 |
2.30 |
1.42 |
12.16 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
2F |
Mean |
7.6 |
8.0 |
48.3 |
7.3 |
7.8 |
47.6 |
7.3 |
7.8 |
47.6 |
7.3 |
6.0 |
53.5 |
7.3 |
6.0 |
53.5 |
|
SD |
2.72 |
2.20 |
15.05 |
2.87 |
2.12 |
15.43 |
2.87 |
2.12 |
15.43 |
2.87 |
1.51 |
13.78 |
2.87 |
1.51 |
13.78 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
3F |
Mean |
6.8 |
8.0 |
46.4 |
6.5 |
7.0 |
47.9 |
6.4 |
6.9 |
47.7 |
6.4 |
5.5 |
52.8 |
6.4 |
5.5 |
52.8 |
|
SD |
1.91 |
3.07 |
12.89 |
2.07 |
2.07 |
10.31 |
2.07 |
1.96 |
10.06 |
2.07 |
1.31 |
11.00 |
2.07 |
1.31 |
11.00 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
4F |
Mean |
7.2 |
6.9 |
51.7 |
7.0 |
6.4 |
52.7 |
6.8 |
6.3 |
52.5 |
6.8 |
4.8 |
58.8 |
6.8 |
4.8 |
58.8 |
|
SD |
1.99 |
2.56 |
13.62 |
2.05 |
2.41 |
13.42 |
1.93 |
2.41 |
12.65 |
1.93 |
1.99 |
13.65 |
1.93 |
1.99 |
13.65 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
@- Includes offspring that died prior to the designated Day 1 of age and excludes unsexed offspring
Table 18: Ano-genital distance – group mean absolute and adjusted values for offspring (F1)
Group /Sex |
|
Body weight (g) Day 1 |
Ano-genital distance (mm) |
Statistics test |
|
Wi |
|
1M |
Mean |
7.3 |
4.2 |
|
SD |
0.75 |
0.27 |
|
N |
10 |
10 |
2M |
Mean |
7.6 |
4.5 |
|
SD |
0.38 |
0.16 |
|
N |
8 |
8 |
3M |
Mean |
6.9 |
4.3 |
|
SD |
0.65 |
0.30 |
|
N |
8 |
8 |
4M |
Mean |
7.0 |
4.3 |
|
SD |
0.38 |
0.34 |
|
N |
10 |
10 |
Adjusted means |
|
|
Statistics test |
Wi |
|
1M |
Mean |
4.2 |
2M |
Mean |
4.4 |
3M |
Mean |
4.3 |
4M |
Mean |
4.4 |
Table 18 (cont): Ano-genital distance – group mean absolute and adjusted values for offspring (F1)
Group /Sex |
|
Body weight (g) Day 1 |
Ano-genital distance (mm) |
Statistics test |
|
Wi |
|
1F |
Mean |
6.9 |
2.2 |
|
SD |
0.73 |
0.16 |
|
N |
10 |
10 |
2F |
Mean |
7.2 |
2.2 |
|
SD |
0.51 |
0.08 |
|
N |
8 |
8 |
3F |
Mean |
6.5 |
2.1 |
|
SD |
0.72 |
0.15 |
|
N |
8 |
8 |
4F |
Mean |
6.6 |
2.1 |
|
SD |
0.54 |
0.13 |
|
N |
10 |
10 |
Adjusted means |
|
|
Statistics test |
Wi |
|
1F |
Mean |
2.2 |
2F |
Mean |
2.2 |
3F |
Mean |
2.1 |
4F |
Mean |
2.1 |
Table 19: Bodyweight – group mean values (g) for offspring (F1)
Group /Sex |
|
Day of age (before bleed) |
Day of age (after bleed) |
Change 1-4 |
Change 4-7 |
Change 7-11 |
Change 11-13 |
Change 1-13 |
|||||
1 |
1@ |
4 |
4 |
7 |
11 |
13 |
|||||||
Statistics test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1M |
Mean |
7.3 |
7.3 |
10.2 |
10.2 |
15.4 |
24.3 |
28.8 |
3.0 |
5.2 |
8.9 |
4.5 |
21.5 |
|
SD |
0.75 |
0.74 |
1.34 |
1.34 |
2.18 |
2.94 |
3.32 |
0.72 |
1.01 |
0.90 |
0.49 |
2.75 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
2M |
Mean |
7.6 |
7.6 |
10.7 |
10.7 |
15.8 |
24.0 |
27.9 |
3.1 |
5.0 |
8.2 |
3.9 |
20.3 |
|
SD |
0.38 |
0.38 |
1.11 |
1.11 |
1.66 |
3.14 |
3.86 |
0.78 |
0.71 |
1.51 |
0.82 |
3.55 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
3M |
Mean |
6.9 |
6.9 |
10.2 |
10.2 |
15.6 |
24.1 |
28.4 |
3.3 |
5.4 |
8.6 |
4.3 |
21.6 |
|
SD |
0.65 |
0.65 |
1.18 |
1.18 |
1.87 |
2.77 |
3.39 |
0.83 |
0.81 |
1.03 |
0.76 |
3.13 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
4M |
Mean |
7.0 |
7.0 |
10.0 |
10.0 |
15.1 |
23.6 |
27.9 |
2.9 |
5.2 |
8.5 |
4.3 |
20.9 |
|
SD |
0.38 |
0.46 |
1.13 |
1.13 |
1.68 |
2.25 |
2.74 |
0.8 |
0.85 |
0.95 |
0.78 |
2.47 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
@ - Includes only those pups surviving after the bleed
Table 19 (cont): Bodyweight – group mean values (g) for offspring (F1)
Group /Sex |
|
Day of age (before bleed) |
Day of age (after bleed) |
Change 1-4 |
Change 4-7 |
Change 7-11 |
Change 11-13 |
Change 1-13 |
|||||
1 |
1@ |
4 |
4 |
7 |
11 |
13 |
|||||||
Statistics test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1F |
Mean |
6.9 |
6.9 |
9.7 |
9.7 |
14.7 |
23.6 |
27.8 |
2.8 |
5.0 |
8.9 |
4.3 |
21.0 |
|
SD |
0.73 |
0.75 |
1.31 |
1.31 |
2.17 |
3.10 |
3.52 |
0.70 |
0.97 |
1.00 |
0.49 |
2.93 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
2F |
Mean |
7.2 |
7.2 |
10.2 |
10.1 |
15.0 |
23.0 |
26.8 |
2.9 |
4.9 |
8.0 |
3.8 |
19.6 |
|
SD |
0.51 |
0.50 |
1.10 |
1.15 |
1.86 |
3.11 |
4.02 |
0.77 |
0.96 |
1.31 |
0.95 |
3.56 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
3F |
Mean |
6.5 |
6.5 |
9.7 |
9.7 |
14.9 |
23.4 |
27.6 |
3.2 |
5.2 |
8.5 |
4.2 |
21.1 |
|
SD |
0.72 |
0.74 |
1.36 |
1.40 |
2.03 |
3.39 |
3.91 |
0.99 |
0.80 |
1.52 |
0.63 |
3.52 |
|
N |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
8 |
4F |
Mean |
6.6 |
6.6 |
9.5 |
9.5 |
14.5 |
22.6 |
26.7 |
2.9 |
4.9 |
8.1 |
4.0 |
20.0 |
|
SD |
0.54 |
0.52 |
1.32 |
1.31 |
1.83 |
2.68 |
3.04 |
0.87 |
0.70 |
1.10 |
0.79 |
2.72 |
|
N |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
@ - Includes only those pups surviving after the bleed
Table 20: Organ weights – group mean absolute and adjusted values (g) for males killed at scheduled termination (F0)
Group /Sex |
|
Terminal Body weight |
Epididymides |
Prostate |
Seminal vesicles with coagulating gland |
Testes |
Statistics test |
Wi |
|
|
|
|
|
1M |
Mean |
459 |
1.245 |
1.120 |
2.129 |
3.542 |
|
SD |
43 |
0.110 |
0.231 |
0.253 |
0.232 |
|
N |
10 |
10 |
10 |
10 |
10 |
2M |
Mean |
471 |
1.253 |
1.047 |
2.208 |
3.550 |
|
SD |
30 |
0.078 |
0.180 |
0.247 |
0.197 |
|
N |
10 |
10 |
10 |
10 |
10 |
3M |
Mean |
450 |
1.249 |
1.040 |
2.109 |
3.708 |
|
SD |
27 |
0.109 |
0.213 |
0.255 |
0.379 |
|
N |
10 |
10 |
10 |
10 |
10 |
3M |
Mean |
436 |
1.222 |
0.961 |
2.127 |
3.482 |
|
SD |
21 |
0.091 |
0.147 |
0.382 |
0.300 |
|
N |
10 |
10 |
10 |
10 |
10 |
Statistics test |
Wi |
Wi |
Wi |
Wi |
|
1M |
Adjusted mean |
1.237 |
1.107 |
2.111 |
3.523 |
2M |
Adjusted mean |
1.225 |
1.003 |
2.146 |
3.488 |
3M |
Adjusted mean |
1.255 |
1.050 |
2.123 |
3.722 |
4M |
Adjusted mean |
1.252 |
1.008 |
2.193 |
3.549 |
Table 21: Organ weights – group mean absolute and adjusted values (g) for females killed on Day 13 of lactation (F0)
Group /Sex |
|
Terminal Body weight |
Ovaries |
Uterus and Cervix and Oviducts |
Statistics test |
Wi |
|
|
|
1F |
Mean |
382 |
0.097 |
0.503 |
|
SD |
16 |
0.007 |
0.129 |
|
N |
10 |
10 |
10 |
2F |
Mean |
371 |
0.088 |
0.423 |
|
SD |
8 |
0.010 |
0.044 |
|
N |
8 |
8 |
8 |
3F |
Mean |
375 |
0.090 |
0.434 |
|
SD |
17 |
0.008 |
0.050 |
|
N |
8 |
8 |
8 |
4F |
Mean |
376 |
0.086 |
0.480 |
|
SD |
15 |
0.018 |
0.061 |
|
N |
10 |
10 |
10 |
Statistics test |
Wi |
Wi |
|
1F |
Adjusted mean |
0.096 |
0.484 |
2F |
Adjusted mean |
0.088 |
0.426 |
3F |
Adjusted mean |
0.090 |
0.432 |
4F |
Adjusted mean |
0.086 |
0.477 |
Table 22: Macropathology – group distribution of findings for males killed at scheduled termination (F0)
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex: No of animals: |
1M 10 |
2M 10 |
3M 10 |
4M 10 |
Number of animals within normal limits |
10 |
10 |
10 |
10 |
Table 23: Macropathology – group distribution of findings for females killed on Day 13 of lactation (F0)
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex: No of animals: |
1F 10 |
2F 8 |
3F 8 |
4F 10 |
Number of animals within normal limits |
9 |
8 |
8 |
9 |
|
Skin and Subcutis Hair Loss |
0 |
0 |
0 |
1 |
|
Uterus Abnormal contents Mass(es) |
1 1 |
0 0 |
0 0 |
0 0 |
Table 24: Histopathology – group distribution of findings for males killed at scheduled termination (F0)
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex: No of animals: |
1M 10 |
2M 10 |
3M 10 |
4M 10 |
Epididymides Infiltrate, Inflammatory Cell |
No. examined Minimal Total |
10 2 2 |
0 0 0 |
0 0 0 |
10 3 3 |
Testes |
No. examined |
10 |
0 |
0 |
10 |
Table 25: Histopathology – group distribution of findings for females killed on Day 13 of lactation (F0)
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex: No of animals: |
1F 10 |
2F 8 |
3F 8 |
4F 10 |
Ovaries |
No. examined
|
10
|
0
|
0
|
10
|
Uterus Implantation site(s)
Dilatation, Luminal |
No. examined Total Minimal Total |
1 1 1 1 |
0 0 0 0 |
0 0 0 0 |
0 0 0 0 |
Table 26: Mean serum T4 concentrations (pg/mL)
Group |
Treatment |
Dose (mg/kg/day) |
|
Adult terminal males |
Male offspring on Day 13 of age |
Female offspring on Day 13 of age |
1 |
Control (Corn Oil) |
0 |
Mean |
43300 |
50700 |
59200 |
SD |
7610 |
10800 |
14400 |
|||
CV % |
17.6 |
21.3 |
24.3 |
|||
N |
10 |
10 |
10 |
|||
2 |
Ethylal |
300 |
Mean |
46000 |
56500 |
51500 |
SD |
7590 |
18300 |
6230 |
|||
CV % |
16.5 |
32.4 |
12.1 |
|||
N |
10 |
8 |
8 |
|||
3 |
Ethylal |
600 |
Mean |
47100 |
55700 |
63200 |
SD |
7000 |
15800 |
14800 |
|||
CV % |
14.9 |
28.4 |
23.4 |
|||
N |
10 |
8 |
8 |
|||
4 |
Ethylal |
1000 |
Mean |
44300 |
59300 |
46400 |
SD |
5960 |
10600 |
12400 |
|||
CV % |
13.5 |
17.9 |
26.7 |
|||
N |
10 |
10 |
10 |
Applicant's summary and conclusion
- Conclusions:
- It was concluded that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development that the no observed adverse effect level (NOAEL) for Ethylal was 1000 mg/kg/day.
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