Registration Dossier
Registration Dossier
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 219-909-0 | CAS number: 2568-90-3
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Reproductive/Development toxicity screening study in the Sprague-Dawley rat by oral gavage administration
The purpose of this study was a screening test for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of the test item, Butylal, by oral gavage administration for at least four weeks.
Three groups of ten male and ten female rats received Butylal at doses of 100, 300 or 1000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of four consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 13 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, corn oil, at the same volume dose (5 mL/kg/day) as the treated groups.
During the study, clinical condition, body weight, food consumption, estrous cycles, pre‑coital interval, mating performance, fertility, gestation length, thyroid hormone analysis, organ weight and macroscopic pathology and histopathology investigations were undertaken.
The clinical condition, litter size and survival, sex ratio, body weight, ano-genital distance and macropathology for all offspring were also assessed. Nipple counts were performed on male offspring on Day 13 of age. Blood samples were collected from selected offspring on Day 4 and Day 13 of age for thyroid hormone analysis.
Treatment of Butylal to parental animals at 100, 300 or 1000 mg/kg/day for two weeks before pairing, during pairing and then up to termination of the males after 4 weeks of treatment and females on Day 13 of lactation was well tolerated. There was no adverse effect on parental clinical condition, body weight performance, food consumption, thyroid hormones, estrus cycles, mating performance, fertility, macropathology or histopathology. The clinical condition and survival of the subsequent F1 offspring were also unaffected by parental treatment.
Adverse findings were limited to offspring derived from the group that received 1000 mg/kg/day which had low absolute weight and bodyweight gain from Day 1 of age. This effect on offspring bodyweight was in the absence of any effect on offspring survival, general condition or thyroid hormones and within the context of this screening study is considered to not warrant the classification of the test item as a reproductive toxicant.
It was therefore concluded that the no observed adverse effect level (NOAEL) was 1000 mg/kg/day for parental systemic toxicity and reproductive parental toxicity. For offspring development 1000 mg/kg/day was considered to be the lowest observed adverse effect level (LOAEL) with a NOAEL of 300 mg/kg/day.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 20 September 2018 to 25 June 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- 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.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: males: 69 to 76 days old; females: 83 to 89 days old
- Weight at study initiation: (P) Males: 283-373 g; Females: 251-304 g
- Fasting period before study: no
- Housing: Pre-pairing up to four animals of one sex
Pairing one male and one female
Males after mating up to four animals
Gestation one female
Lactation one female + litter
- Diet: ad libitum SDS VRF1 Certified pelleted diet
- Water: ad libitum Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals.
- Acclimation period: Males: six days prior to the commencement of treatment. Females: 20 days prior to the commencement of treatment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24ºC
- Humidity (%): 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
IN-LIFE DATES: From: 10 October 2018 To: 22 December 2018 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Starting with the lowest concentration, the required amount of test item was weighed. Approximately 50% of the final volume of vehicle was added and magnetically stirred until the test material was uniformly mixed. The remaining vehicle was added to achieve the required volume and the formulation was mixed using a magnetic stirrer until homogeneous.
VEHICLE
- Concentration in vehicle: 0, 20, 60 and 200 mg/ml
- Amount of vehicle (if gavage): 5ml/kg - Details on mating procedure:
- - M/F ratio per cage: 1:1 from within the same treatment groups
- Length of cohabitation: Up to two weeks
- Proof of pregnancy: Ejected copulation plugs in cage tray and sperm in the vaginal smear. Day 0 of gestation: When positive evidence of mating was detected
- After successful mating each pregnant female was caged individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of each formulation prepared for administration in the first and last weeks of treatment were analyzed for achieved concentration of the test item.
The analytical method involved extraction and dilution in acetone followed by gas chromatographic analysis with flame ionization detection. Sample concentrations were determined with reference to external standards prepared in the concentration range 10 μg/mL to 100 μg/mL.
For the First and Last Week of dosing, all groups were sampled (4 × 1 mL, accurately weighed) from the middle of the formulation by Pharmacy personnel.
Two samples from each group were analyzed in accordance with the analytical procedure. The remaining samples were retained for contingency. Samples were disposed of once results were obtained.
Procedural recoveries were prepared as a quality control measure and were not used to correct for the formulation samples.
The mean concentrations of Butylal in test formulations analyzed during the study and the deviation of the mean result from the nominal value are detailed in Table 1.
The mean concentrations were within +10/-15% of the nominal concentration, confirming accurate formulation. The percentage difference from mean values remained within 2%, confirming precise analysis.
Procedural recovery values were within the validated range confirming the continued accuracy of the analytical procedure. - Duration of treatment / exposure:
- Dosing was restricted to the F0 generation. Animals of the F1 generation were not dosed directly.
Once daily at approximately the same time each day. Animals were not dosed if parturition was in progress at the scheduled time of administration.
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 - Frequency of treatment:
- Once daily at approximately the same time each day
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels of 0, 100, 300 and 1000 mg/kg/day were selected in conjunction with the Sponsor based on findings from a preliminary 4-week repeat dose toxicity study in the Sprague-Dawley rat.
In the 4-week preliminary study dose levels of 500, 750, and 1000 mg/kg/day had no effect on general condition, body weight, food consumption or macropathology. Effects were limited to high liver weights for males that received 1000 mg/kg/day and for females at all dose levels.
It was therefore considered that a high dose of 1000 mg/kg/day would be tolerated in this OECD 421 screening study. The low and intermediate doses were 100 and 300 mg/kg/day, providing approximate 3-fold dose increments and allowing investigation of any dose-related response.
- Rationale for animal assignment: On arrival and non-selective allocation to cages - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 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).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed observations were recorded at the following times in relation to dose administration: Pre-dose observation, One to two hours after completion of dosing, As late as possible in the working 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, 7 and 13
BODY WEIGHT: Yes
- Time schedule for examinations: 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, 7 and 13 of lactation, On the day of necropsy.
FOOD CONSUMPTION AND COMPOUND INTAKE:
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.
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.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
PARTURITION OBSERVATIONS AND GESTATION LENGTH:
Duration of gestation: Time elapsing between the detection of mating and commencement of parturition.
Parturition 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. - 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 (nominally Days 10 to 13 of lactation). - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups, thyroid hormone analysis. Particular attention was paid to the external reproductive genitals which should be examined for signs of altered development; gross evaluation of external genitalia
GROSS EXAMINATION OF DEAD PUPS:
yes
Premature deaths: Where possible, a fresh macroscopic examination (external and internal) with an assessment of stomach for milk content - Postmortem examinations (parental animals):
- SACRIFICE
Sequence: To allow satisfactory inter-group comparison
GROSS NECROPSY
All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected for thyroid hormone analysis: Scheduled kill - Day 13 of age
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
F1 offspring on Day 4 of age: Externally normal offspring were discarded without examination. Externally abnormal offspring were subject to an external macroscopic examination and retained pending possible future examination.
F1 offspring on Day 13 of age: All animals were subject to an external macroscopic examination; particular attention was paid to the external genitalia. Abnormalities were retained in appropriate fixative. Thyroid glands were preserved from two offspring per litter, one male and one female in each litter, where possible. - Statistics:
- Statistical analyses were performed on the majority of data presented and results of these tests, whether significant or non-significant, are presented on the relevant tables. For some parameters, including estrous cycles before treatment, pre coital interval, mating performance, gestation length and index and stage of estrous cycle at termination, the similarity of the data was such that analyses were not considered to be necessary.
All statistical analyses were carried out separately for males and females. Data relating to food consumption were analyzed on a cage basis. For all other adult parameters, the analyses were carried out using the individual animal as the basic experimental unit. For litter/fetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population.
A parametric analysis was performed if Bartlett's test for variance homogeneity (Bartlett 1937) was not significant at the 1% level. A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. - Reproductive indices:
- Estrous Cycle
The incidence and percentage females showing the following classifications of estrous cycles before treatment commenced and during treatment are presented:
Regular: All observed cycles of 4 or 5 days (divided into cycles of 4, 4 and 5 and 5 days)
Irregular: At least one cycle of 2, 3 or 6 to 10 days
Acyclic: At least 10 days without estrus
Vaginal smearing prior to termination is presented in terms of numbers of females that showed estrus during this period and the cycle stage at termination.
Pre-Coital Interval
Individual intervals were tabulated for females only, for the time elapsing between initial pairing and mating. Percentage of females with pre-coital intervals calculated for durations of 1-4, 5-8, 9-12 and 13-14 days of pairing.
Mating Performance and Fertility
Individual data were tabulated. Group values were calculated for males and females separately for the following:
Percentage mating (%) = (Number of animals mating x 100) / Animals paired
Conception rate (%) = (Number of animals achieving pregnancy x 100) / Animals mated
Fertility index (%) = (Number of animals achieving pregnancy x 100) /Animals paired
Gestation Length and Index
Gestation length was calculated as the number of gestation days up to and including the day on which offspring were first observed, with Day 1 = day of mating for calculation purposes. Where parturition had started overnight, this value was adjusted by subtracting half of one day. Gestation index was calculated for each group as:
Gestation index (%) = (Number of live litters born x 100) / Number pregnant - Offspring viability indices:
- The following were calculated for each litter:
Post-implantation survival index (%) = (Total number of offspring born x 100) / Total number of uterine implantation sites
Post-implantation survival index was expressed as 100% where the number of offspring exceeded the number of implantation sites recorded.
Live birth index (%) = (Number of live offspring on Day 1 after littering x 100) / Total number of offspring born
Viability index (%) = (Number of live offspring on Day 4 (before blood sampling) x 100) / Number live offspring on Day 1 after littering
Lactation index (%) = (Number of live offspring on Day 13 after littering x 100) / Number of live offspring on Day 4 (after blood sampling) - Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no signs at routine physical examination that could be related to treatment.
Signs associated with dose administration were limited to a low incidence of increased salivation with associated chin rubbing for animals receiving 1000 mg/kg/day; these signs are often seen in association with dosing by oral gavage and are considered to relate to the palatability of the formulations rather than a direct effect of treatment with the test item. - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gain for males during treatment and for females before pairing was unaffected by treatment.
During early gestation (GD0-7) females receiving 1000 mg/kg/day showed significantly low weight gain when compared with Controls (p<0.05); however subsequent weight gain and the overall weight gain during gestation was essentially similar to Controls.
During lactation the absolute body weights for females receiving 1000 mg/kg/day on LD1 and LD7 were slightly but significantly low when compared with Controls (p<0.05). Body weight gain (LD7-13 and LD1-13) for females at 1000 mg/kg/day was high when compared with Controls although the difference did not attain statistical significance.
Body weight gain at 100 and 300 mg/kg/day was unaffected by treatment during both gestation and lactation. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption for the two-week period before pairing was unaffected by treatment.
During GD14-19 food consumption for females receiving 1000 mg/kg/day was low when compared with Controls with the difference attaining statistical significance (p<0.01).
During lactation food consumption for females receiving 1000 mg/kg/day was slightly low at approximately 94% of Controls; however, the differences for each recording period did not attain statistical significance.
Food consumption at 100 and 300 mg/kg/day was unaffected by treatment during both gestation and lactation. - Endocrine findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Individual serum TSH concentrations were found to be variable.
Both male and female mean serum TSH concentrations were slightly low in the groups that received Butylal via oral gavage when compared with the Control Group. However, these differences did not attain statistical significance.
Thyroxine levels in females that received 1000 mg/kg/day and in F1 offspring on Day 13 of age at 300 or 1000 mg/kg/day were slightly low when compared with Controls; this was not evident in F0 males or F1 female offspring on Day 4 of age. The data was highly variable and the differences from Control were slight, therefore there was no conclusive evidence that could attribute this to treatment with Butylal. - Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The microscopic examination performed after at least 4 weeks of treatment revealed no test item related lesions in the tissues examined (testes, epididymides and ovaries).
Incidental Findings:
All histological changes were considered to be unrelated to treatment.
One Group 3 female had a mammary adenocarcinoma which is an incidental finding and not unusual in female rats of this age.
Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages. No cell or stage specific abnormalities were noted. - Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Estrous cycles during treatment, pre-coital interval, mating performance, fertility, gestation length and gestation index were unaffected by parental treatment. At termination all females were confirmed to be in diestrus.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Estrous cycles during treatment, pre-coital interval, mating performance, fertility, gestation length and gestation index were unaffected by parental treatment. At termination all females were confirmed to be in diestrus.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
- histopathology: non-neoplastic
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no signs that were considered to relate to treatment
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- The mean number of implantations for females receiving 1000 mg/kg/day was slightly but significantly high when compared with Controls; subsequent litter size was slightly high but these differences did not attain statistical significance. This difference was not considered to be of any toxicological significance.
Litter size at 100 or 300 mg/kg/day and offspring survival at all dose levels was unaffected by parental treatment.
The mean percentage of male offspring in the treated groups was slightly but significantly low when compared with Controls on Day 1 and 4 of age (the values on Day 4 and 13 after females are selected to provide blood samples of T4 analysis are not considered relevant); however this is considered to be unrelated to treatment as the Control mean was atypically high. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg/day the absolute mean body weight for offspring on Day 1 of age (p<0.01) and subsequent mean weight gain up to termination on Day 13 of age was low when compared with Controls (80% of Controls for male offspring, p<0.05, and 84% of Controls for female offspring); the mean values at 1000 mg/kg/day exceeded the historical control range.
Offspring body weight at 100 or 300 mg/kg/day was unaffected by parental treatment. - Anogenital distance (AGD):
- no effects observed
- Description (incidence and severity):
- Ano-genital distance for both male and female offspring was unaffected by parental treatment.
- Nipple retention in male pups:
- no effects observed
- Description (incidence and severity):
- No nipples were apparent for male offspring on Day 13 of age
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopic examination of offspring that either died prematurely or at scheduled termination did not reveal any findings that could be related to parental treatment
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- Treatment of Butylal to parental animals at 100, 300 or 1000 mg/kg/day for two weeks before pairing, during pairing and then up to termination of the males after 4 weeks of treatment and females on Day 13 of lactation was well tolerated. There was no adverse effect on parental clinical condition, body weight performance, food consumption, thyroid hormones, estrus cycles, mating performance, fertility, macropathology or histopathology. The clinical condition and survival of the subsequent F1 offspring were also unaffected by parental treatment.
Adverse findings were limited to offspring derived from the group that received 1000 mg/kg/day which had low absolute weight and bodyweight gain from Day 1 of age. This effect on offspring bodyweight was in the absence of any effect on offspring survival, general condition or thyroid hormones and within the context of this screening study is considered to not warrant the classification of the test item as a reproductive toxicant.
It was therefore concluded that the no observed adverse effect level (NOAEL) was 1000 mg/kg/day for parental systemic toxicity and reproductive parental toxicity. For offspring development 1000 mg/kg/day was considered to be the lowest observed adverse effect level (LOAEL) with a NOAEL of 300 mg/kg/day. - Executive summary:
The purpose of this study was a screening test for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of the test item, Butylal, by oral gavage administration for at least four weeks.
Three groups of ten male and ten female rats received Butylal at doses of 100, 300 or 1000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of four consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 13 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, corn oil, at the same volume dose (5 mL/kg/day) as the treated groups.
During the study, clinical condition, body weight, food consumption, estrous cycles, pre‑coital interval, mating performance, fertility, gestation length, thyroid hormone analysis, organ weight and macroscopic pathology and histopathology investigations were undertaken.
The clinical condition, litter size and survival, sex ratio, body weight, ano-genital distance and macropathology for all offspring were also assessed. Nipple counts were performed on male offspring on Day 13 of age. Blood samples were collected from selected offspring on Day 4 and Day 13 of age for thyroid hormone analysis.
Results
Parental responses
General condition, estrous cycles, mating performance, fertility, gestation length/index, thyroid hormones, macropathology, organ weights and histopathology were unaffected by treatment at dose levels up to and including 1000 mg/kg/day.
Body weight and food consumption during the two week period prior to pairing for mating was unaffected by treatment at dose levels up to and including 1000 mg/kg/day.
During gestation females receiving 1000 mg/kg/day showed low weight gain during the first week of gestation (GD0-7); however overall body weight gain during gestation was similar to Controls.
During lactation females receiving 1000 mg/kg/day had low absolute body weight during Week 1 (LD1 and LD7); these females showed slightly high weight gain during Week 2 of lactation, resulting in a mean body weight on Day 13 that was similar to Controls.
At 1000 mg/kg/day females showed low food consumption during the last week of gestation (GD14-19) and the last week of lactation (LD7-13).
Bodyweight and food consumption after mating and during lactation for females receiving 100 or 300 mg/kg/day was unaffected by treatment.
Litter responses
Litter size, offspring survival, sex ratio, ano-genital distance, general condition, thyroid hormones and macropathology showed no adverse effects of parental treatment.
At 1000 mg/kg/day the absolute mean body weight for offspring on Day 1 of age and subsequent mean weight gain up to termination on Day 13 of age was low when compared with Controls (80% of Controls for male offspring, p<0.05, and 84% of Controls for female offspring)
Offspring body weight at 100 or 300 mg/kg/day was unaffected by parental treatment.
Conclusion
Treatment of Butylal to parental animals at 100, 300 or 1000 mg/kg/day for two weeks before pairing, during pairing and then up to termination of the males after 4 weeks of treatment and females on Day 13 of lactation was well tolerated. There was no adverse effect on parental clinical condition, body weight performance, food consumption, thyroid hormones, estrus cycles, mating performance, fertility, macropathology or histopathology. The clinical condition and survival of the subsequent F1 offspring were also unaffected by parental treatment.
Adverse findings were limited to offspring derived from the group that received 1000 mg/kg/day which had low absolute weight and bodyweight gain from Day 1 of age. This effect on offspring bodyweight was in the absence of any effect on offspring survival, general condition or thyroid hormones and within the context of this screening study is considered to not warrant the classification of the test item as a reproductive toxicant.
It was therefore concluded that the no observed adverse effect level (NOAEL) was 1000 mg/kg/day for parental systemic toxicity and reproductive parental toxicity. For offspring development 1000 mg/kg/day was considered to be the lowest observed adverse effect level (LOAEL) with a NOAEL of 300 mg/kg/day.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Study performed according to OECD TG 421 and GLP; Klimisch code 1
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Short description of key information:
no data available
Effects on developmental toxicity
Description of key information
Prenatal Developmental Toxicity Study rats - oral gavage
The purpose of this study was to assess of the influence of Butylal (an industrial chemical) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Sprague-Dawley rat.
Three groups of 20 females received Butylal at doses of 100, 330 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, corn oil at the same volume dose as treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.
Clinical observations, body weight and food consumption were recorded. On Day 20 after mating adult females were subject to macroscopic and microscopic pathology investigation and the gravid uterine weight and thyroid weight recorded. Ano-genital distance were measured for all fetuses and were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
Oral administration of Butylal to pregnant Sprague-Dawley rats during organogenesis and the fetal growth phase at 100, 330 and 1000 mg/kg/day was well tolerated with no effects on maternal clinical condition, thyroid weight and associated hormones or macropathology.
Embryo-fetal survival, fetal weight and ano-genital distance were unaffected by maternal treatment.
Maternal effects were limited to low body weight gain, adjusted maternal weight gain and food consumption at 1000 mg/kg/day. In addition the gravid uterine weight for females at 1000 mg/kg/day was low but in the absence of any effect on litter size or fetal weight this was not considered to be toxicologically significant.
Fetal effects were limited to a non-adverse increase in the fetal/litter incidence of the skeletal variant of short supernumerary 14th rib at 1000 mg/kg/day.
Based on the findings in this study the no observed adverse effect level for both maternal animals and embryo-fetal development was considered to be 1000 mg/kg/day.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 9 JANUARY 2019 to 06 APRIL 2019
- Reliability:
- 1 (reliable without restriction)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2018
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: Approximately 71 days old
- Weight at study initiation: 211 to 281 g
- Fasting period before study: No
- Housing: Acclimatization: up to four animals; During pairing: one (stock) male and one female ; Gestation: one female
- Diet (e.g. ad libitum): SDS VRF1 Certified pelleted diet. ad libitum
- Water (e.g. ad libitum): Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals. ad libitum
- Acclimation period: Five days before commencement of pairing
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24ºC
- Humidity (%): 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 dark : 12 hours light
IN-LIFE DATES: From: 16 January 2019 To: 11 to 14 February 2019 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The required amount of test material was weighed out into a suitable container. Approximately 50% of the final volume of vehicle was added to the test material and mixed with a magnetic stirrer until homogenous. The solution was then made up to the required volume with vehicle. The formulation was transferred to a final container and mixed with a magnetic stirrer until homogenous.
A series of suspensions at the required concentrations were prepared by dilution of individual weighings of the test item.
VEHICLE
- Concentration in vehicle: 0, 20, 66, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analytical method involved extraction and dilution in acetone followed by gas chromatographic analysis with flame ionization detection. Sample concentrations were determined with reference to external standards prepared in the concentration range 10 μg/mL to 100 μg/mL.
An accurate volume of internal standard solution (100 μL) was added to all standard and sample solutions (1000 μL) and mixed by vortex to provide a final concentration of ca. 50 μg/mL of tetradecane. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1 with identified stock males
- Proof of pregnancy: Ejected copulation plugs in cage tray and vaginal smears were checked for the presence of sperm referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Females were treated from Day 6 to Day 19 (inclusive) after mating
- Frequency of treatment:
- Daily (at approximately the same time each day)
- Duration of test:
- up to day 20 (necropsy)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 330 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 20 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels of 0, 100, 330 and 1000 mg/kg/day were selected in conjunction with the Sponsor based on findings from a preliminary embryo-fetal development study conducted at these laboratories.
In the preliminary study oral administration of Butylal at 250, 500 and 1000 mg/kg/day was well tolerated with no effects on maternal clinical condition, macropathology, embryo-fetal survival or development. Effects were limited to low maternal body weight gain at 500 and 1000 mg/kg/day and low maternal food consumption at 1000 mg/kg/day.
Based on these findings there was nothing to preclude the use of 1000 mg/kg/day as the high dose level in this study. Dose levels of 100 and 330 mg/kg/day were then selected as low and intermediate dose levels to provide approximate 3-fold dose intervals and to allow assessment of any dose response. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health
BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each adult was recorded on Days 0, 3, 6-20 after mating.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 0-2, 3-5, 6-9, 10-13, 14-17 and 18-19 inclusive after mating
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative. - 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: Number of fetuses live and dead - Fetal examinations:
- - External examinations: Yes: Examination of all viable fetuses and placentae
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes - Statistics:
- For all adult parameters, the analyses were carried out using the individual animal as the basic experimental unit. For litter/fetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population.
- Historical control data:
- Historical control data on major fetal examinations, skeletal fetal examinations and visceral fetal examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Two animals receiving 1000 mg/kg/day showed increased salivation; this is often associated with dosing and is considered to relate to the palatability of the formulation rather than a direct effect of treatment
Tables 2 and 3 - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Overall group mean body weight gain during treatment (Gestation Days 6 to 19) for females receiving 1000 mg/kg/day was low when compared with Controls (p<0.01) and mean body weight at the end of dosing (GD 20) was significantly low when compared with Controls (p<0.05). For females receiving 100 or 330 mg/kg/day mean body weight gain during treatment was similar to the Controls.
At 1000 mg/kg/day the gravid uterine weight was low when compared with Controls (p<0.05) and the maternal body weight gain following adjustment for the gravid uterine weight was also low for females at the high dose (p<0.01); the gravid uterine weight and adjusted maternal weight gain at 100 or 330 mg/kg/day were similar to the Controls.
Tables 4 and 5 - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- During the treatment period group mean food consumption was low for females receiving 1000 mg/kg/day; with the difference attaining statistical significance GD6-9 (p<0.05) and GD10-17 (p<0.01).
Overall food consumption for females receiving 100 or 330 mg/kg/day was similar to the Controls.
Table 6 - Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Thyroid weight for females on GD20 were unaffected by treatment with Butylal.
Table 7 - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopic examination of females on Day 20 after mating did not reveal any findings that could be attributed to treatment.
Table 8 - Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Microscopic examination of the thyroid glands showed no changes that could be related to treatment with Butylal.
Table 9 - Other effects:
- no effects observed
- Description (incidence and severity):
- There was no clear effect on serum T3 concentrations and its prohormone T4 in pregnant rats following administration of Butylal.
There was no dose related effect evident on serum TSH concentrations in pregnant rats after the administration of Butylal via oral gavage. - Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Table 11
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Table 1
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Table 11
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Tables 10 and 11
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Table 11
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- changes in number of pregnant
- clinical signs
- dead fetuses
- early or late resorptions
- food consumption and compound intake
- gross pathology
- histopathology: non-neoplastic
- maternal abnormalities
- mortality
- necropsy findings
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Placental, litter or fetal weights were unaffected by maternal treatment.
Table 12 - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- Tables 10 and 12
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Table 11
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Placental, litter or fetal weights were unaffected by maternal treatment.
Table 12 - External malformations:
- no effects observed
- Description (incidence and severity):
- Ano-genital of fetuses on GD20 were unaffected by maternal treatment with Butylal.
Table 13
There was no evidence on an increase in major malformations associated with administration of Butylal treatment
Tables 14, 15,16 and 17 - Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- At 330 and 1000 mg/kg/day there was an increased incidence of short supernumerary 14th rib when compared with the concurrent Controls; the fetal and litter incidence at 1000 mg/kg/day was outside the Historical Control data (HCD) range. Studies have shown that this finding does not persist in the rat and therefore in isolation the increased incidence in this variant is considered not to be adverse.
In the intermediate and high dose groups, there appeared to be lower incidences of incompletely ossified cranial centres, hyoid, sternebrae and sacrocaudal vertebrae compared to the Control group and in the low dose group (100 mg/kg/day). However, all incidences were within HCD ranges and therefore it was concluded that these findings at 330 and 1000 mg/kg/day are not adverse.
Tables 18, 19, 20 and 21 - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Tables 22, 23, 24 and 25
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
- external malformations
- skeletal malformations
- visceral malformations
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Oral administration of Butylal to pregnant Sprague-Dawley rats during organogenesis and the fetal growth phase at 100, 330 and 1000 mg/kg/day was well tolerated with no effects on maternal clinical condition, thyroid weight and associated hormones or macropathology. Embryo-fetal survival, fetal weight and ano-genital distance were unaffected by maternal treatment.
Maternal effects were limited to low body weight gain, adjusted maternal weight gain and food consumption at 1000 mg/kg/day. In addition the gravid uterine weight for females at 1000 mg/kg/day was low but in the absence of any effect on litter size or fetal weight this was not considered to be toxicologically significant.
Fetal effects were limited to a non-adverse increase in the fetal/litter incidence of the skeletal variant of short supernumerary 14th rib at 1000 mg/kg/day.
Based on the findings in this study the no observed adverse effect level for both maternal animals and embryo-fetal development was considered to be 1000 mg/kg/day. - Executive summary:
The purpose of this study was to assess of the influence of Butylal (an industrial chemical) on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Sprague-Dawley rat.
Three groups of 20 females received Butylal at doses of 100, 330 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, corn oil at the same volume dose as treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.
Clinical observations, body weight and food consumption were recorded. On Day 20 after mating adult females were subject to macroscopic and microscopic pathology investigation and the gravid uterine weight and thyroid weight recorded. Ano-genital distance were measured for all fetuses and were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.
Results and conclusion
Oral administration of Butylal to pregnant Sprague-Dawley rats during organogenesis and the fetal growth phase at 100, 330 and 1000 mg/kg/day was well tolerated with no effects on maternal clinical condition, thyroid weight and associated hormones or macropathology. Embryo-fetal survival, fetal weight and ano-genital distance were unaffected by maternal treatment.
Maternal effects were limited to low body weight gain, adjusted maternal weight gain and food consumption at 1000 mg/kg/day. In addition the gravid uterine weight for females at 1000 mg/kg/day was low but in the absence of any effect on litter size or fetal weight this was not considered to be toxicologically significant.
Fetal effects were limited to a non-adverse increase in the fetal/litter incidence of the skeletal variant of short supernumerary 14th rib at 1000 mg/kg/day.
Based on the findings in this study the no observed adverse effect level for both maternal animals and embryo-fetal development was considered to be 1000 mg/kg/day.
Reference
| Control | Butylal | ||
Dose group | 1 | 2 | 3 | 4 |
Dose (mg/kg/day) | 0 | 100 | 330 | 1000 |
Table 1: Summary of maternal disposition
| Group 1 | Group 2 | Group 3 | Group 4 |
| Number of animals | |||
Number mated | 20 | 20 | 20 | 20 |
Number not pregnant | 0 | 0 | 0 | 0 |
Number pregnant | 20 | 20 | 20 | 20 |
Number of early deliveries | 0 | 0 | 0 | 0 |
Number of litters with dead fetuses | 0 | 0 | 0 | 0 |
Number of litters with resorptions | 8 | 10 | 7 | 9 |
Number of litters subject to fetal pathology | 20 | 20 | 20 | 20 |
Table 2: Signs associated with dosing – group distribution of observations during gestation
|
|
| Number of animals affected | |||
Category | Observation | Group/Sex: Initial no: | 1F 20 | 2F 20 | 3F 20 | 4F 20 |
Behavior | Salivation |
| 0 | 0 | 0 | 2 |
Table 3: Clinical signs – group distribution of observations during gestation
|
|
| Number of animals affected | |||
Category | Observation | Group/Sex: Initial no: | 1F 20 | 2F 20 | 3F 20 | 4F 20 |
Behavior | Salivation Vocalization |
| 0 0 | 0 0 | 0 0 | 2 1 |
Coat | Hair loss, Forelimbs Hair loss, Hindlimbs Hair loss, Ventral surface |
| 3 1 1 | 1 0 0 | 0 0 0 | 1 0 0 |
Skin | Encrustation, Ear – right Encrustation, Hindlimb – left |
| 0 1 | 1 0 | 0 0 | 0 0 |
Staining | Abnormal color, Brown, Ears Abnormal color, Brown, Forelimbs Abnormal color, Brown, Head Abnormal color, Brown, Upper dorsal surface |
| 1 1 3 1 | 0 0 2 3 | 0 0 1 1 | 0 0 0 1 |
Table 4: Body weight and body weight change - group mean values (g) during gestation
Group /Sex |
| Day | ||||||||||||
0 | 3 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | ||
Statistics test | Av | Av | Av | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | |
1F | Mean | 245 | 261 | 277 | 278 | 282 | 286 | 291 | 297 | 304 | 307 | 312 | 320 | 331 |
| SD | 17.8 | 18.6 | 19.6 | 18.4 | 17.6 | 18.7 | 18.7 | 18.9 | 20.1 | 20.7 | 20.7 | 21.4 | 22.3 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
2F | Mean | 247 | 265 | 280 | 281 | 285 | 290 | 295 | 302 | 306 | 311 | 317 | 325 | 336 |
| SD | 19.3 | 21.0 | 22.0 | 22.6 | 22.8 | 22.1 | 24.1 | 24.7 | 25.2 | 24.7 | 25.3 | 26.1 | 25.8 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
3F | Mean | 244 | 262 | 277 | 276 | 280 | 285 | 291 | 297 | 301 | 306 | 311 | 317 | 328 |
| SD | 18.6 | 19.5 | 19.7 | 20.7 | 20.5 | 21.5 | 21.9 | 22.2 | 22.4 | 22.6 | 22.7 | 23.7 | 23.2 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
4F | Mean | 244 | 260 | 275 | 271 | 274 | 277 | 284 | 290 | 294 | 298 | 305 | 311 | 319 |
| SD | 14.4 | 14.8 | 15.3 | 14.5 | 13.7 | 16.9 | 14.8 | 15.0 | 14.9 | 14.9 | 14.3 | 14.8 | 16.1 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
Table 4 (cont): Body weight and body weight change - group mean values (g) during gestation
Group /Sex |
| Day 17 |
18 |
19 |
20 | Change 0-3 | Change 0-6 | Change 6-7 | Change 6-8 | Change 6-9 | Change 6-10 | Change 6-11 | Change 6-12 |
Statistics test | Wi | Wi | Wi | Wi | Av | Av | Wi | Wi | Sh | Wi | Wi | Wi | |
1F | Mean | 345 | 360 | 373 | 389 | 16 | 32 | 1 | 4 | 9 | 13 | 20 | 26 |
| SD | 23.6 | 24.9 | 27.8 | 29.9 | 6.1 | 6.9 | 3.6 | 5.2 | 4.4 | 5.0 | 4.7 | 5.7 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
2F | Mean | 350 | 366 | 381 | 396 | 18 | 34 | 0 | 4 | 10 | 14 | 21 | 26 |
| SD | 26.5 | 27.6 | 29.3 | 30.2 | 5.5 | 6.3 | 4.2 | 2.9 | 4.8 | 6.0 | 5.7 | 6.5 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
3F | Mean | 341 | 356 | 368 | 385 | 18 | 33 | -1 | 3 | 8 | 14 | 19 | 24 |
| SD | 27.1 | 26.0 | 27.6 | 28.1 | 4.4 | 5.9 | 4.4 | 3.8 | 4.6 | 5.0 | 5.9 | 6.4 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
4F | Mean | 329* | 343* | 354* | 368* | 15 | 31 | -4** | -1** | 2** | 9* | 15** | 18** |
| SD | 15.5 | 17.4 | 16.8 | 19.0 | 3.4 | 5.8 | 5.0 | 5.0 | 9.1 | 5.4 | 5.7 | 5.6 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
Table 4 (cont): Body weight and body weight change - group mean values (g) during gestation
Group /Sex |
| Change 6-13 | Change 6-14 | Change 6-15 | Change 6-16 | Change 6-17 | Change 6-18 | Change 6-19 | Change 6-20 |
Statistics test | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | |
1F | Mean | 30 | 35 | 43 | 54 | 68 | 83 | 96 | 111 |
| SD | 5.1 | 4.9 | 5.4 | 6.5 | 7.9 | 9.9 | 13.6 | 15.4 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
2F | Mean | 30 | 36 | 44 | 55 | 69 | 86 | 100 | 116 |
| SD | 6.0 | 6.8 | 8.8 | 9.4 | 10.4 | 11.3 | 14.0 | 13.2 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
3F | Mean | 29 | 34 | 40 | 51 | 64 | 79 | 91 | 107 |
| SD | 6.1 | 5.6 | 7.4 | 7.6 | 11.3 | 11.2 | 13.5 | 14.9 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
4F | Mean | 23** | 30** | 36** | 44** | 54** | 68** | 79** | 93** |
| SD | 6.8 | 6.4 | 7.3 | 8.0 | 8.9 | 9.4 | 11.4 | 13.1 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
Table 5: Gravid uterine weight, adjusted body weight and adjusted body weight change - group mean values (g) on Day 20 of gestation
Group /Sex |
| Body weight Day 6 | Terminal body weight Day 20 | Body weight change 6-20 | Gravid uterine weight | Adjusted body weight Day 20 | Adjusted body weight change 6-20 |
Statistics test | Av | Wi | Wi | Wi | Wi | Wi | |
1F | Mean | 277 | 389 | 111 | 86.4 | 302 | 25 |
| SD | 19.6 | 30.2 | 15.6 | 15.01 | 25.1 | 8.5 |
| N | 20 | 20 | 20 | 20 | 20 | 20 |
2F | Mean | 280 | 397 | 117 | 90.1 | 307 | 26 |
| SD | 22.0 | 30.1 | 13.6 | 8.13 | 25.4 | 9.7 |
| N | 20 | 20 | 20 | 20 | 20 | 20 |
3F | Mean | 277 | 385 | 108 | 83.0 | 302 | 24 |
| SD | 19.7 | 28.2 | 14.9 | 11.89 | 24.6 | 8.3 |
| N | 20 | 20 | 20 | 20 | 20 | 20 |
4F | Mean | 275 | 368* | 93** | 78.3* | 290 | 14** |
| SD | 15.3 | 19.0 | 13.0 | 11.54 | 14.0 | 7.5 |
| N | 20 | 20 | 20 | 20 | 20 | 20 |
Table 6: Food consumption - group mean values (g/animal/day) during gestation
Group /Sex |
| Day 0-2 |
3-5 |
6-9 |
10-13 |
14-17 |
18-19 | Total 6-19 | As % Control |
Statistics test | Av | Av | Wi | Wi | Wi | Wi |
|
| |
1F | Mean | 20 | 22 | 19 | 21 | 24 | 21 | 298 | - |
| SD | 1.9 | 1.7 | 1.9 | 1.9 | 1.6 | 3.0 |
|
|
| N | 20 | 20 | 20 | 20 | 20 | 20 |
|
|
2F | Mean | 22 | 24 | 20 | 22 | 24 | 22 | 309 | 103 |
| SD | 2.9 | 2.6 | 2.6 | 2.5 | 2.7 | 3.0 |
|
|
| N | 20 | 20 | 20 | 20 | 20 | 20 |
|
|
3F | Mean | 21 | 23 | 20 | 21 | 23 | 21 | 298 | 100 |
| SD | 2.1 | 1.9 | 2.1 | 2.1 | 2.4 | 2.8 |
|
|
| N | 20 | 20 | 20 | 20 | 20 | 20 |
|
|
4F | Mean | 21 | 23 | 17* | 19** | 20** | 19 | 262 | 88 |
| SD | 1.6 | 2.0 | 1.9 | 1.8 | 1.7 | 2.5 |
|
|
| N | 20 | 20 | 20 | 20 | 20 | 20 |
|
|
Table 7: Organ weights - group mean absolute and adjusted values (g) on Day 20 of gestation
Group /Sex |
| Terminal Body weight | Thyroids and Parathyroids |
Statistics test | Wi |
| |
1F | Mean | 389 | 0.015 |
| SD | 30 | 0.002 |
| N | 20 | 20 |
2F | Mean | 397 | 0.014 |
| SD | 30 | 0.003 |
| N | 20 | 20 |
3F | Mean | 385 | 0.015 |
| SD | 28 | 0.003 |
| N | 20 | 20 |
4F | Mean | 368* | 0.013 |
| SD | 19 | 0.003 |
| N | 20 | 20 |
| Thyroids and Parathyroids | |
Statistics test | Wi | |
1F | Adjusted Mean | 0.015 |
2F | Adjusted Mean | 0.013 |
3F | Adjusted Mean | 0.015 |
4F | Adjusted Mean | 0.013 |
Table 8: Macropathology - group distribution of findings on Day 20 of gestation
|
| Number of animals affected | |||
Tissue/Organ and Findings | Group/Sex No. of animals | 1F | 2F 20 | 3F | 4F 20 |
Vagina Abnormal contents |
|
0 |
0 |
1 |
0 |
Table 9: Histopathology - group distribution of findings on Day 20 of gestation
|
| Number of animals affected | |||
Tissue/Organ and Findings | Group/Sex No. of animals | 1F | 2F 20 | 3F | 4F 20 |
Thyroids Cyst(s), Follicular
| No. examined Minimal Total | 20 0 0 | 20 0 0 | 20 1 1 | 20 0 0 |
Table 10: Litter data - summary
Live offspring compared to | 0 mg/kg/day | 100 mg/kg/day | 300 mg/kg/day | 1000 mg/kg/day |
Dead fetuses (%) | 100 | 100 | 100 | 100 |
Concurrent controls (%) | 100 | 107 | 97 | 95 |
Number of implantations (%) | 100 | 95 | 96 | 94 |
Table 11: Litter data - group mean values on Day 20 of gestation
Group /Sex |
| Corpora lutea | Implantations | Resorption | Implantation loss (%) | Implantation loss# | Live young | Sex ratio (%M) | ||||||
Early | Late | Total | Pre- | Post- | Pre- | Post- | Male | Female | Total | |||||
Statistics test | Wi | Sh |
|
|
| Wi | Wi |
|
|
|
| Wi | Wi | |
1F | Mean | 16.6 | 15.2 | 0.6 | 0.0 | 0.6 | 10.0 | 3.9 | 1.4 | 0.6 | 7.6 | 7.0 | 14.6 | 50.8 |
| SD | 2.65 | 3.17 | 0.88 | 0.00 | 0.88 | 14.60 | 5.52 |
|
| 2.78 | 1.97 | 3.03 | 13.48 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
2F | Mean | 17.1 | 16.3 | 0.8 | 0.0 | 0.8 | 5.3 | 4.6 | 0.9 | 0.8 | 7.7 | 7.8 | 15.5 | 49.5 |
| SD | 1.37 | 1.29 | 0.91 | 0.00 | 0.91 | 6.93 | 5.67 |
|
| 1.98 | 1.77 | 1.54 | 10.86 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
3F | Mean | 17.2 | 14.7 | 0.6 | 0.0 | 0.6 | 14.0 | 3.5 | 2.5 | 0.6 | 7.2 | 6.9 | 14.1 | 50.7 |
| SD | 2.92 | 2.48 | 0.94 | 0.00 | 0.94 | 11.55 | 5.54 |
|
| 2.24 | 1.80 | 2.25 | 11.92 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
4F | Mean | 15.9 | 14.8 | 0.9 | 0.0 | 0.9 | 7.7 | 6.1 | 1.2 | 0.9 | 7.1 | 6.8 | 13.9 | 50.5 |
| SD | 2.02 | 2.31 | 1.21 | 0.00 | 1.21 | 10.31 | 8.63 |
|
| 2.59 | 2.17 | 2.37 | 15.74 |
| N | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 | 20 |
# Calculated using the sum of individual values within each group/number of litters per group
Table 12: Placental, litter and fetal weights - group mean values (g) on Day 20 of gestation
Group /Sex |
| Placental weight | Total litter weight | Male fetal weight | Female fetal weight | Overall fetal weight |
Statistics test | Wi | Wi | Wi | Wi | Wi | |
1F | Mean | 0.50 | 54.29 | 3.90 | 3.61 | 3.75 |
| SD | 0.060 | 10.113 | 0.240 | 0.231 | 0.224 |
| N | 20 | 20 | 20 | 20 | 20 |
2F | Mean | 0.51 | 56.75 | 3.80 | 3.56 | 3.68 |
| SD | 0.048 | 5.861 | 0.267 | 0.223 | 0.231 |
| N | 20 | 20 | 20 | 20 | 20 |
3F | Mean | 0.52 | 52.48 | 3.78 | 3.67 | 3.73 |
| SD | 0.057 | 8.020 | 0.256 | 0.255 | 0.247 |
| N | 20 | 20 | 20 | 20 | 20 |
4F | Mean | 0.50 | 50.69 | 3.76 | 3.57 | 3.68 |
| SD | 0.060 | 8.117 | 0.225 | 0.261 | 0.247 |
| N | 20 | 20 | 20 | 20 | 20 |
Table 13: Ano-genital distance - group mean absolute and adjusted values for fetuses
Group /Sex |
| Fetal weight (g) | Ano-genital distance (mm) |
Statistics test | Wi |
| |
1M | Mean | 3.9 | 4.1 |
| SD | 0.24 | 0.22 |
| N | 20 | 20 |
2M | Mean | 3.8 | 4.1 |
| SD | 0.27 | 0.15 |
| N | 20 | 20 |
3M | Mean | 3.7 | 4.1 |
| SD | 0.28 | 0.27 |
| N | 20 | 20 |
4M | Mean | 3.8 | 4.1 |
| SD | 0.23 | 0.17 |
| N | 20 | 20 |
| Ano-genital distance | |
Statistics test | Wi | |
1M | Adjusted Mean | 4.1 |
2M | Adjusted Mean | 4.1 |
3M | Adjusted Mean | 4.1 |
4M | Adjusted Mean | 4.1 |
Table 13 (cont): Ano-genital distance - group mean absolute and adjusted values for fetuses
Group /Sex |
| Fetal weight (g) | Ano-genital distance (mm) | ||
Statistics test | Wi |
| |||
1F | Mean | 3.6 | 2.5 | ||
| SD | 0.23 | 0.19 | ||
| N | 20 | 20 | ||
2F | Mean | 3.6 | 2.5 | ||
| SD | 0.22 | 0.21 | ||
| N | 20 | 20 | ||
3F | Mean | 3.7 | 2.5 | ||
| SD | 0.26 | 0.18 | ||
| N | 20 | 20 | ||
4F | Mean | 3.6 | 2.5 | ||
| SD | 0.26 | 0.16 | ||
| N | 20 | 20 | ||
| Ano-genital distance | ||||
Statistics test | Wi | ||||
1F | Adjusted Mean | 2.5 | |||
2F | Adjusted Mean | 2.5 | |||
3F | Adjusted Mean | 2.5 | |||
4F | Adjusted Mean | 2.5 | |||
Table 14: Fetal examinations - major abnormality findings - group incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 291* | 310** | 282*** | 277 | 20 | 20 | 20 | 20 |
Total Number Affected |
| 1 | 3 | 1 | 1 | 1 | 2 | 1 | 1 |
Head Skeletal External |
Brachygnathia Cleft palate Protruding tongue |
0 0 0 |
0 0 0 |
0 0 0 |
1 1 1 |
0 0 0 |
0 0 0 |
0 0 0 |
1 1 1 |
Cervical/Thoracic Skeletal Visceral |
Partially split sternum Retroesophageal aortic arch Dorsally displaced pulmonary trunk Muscular ventricular septal defect Malrotated heart Thoracic situs inversus |
0 1 0 0 1 0 |
1 0 1 1 1 0 |
0 0 0 1 0 1 |
0 0 0 0 0 0 |
0 1 0 0 1 0 |
1 0 1 1 1 0 |
0 0 0 1 0 1 |
0 0 0 0 0 0 |
Lumbar (and abdominal)/Sacral/Caudal Skeletal External
Visceral |
Termination vertebral column sacral region Gastroschisis Threadlike tail Imperforate anus Abdominal situs inversus |
0 0 0 0 0 |
1 1 1 1 1 |
0 0 0 0 0 |
0 0 0 0 0 |
0 0 0 0 0 |
1 1 1 1 1 |
0 0 0 0 0 |
0 0 0 0 0 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 13, 7 fetuses heads only examined, included in tabulated data.
**Litter 26 head only examined for one fetus, included in tabulated data.
***Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated.
Table 14 (cont): Fetal examinations - major abnormality findings - group incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 291* | 310** | 282*** | 277 | 20 | 20 | 20 | 20 |
Total Number Affected |
| 1 | 3 | 1 | 1 | 1 | 2 | 1 | 1 |
Appendicular Skeletal |
Short/bent/thickened long bones Clavicle bent/incompletely ossified |
0 0 |
0 0 |
0 0 |
1 1 |
0 0 |
0 0 |
0 0 |
1 1 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 13, 7 fetuses heads only examined, included in tabulated data.
**Litter 26 head only examined for one fetus, included in tabulated data.
***Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated
Table 15: Fetal examinations - major abnormality findings - group percentage incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 291* | 310** | 282*** | 277 | 20 | 20 | 20 | 20 |
Total Number Affected |
| 1 | 3 | 1 | 1 | 1 | 2 | 1 | 1 |
Head Skeletal External |
Brachygnathia Cleft palate Protruding tongue |
0.0 0.0 0.0 |
0.0 0.0 0.0 |
0.0 0.0 0.0 |
0.7 0.4 0.4 |
0.0 0.0 0.0 |
0.0 0.0 0.0 |
0.0 0.0 0.0 |
5.0 5.0 5.0 |
Cervical/Thoracic Skeletal Visceral |
Partially split sternum Retroesophageal aortic arch Dorsally displaced pulmonary trunk Muscular ventricular septal defect Malrotated heart Thoracic situs inversus |
0.0 0.7 0.0 0.0 0.7 0.0 |
0.6 0.0 0.6 0.6 0.6 0.0 |
0.0 0.0 0.0 0.7 0.0 0.7 |
0.0 0.0 0.0 0.0 0.0 0.0 |
0.0 5.0 0.0 0.0 5.0 0.0 |
5.0 0.0 5.0 5.0 5.0 0.0 |
0.0 0.0 0.0 5.0 0.0 5.0 |
0.0 0.0 0.0 0.0 0.0 0.0 |
Lumbar (and abdominal)/Sacral/Caudal Skeletal External
Visceral |
Termination vertebral column sacral region Gastroschisis Threadlike tail Imperforate anus Abdominal situs inversus |
0.0 0.0 0.0 0.0 0.0 |
0.6 0.3 0.3 0.3 0.6 |
0.0 0.0 0.0 0.0 0.0 |
0.0 0.0 0.0 0.0 0.0 |
0.0 0.0 0.0 0.0 0.0 |
5.0 5.0 5.0 5.0 5.0 |
0.0 0.0 0.0 0.0 0.0 |
0.0 0.0 0.0 0.0 0.0 |
Appendicular Skeletal |
Short/bent/thickened long bones Clavicle bent/incompletely ossified |
0.0 0.0 |
0.0 0.0 |
0.0 0.0 |
0.7 0.7 |
0.0 0.0 |
0.0 0.0 |
0.0 0.0 |
5.0 5.0 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 13, 7 fetuses heads only examined, included in tabulated data.
**Litter 26 head only examined for one fetus, included in tabulated data.
***Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated
Table 16: Fetal examinations - Major Historical Control Data - incidence
Species/strain/source | Rat/ Crl:CD(SD) / Charles River UK |
Necropsy date range | Aug 2018– Apr 2019 |
Number of studies | 8 |
Study types | Main |
|
| GB01PV | HCD Range | ||||||||
|
| Fetuses | Litters | Fetuses | Litters | ||||||
Group | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
|
| |
Number Examined | 291 | 310 | 282 | 277 | 20 | 20 | 20 | 20 | 2098 | 141 | |
Head |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Brachygnathia | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-1 | 0-1 |
External | Cleft palate | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-0 | 0-0 |
| Protruding tongue | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-1 | 0-1 |
Cervical/Thoracic |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Partially split sternum | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-1 | 0-1 |
Visceral | Dorsally displaced pulmonary trunk | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-0 | 0-0 |
| Muscular ventricular septal defect | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 0 | 0-0 | 0-0 |
| Thoracic situs inversus | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0-0 | 0-0 |
Lumbar (and abdominal)/Sacral/Caudal |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Termination vertebral column sacral region | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-0 | 0-0 |
External | Gastroschisis | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-0 | 0-0 |
| Threadlike tail | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-0 | 0-0 |
| Imperforate anus | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-0 | 0-0 |
Visceral | Abdominal situs inversus | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-0 | 0-0 |
Appendicular |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Short/bent/thickened long bones | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-1 | 0-1 |
| Clavicle bent/incompletely ossified | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-1 | 0-1 |
Table 17: Fetal examinations - Major Historical Control Data - percentage (%)
Species/strain/source | Rat/ Crl:CD(SD) / Charles River UK |
Necropsy date range | Aug 2018– Apr 2019 |
Number of studies | 8 |
Study types | Main |
|
| GB01PV | HCD Range | ||||||||
|
| Fetuses | Litters | Fetuses | Litters | ||||||
Group | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
|
| |
Number Examined | 291 | 310 | 282 | 277 | 20 | 20 | 20 | 20 | 2098 | 141 | |
Head |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Brachygnathia* | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.7 | 0.0-5.3 |
External | Cleft palate | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.0 | 0.0-0.0 |
| Protruding tongue | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.3 | 0.0-5.3 |
Cervical/Thoracic |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Partially split sternum* | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-1.0 | 0.0-16.7 |
Visceral | Dorsally displaced pulmonary trunk** | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
| Muscular ventricular septal defect** | 0.0 | 0.6 | 0.7 | 0.0 | 0.0 | 5.0 | 5.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
| Thoracic situs inversus! | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Lumbar (and abdominal)/Sacral/Caudal |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Termination vertebral column sacral region* | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
External | Gastroschisis | 0.0 | 0.3 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
| Threadlike tail | 0.0 | 0.3 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
| Imperforate anus | 0.0 | 0.3 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Visceral | Abdominal situs inversus | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Appendicular |
|
|
|
|
|
|
|
|
|
| |
Skeletal | Short/bent/thickened long bones* | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.7 | 0.0-5.3 |
| Clavicle bent/incompletely ossified* | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.7 | 0.0-5.3 |
* Findings noted at skeletal examination, therefore % was calculated from number of skeletons examined
** Findings noted at visceral examination, therefore % was calculated from number of fixed fetuses.
Table 18: Fetal examinations - minor skeletal abnormality and variants findings - group incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3* | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 144 | 154 | 141 | 138 | 20 | 20 | 20 | 20 |
Minor skeletal abnormalities Cranial Vertebral element abnormality Ribs Sternebrae
Costal cartilage
Total affected by one or more of the above |
Sutural bone(s) Thoracic Medially thickened/kinked Misaligned ossification sites Misshapen Partially fused Misaligned 7th not connected to sternum |
0 0 0 1 0 1 1 0 2 |
0 1 1 0 1 0 0 0 3 |
0 0 0 0 0 0 0 0 0 |
1 1 2 1 0 0 0 1 5 |
0 0 0 1 0 1 1 0 2 |
0 1 1 0 1 0 0 0 3 |
0 0 0 0 0 0 0 0 0 |
1 1 2 1 0 0 0 1 5 |
Rib and vertebral configuration Cervical rib 1st rib 13th rib Number of 14th ribs
Thoracolumbar vertebrae Pelvic girdle |
Short supernumerary Short with costal cartilage Short with/without costal cartilage Short supernumerary Total 20 Unilateral cranial shift |
0 1 5 3 3 1 0 |
0 0 1 6 6 0 1 |
0 0 4 14 14 0 0 |
1 0 0 23 23 1 0 |
0 1 4 3 3 1 0 |
0 0 1 6 6 0 1 |
0 0 3 8 8 0 0 |
1 0 0 12 12 1 0 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated.
Table 18 (cont): Fetal examinations - minor skeletal abnormality and variants findings - group incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3* | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 144 | 154 | 141 | 138 | 20 | 20 | 20 | 20 |
Delayed/Incomplete ossification/unossified Cranial
Sternebrae
Vertebrae
Ribs Appendicular
Increased ossification Cervical vertebral centra |
Large nasofrontal suture Cranial centres Hyoid 5th and/or 6th Other Total Cervical Thoracic Lumbar Sacrocaudal Caudal Any Scapula(e) Pelvic bones Metacarpals Metatarsals
All ossified |
0 15 17 92 14 93 4 10 1 13 1 0 0 8 3 2
0 |
1 10 17 113 22 115 2 5 1 14 2 0 0 10 1 1
2 |
0 4 8 71 7 73 0 5 0 4 3 0 0 5 0 0
0 |
0 1 0 50 8 52 1 17 1 1 1 1 1 1 0 0
0 |
0 8 7 20 9 20 4 9 1 9 1 0 0 5 2 2
0 |
1 5 11 20 11 20 2 5 1 7 2 0 0 5 1 1
2 |
0 2 6 18 3 18 0 5 0 2 1 0 0 3 0 0
0 |
0 1 0 18 8 18 1 11 1 1 1 1 1 1 0 0
0 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated.
Table 19: Fetal examinations - minor skeletal abnormality and variants findings - group percentage incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3* | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 144 | 154 | 141 | 138 | 20 | 20 | 20 | 20 |
Minor skeletal abnormalities Cranial Vertebral element abnormality Ribs Sternebrae
Costal cartilage
Total affected by one or more of the above |
Sutural bone(s) Thoracic Medially thickened/kinked Misaligned ossification sites Misshapen Partially fused Misaligned 7th not connected to sternum |
0.0 0.0 0.0 0.7 0.0 0.7 0.7 0.0 1.4 |
0.0 0.6 0.6 0.0 0.6 0.0 0.0 0.0 1.9 |
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 |
0.7 0.7 1.4 0.7 0.0 0.0 0.0 0.7 3.6 |
0.0 0.0 0.0 5.0 0.0 5.0 5.0 0.0 10.0 |
0.0 5.0 5.0 0.0 5.0 0.0 0.0 0.0 15.0 |
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 |
5.0 5.0 10.0 5.0 0.0 0.0 0.0 5.0 25.0 |
Rib and vertebral configuration Cervical rib 1st rib 13th rib Number of 14th ribs
Thoracolumbar vertebrae Pelvic girdle |
Short supernumerary Short with costal cartilage Short with/without costal cartilage Short supernumerary Total 20 Unilateral cranial shift |
0.0 0.7 3.5 2.1 2.1 0.7 0.0 |
0.0 0.0 0.6 3.9 3.9 0.0 0.6 |
0.0 0.0 2.8 9.9 9.9 0.0 0.0 |
0.7 0.0 0.0 16.7 16.7 0.7 0.0 |
0.0 5.0 20.0 15.0 15.0 5.0 0.0 |
0.0 0.0 5.0 30.0 30.0 0.0 5.0 |
0.0 0.0 15.0 40.0 40.0 0.0 0.0 |
5.0 0.0 0.0 60.0 60.0 5.0 0.0 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated.
Table 19 (cont): Fetal examinations - minor skeletal abnormality and variants findings - group percentage incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3* | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 144 | 154 | 141 | 138 | 20 | 20 | 20 | 20 |
Delayed/Incomplete ossification/unossified Cranial
Sternebrae
Vertebrae
Ribs Appendicular
Increased ossification Cervical vertebral centra |
Large nasofrontal suture Cranial centres Hyoid 5th and/or 6th Other Total Cervical Thoracic Lumbar Sacrocaudal Caudal Any Scapula(e) Pelvic bones Metacarpals Metatarsals
All ossified |
0.0 10.4 11.8 63.9 9.7 64.6 2.8 6.9 0.7 9.0 0.7 0.0 0.0 5.6 2.1 1.4
0.0 |
0.6 6.5 11.0 73.4 14.3 74.7 1.3 3.2 0.6 9.1 1.3 0.0 0.0 6.5 0.6 0.6
1.3 |
0.0 2.8 5.7 50.4 5.0 51.8 0.0 3.5 0.0 2.8 2.1 0.0 0.0 3.5 0.0 0.0
0.0 |
0.0 0.7 0.0 36.2 5.8 37.7 0.7 12.3 0.7 0.7 0.7 0.7 0.7 0.7 0.0 0.0
0.0 |
0.0 40.0 35.0 100.0 45.0 100.0 20.0 45.0 5.0 45.0 5.0 0.0 0.0 25.0 10.0 10.0
0.0 |
5.0 25.0 55.0 100.0 55.0 100.0 10.0 25.0 5.0 35.0 10.0 0.0 0.0 25.0 5.0 5.0
10.0 |
0.0 10.0 30.0 90.0 15.0 90.0 0.0 25.0 0.0 10.0 5.0 0.0 0.0 15.0 0.0 0.0
0.0 |
0.0 5.0 0.0 90.0 40.0 90.0 5.0 55.0 5.0 5.0 5.0 5.0 5.0 5.0 0.0 0.0
0.0 |
Table 20: Fetal examinations - Skeletal Historical Control Data - incidence
Species/strain/source | Rat/ Crl:CD(SD) / Charles River UK |
Necropsy date range | Aug 2018– Apr 2019 |
Number of studies | 8 |
Study types | Main |
|
| GP01PV | HCD Range | ||||||||
|
| Fetuses | Litters | Fetuses | Litters | ||||||
Group | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
|
| |
Number Examined | 144 | 154 | 141 | 138 | 20 | 20 | 20 | 20 | 1105 | 141 | |
Minor skeletal abnormalities |
|
|
|
|
|
|
|
|
|
| |
Cranial | sutural bone(s) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-0 | 0-0 |
Vertebral element abnormality | thoracic | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 0-1 | 0-1 |
Ribs | medially thickened/kinked | 0 | 1 | 0 | 2 | 0 | 1 | 0 | 2 | 0-1 | 0-1 |
Sternebrae | misshapen | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-0 | 0-0 |
Costal cartilage | 7th not connected to sternum | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-1 | 0-1 |
Rib and vertebral configuration |
|
|
|
|
|
|
|
|
|
| |
Cervical rib | short supernumerary | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-2 | 0-1 |
Number of 14th ribs | short supernumerary | 3 | 6 | 14 | 23 | 3 | 6 | 8 | 12 | 1-14 | 1-8 |
Pelvic girdle | unilateral cranial shift | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-1 | 0-1 |
Delayed/Incomplete ossification/unossified |
|
|
|
|
|
|
|
|
|
| |
Cranial | large nasofrontal suture | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0-3 | 0-2 |
| cranial centres | 15 | 10 | 4 | 1 | 8 | 5 | 2 | 1 | 1-20 | 1-11 |
| hyoid | 17 | 17 | 8 | 0 | 7 | 11 | 6 | 0 | 10-29 | 4-13 |
Sternebrae | 5th and/or 6th | 92 | 113 | 71 | 50 | 20 | 20 | 18 | 18 | 42-99 | 6-20 |
| other | 14 | 22 | 7 | 8 | 9 | 11 | 3 | 8 | 4-11 | 1-9 |
| total | 93 | 115 | 73 | 52 | 20 | 20 | 18 | 18 | 45-99 | 6-20 |
Vertebrae | sacrocaudal | 13 | 14 | 4 | 1 | 9 | 7 | 2 | 1 | 0-18 | 0-8 |
Ribs | any | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-1 | 0-1 |
Appendicular | Scapula | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-0 | 0-0 |
Increased ossification |
|
|
|
|
|
|
|
|
|
| |
Cervical vertebral centra | all ossified | 0 | 2 | 0 | 0 | 0 | 2 | 0 | 0 | 0-0 | 0-0 |
Table 21: Fetal examinations - Skeletal Historical Control Data - percentage (%)
| Species/strain/source | Rat/ Crl:CD(SD) / Charles River UK |
| Necropsy date range | Aug 2018– Apr 2019 |
| Number of studies | 8 |
| Study types | Main |
|
| GP01PV | HCD Range | ||||||||
|
| Fetuses | Litters | Fetuses | Litters | ||||||
Group | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
|
| |
Number Examined | 144 | 154 | 141 | 138 | 20 | 20 | 20 | 20 | 1105 | 141 | |
Minor skeletal abnormalities |
|
|
|
|
|
|
|
|
|
| |
Cranial | sutural bone(s) | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.0 | 0.0-0.0 |
Vertebral element abnormality | thoracic | 0.0 | 0.6 | 0.0 | 0.7 | 0.0 | 5.0 | 0.0 | 5.0 | 0.0-0.7 | 0.0-5.3 |
Ribs | medially thickened/kinked | 0.0 | 0.6 | 0.0 | 1.4 | 0.0 | 5.0 | 0.0 | 10.0 | 0.0-0.7 | 0.0-5.3 |
Sternebrae | misshapen | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Costal cartilage | 7th not connected to sternum | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.7 | 0.0-5.3 |
Rib and vertebral configuration |
|
|
|
|
|
|
|
|
|
| |
Cervical rib | short supernumerary | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-1.3 | 0.0-5.6 |
Number of 14th ribs | short supernumerary | 2.1 | 3.9 | 9.9 | 16.7 | 15.0 | 30.0 | 40.0 | 60.0 | 0.7-10.9 | 5.3-50.0 |
Pelvic girdle | unilateral cranial shift | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-0.7 | 0.0-5.3 |
Delayed/Incomplete ossification/unossified |
|
|
|
|
|
|
|
|
|
| |
Cranial | large nasofrontal suture | 0.0 | 0.6 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0 | 0.0-2.2 | 0.0-11.1 |
| cranial centres | 10.4 | 6.5 | 2.8 | 0.7 | 40.0 | 25.0 | 10.0 | 5.0 | 1.0-13.7 | 15.8-55.0 |
| hyoid | 11.8 | 11.0 | 5.7 | 0.0 | 35.0 | 55.0 | 30.0 | 0.0 | 7.5-20.4 | 31.6-66.7 |
Sternebrae | 5th and/or 6th | 63.9 | 73.4 | 50.4 | 36.2 | 100.0 | 100.0 | 90.0 | 90.0 | 41.6-67.8 | 88.9-100.0 |
| other | 9.7 | 14.3 | 5.0 | 5.8 | 45.0 | 55.0 | 15.0 | 40.0 | 2.7-7.7 | 16.7-45.0 |
| total | 64.6 | 74.7 | 51.8 | 37.7 | 100.0 | 100.0 | 90.0 | 90.0 | 44.6-67.8 | 88.9-100.0 |
Vertebrae | sacrocaudal | 9.0 | 9.1 | 2.8 | 0.7 | 45.0 | 35.0 | 10.0 | 5.0 | 0.0-13.4 | 0.0-44.4 |
Ribs | any | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.7 | 0.0-5.6 |
Appendicular | scapula | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.0 | 0.0-0.0 |
Increased ossification |
|
|
|
|
|
|
|
|
|
| |
Cervical vertebral centra | all ossified | 0.0 | 1.3 | 0.0 | 0.0 | 0.0 | 10.0 | 0.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Table 22: Fetal examinations - minor visceral abnormality and necropsy findings - group incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 147* | 156** | 141*** | 139 | 20 | 20 | 20 | 20 |
Total Number Affected |
| 31 | 20 | 24 | 26 | 16 | 13 | 14 | 14 |
Visceral abnormalities Brain Eyes
Thymus
Lungs Caudal vena cava Diaphragm Liver Adrenal(s) Ureter(s) Testis(es)
Umbilical artery |
Dilated interventricular foramen Folded retina Dilated orbital sinus Variation in lens shape Partially undescended lobe Thymic remnant Absent accessory lobe Anomalous confluence/left hepatic vein Thinning with liver protrusion Fissured posterior caudate lobe Dark Dilated Undescended Malpositioned Left |
0 1 1 1 5 0 0 2 2 1 0 1 0 2 2 |
0 0 0 0 5 0 0 0 0 0 0 0 0 1 3 |
0 2 1 0 1 1 1 0 0 0 1 0 1 3 1 |
1 0 0 0 5 0 0 0 0 0 0 0 1 1 2 |
0 1 1 1 4 0 0 1 2 1 0 1 0 2 2 |
0 0 0 0 4 0 0 0 0 0 0 0 0 1 3 |
0 2 1 0 1 1 1 0 0 0 1 0 1 3 1 |
1 0 0 0 3 0 0 0 0 0 0 0 1 1 2 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 13, 7 fetuses heads only examined, included in tabulated data.
**Litter 26 head only examined for one fetus, included in tabulated data.
***Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated
Table 22 (cont): Fetal examinations - minor visceral abnormality and necropsy findings - group incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 147* | 156** | 141*** | 139 | 20 | 20 | 20 | 20 |
Total Number Affected |
| 31 | 20 | 24 | 26 | 16 | 13 | 14 | 14 |
Haemorrhages Head
Neck/Thorax
Abdomen
General |
Brain Vitreous humour eye Eye lid(s) Dorsal fat pad Thoracic cavity Abdomen cavity Liver lobes Subcutaneous |
3 1 1 1 0 12 1 1 |
5 0 0 0 0 6 0 0 |
3 0 0 1 0 5 0 2 |
6 0 0 1 1 6 0 1 |
3 1 1 1 0 8 1 1 |
5 0 0 0 0 4 0 0 |
2 0 0 1 0 3 0 2 |
6 0 0 1 1 5 0 1 |
Necropsy observations (external) Skin
Head Tail |
Shiny Subcutaneous edema Short snout Curled |
1 0 0 0 |
0 0 0 0 |
3 1 0 0 |
0 0 1 1 |
1 0 0 0 |
0 0 0 0 |
2 1 0 0 |
0 0 1 1 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 13, 7 fetuses heads only examined, included in tabulated data.
**Litter 26 head only examined for one fetus, included in tabulated data.
***Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated
Table 23: Fetal examinations - minor visceral abnormality and necropsy findings – group percentage incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 147* | 156** | 141*** | 139 | 20 | 20 | 20 | 20 |
Total Number Affected |
| 31 | 20 | 24 | 26 | 16 | 13 | 14 | 14 |
Visceral abnormalities Brain Eyes
Thymus
Lungs Caudal vena cava Diaphragm Liver Adrenal(s) Ureter(s) Testis(es)
Umbilical artery |
Dilated interventricular foramen Folded retina Dilated orbital sinus Variation in lens shape Partially undescended lobe Thymic remnant Absent accessory lobe Anomalous confluence/left hepatic vein Thinning with liver protrusion Fissured posterior caudate lobe Dark Dilated Undescended Malpositioned Left |
0.0 0.7 0.7 0.7 3.4 0.0 0.0 1.4 1.4 0.7 0.0 0.7 0.0 1.4 1.4 |
0.0 0.0 0.0 0.0 3.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.6 1.9 |
0.0 1.4 0.7 0.0 0.7 0.7 0.7 0.0 0.0 0.0 0.7 0.0 0.7 2.1 0.7 |
0.7 0.0 0.0 0.0 3.6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.7 0.7 1.4 |
0.0 5.0 5.0 5.0 20.0 0.0 0.0 5.0 10.0 5.0 0.0 5.0 0.0 10.0 10.0 |
0.0 0.0 0.0 0.0 20.0 0.0 0.0 5.0 10.0 5.0 0.0 5.0 0.0 10.0 10.0 |
0.0 10.0 5.0 0.0 5.0 5.0 5.0 0.0 0.0 0.0 5.0 0.0 5.0 15.0 5.0 |
5.0 0.0 0.0 0.0 15.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5.0 5.0 10.0 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 13, 7 fetuses heads only examined, included in tabulated data.
**Litter 26 head only examined for one fetus, included in tabulated data.
***Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated
Table 23 (cont): Fetal examinations - minor visceral abnormality and necropsy findings – group percentage incidences
|
| Fetuses | Litters | ||||||
Group |
| 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number Examined |
| 147* | 156** | 141*** | 139 | 20 | 20 | 20 | 20 |
Total Number Affected |
| 31 | 20 | 24 | 26 | 16 | 13 | 14 | 14 |
Haemorrhages Head
Neck/Thorax
Abdomen
General |
Brain Vitreous humour eye Eye lid(s) Dorsal fat pad Thoracic cavity Abdomen cavity Liver lobes Subcutaneous |
2.0 0.7 0.7 0.7 0.0 8.2 0.7 0.7 |
3.2 0.0 0.0 0.0 0.0 3.8 0.0 0.0 |
2.1 0.0 0.0 0.7 0.0 3.5 0.0 1.4 |
4.3 0.0 0.0 0.7 0.7 4.3 0.0 0.7 |
15.0 5.0 5.0 5.0 0.0 40.0 5.0 5.0 |
25.0 0.0 0.0 0.0 0.0 20.0 0.0 0.0 |
10.0 0.0 0.0 5.0 0.0 15.0 0.0 10.0 |
30.0 0.0 0.0 5.0 5.0 25.0 0.0 5.0 |
Necropsy observations (external) Skin
Head Tail |
Shiny Subcutaneous edema Short snout Curled |
0.3 0.0 0.0 0.0 |
0.0 0.0 0.0 0.0 |
1.1 0.4 0.0 0.0 |
0.0 0.0 0.4 0.4 |
5.0 0.0 0.0 0.0 |
0.0 0.0 0.0 0.0 |
10.0 5.0 0.0 0.0 |
0.0 0.0 5.0 5.0 |
Note: Individual fetuses/litters may occur in more than one category.
*Litter 13, 7 fetuses heads only examined, included in tabulated data.
**Litter 26 head only examined for one fetus, included in tabulated data.
***Litter 48 ID tags detached for 2 fetuses, ID’s randomly allocated
Table 24: Fetal examinations - Visceral Historical Control Data - incidence
Species/strain/source | Rat/ Crl:CD(SD) / Charles River UK |
Necropsy date range | Aug 2018– Apr 2019 |
Number of studies | 8 |
Study types | Main |
|
| GB01PV | HCD Range | ||||||||
|
| Fetuses | Litters | Fetuses | Litters | ||||||
Group | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
|
| |
Number Examined | 147 | 156 | 141 | 139 | 20 | 20 | 20 | 20 | 1094 | 141 | |
Visceral abnormalities |
|
|
|
|
|
|
|
|
|
| |
Brain | dilated interventricular foramen | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-3 | 0-3 |
Thymus | thymic remnant | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0-1 | 0-1 |
Lungs | absent accessory lobe | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0-0 | 0-0 |
Adrenal(s) | dark | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0-0 | 0-0 |
Testis(es) | undescended | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 0-1 | 0-1 |
Haemorrhages |
|
|
|
|
|
|
|
|
|
| |
Neck/Thorax | thoracic cavity | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-0 | 0-0 |
Necropsy observations (external) |
|
|
|
|
|
|
|
|
|
| |
Skin | subcutaneous edema | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0-0 | 0-0 |
Head | short snout | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-1 | 0-1 |
Tail | curled | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0-0 | 0-0 |
Table 25: Fetal examinations - Visceral Historical Control Data - percentage (%)
Species/strain/source | Rat/ Crl:CD(SD) / Charles River UK |
Necropsy date range | Aug 2018– Apr 2019 |
Number of studies | 8 |
Study types | Main |
|
| GB01PV | HCD Range | ||||||||
|
| Fetuses | Litters | Fetuses | Litters | ||||||
Group | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
|
| |
Number Examined | 147 | 156 | 141 | 139 | 20 | 20 | 20 | 20 | 1094 | 141 | |
Visceral abnormalities |
|
|
|
|
|
|
|
|
|
| |
Brain | dilated interventricular foramen | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-2.2 | 0.0-15.8 |
Thymus | thymic remnant | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0-0.6 | 0.0-5.0 |
Lungs | absent accessory lobe | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Adrenal(s) | dark | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Testis(es) | undescended | 0.0 | 0.0 | 0.7 | 0.7 | 0.0 | 0.0 | 5.0 | 5.0 | 0.0-0.7 | 0.0-5.3 |
Haemorrhages |
|
|
|
|
|
|
|
|
|
| |
Neck/Thorax | thoracic cavity | 0.0 | 0.0 | 0.0 | 0.7 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.0 | 0.0-0.0 |
Necropsy observations (external) |
|
|
|
|
|
|
|
|
|
| |
Skin | subcutaneous edema | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0 | 0.0-0.0 | 0.0-0.0 |
Head | short snout | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.3 | 0.0-5.3 |
Tail | curled | 0.0 | 0.0 | 0.0 | 0.4 | 0.0 | 0.0 | 0.0 | 5.0 | 0.0-0.0 | 0.0-0.0 |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Study performed according to OECD TG 414 and GLP; Klimisch code 1
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
