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EC number: 202-009-7 | CAS number: 90-66-4
- 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
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- Flash point
- Auto flammability
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- 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
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- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
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- Endpoint summary
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- 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
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- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
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- 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
Endpoint summary
Administrative data
Description of key information
No Observed Adverse Effect Level (NOAEL) of at least 500 mg/kg was derived for 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol test item
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 04 November 2016 to 30 December 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Remarks:
- see "Any other information on materials and methods incl. tables" for details
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- see "Any other information on materials and methods incl. tables" for details
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents, July 2000.
- Deviations:
- yes
- Remarks:
- see "Any other information on materials and methods incl. tables" for details
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2000
- Deviations:
- yes
- Remarks:
- see "Any other information on materials and methods incl. tables" for details
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
- Specific details on test material used for the study:
- Internal identification number: 207570/A
Identification: LOWINOX® TBP-6
Appearance: White powder
Batch: C034J0059
Purity/Composition: 99.8 %
Test item storage: At room temperature
Stable under storage conditions until: 12 May 2017 (expiry date) - Species:
- rat
- Strain:
- other: Crl:WI(Han) (outbred, SPF-Quality).
- Details on species / strain selection:
- This species and strain of rat has been recognized as appropriate for general and reproduction toxicity studies. Charles River Den Bosch has general and reproduction/developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Test system: Rat: Crl:WI(Han) (outbred, SPF-Quality). Nulliparous and non-pregnant females and untreated animals were used at initiation of the study.
Source F0:Charles River Deutschland, Sulzfeld, Germany.
Age at start pretest: Females - approximately 11 weeks.
Age at start F0-treatment: Males - approximately 10 weeks / Females: approximately 13 weeks.
Number of F0-animals: 48 females and 40 males.
At the end of the pretest phase, 40 females with at least two regular estrous cycles were selected at random and further used in the study. The remaining females were removed from the study.
Acclimatization F0: At least 5 days prior to start of pretest (females) or treatment (males).
Health inspection F0: At least upon receipt of the animals.
Randomization F0: Before initiation of pretest, by computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean.
Identification F0: During pretest (females) and treatment (males and females): by earmark and tattoo. Reserve females were numbered R1 through R8 at random by indelible marker. Any reserve female replacing an allocated female prior to treatment received identification by earmark and tattoo.
Mating procedures
Following a minimum of 14 days of exposure for the males and females, one female was cohabitated with one male of the same treatment group, avoiding sibling mating. Detection of mating was confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating was confirmed, the males and females were separated. A maximum of 14 days was allowed for mating, after which females who had not shown evidence of mating were separated from their males.
Parturition
The females were allowed to litter normally. Postnatal day (PND) 1 was defined as the day when a litter was found completed (i.e. membranes and placentas cleaned up, nest built and/or feeding of pups started). Females that were littering were left undisturbed.
Number of pups: 424 pups.
Identification of pups
On PND 1, all pups were randomized per litter and individually identified by means of subcutaneous injection of Indian ink.
When general hair growth blurred the identification, the pups were identified by tattoo on the feet.
Culling
To reduce variability among the litters, on PND 4 eight pups from each litter of equal sex distribution (if possible) were selected. Blood samples were collected from two of the surplus pups (see section 0). Selective elimination of pups, e.g. based upon body weight, or anogenital distance was not done. Whenever the number of male or female pups prevented having four of each sex per litter, partial adjustment (for example, five males and three females) was acceptable.
Animal Husbandry
Room number: Room A0.07 (A0.23 for motor activity measurements).
Conditions: Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 room air changes/hour, and a 12-hour light/12-hour dark cycle: the photoperiod is between 07:00 and 19:00 hrs daily. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.
Accommodation
Pretest: Females were housed in groups of 5 females/cage in Macrolon plastic cages (MIV type, height 18 cm).
Pre-mating: Animals were housed in groups of 5 animals/sex/cage in Macrolon plastic cages (MIV type, height 18 cm).
Mating: Females were caged together with males on a one-to-one-basis in Macrolon plastic cages (MIII type, height 18 cm).
Post-mating: Males were housed in their home cage (Macrolon plastic cages, MIV type, height 18 cm) with a maximum of 5 animals/cage. Females were individually housed in Macrolon plastic cages (MIII type, height 18 cm).
Lactation
Females were housed in Macrolon plastic cages (MIII type, height 18 cm). Pups were housed with the dam, except during locomotor activity monitoring of the dams, when the pups were kept warm in their home cage using bottles filled with warm water. In order to avoid hypothermia of pups, pups were not left without their dam or a bottle filled with warm water for longer than 30 40 minutes.
General
Sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment/nesting material (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom) were supplied. During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20.3 cm) without cage-enrichment, bedding material, food and water.
Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
Water: Free access to tap-water.
Diet, water, bedding and cage-enrichment/nesting material evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study. - Route of administration:
- oral: gavage
- Details on route of administration:
- Oral gavage, using a plastic feeding tube. Formulations were placed on a magnetic stirrer during dosing. A dose control system (DCS) was used as additional check to verify the dosing procedure according to Standard Operating Procedures. (Test Facility Study No. 513607 was used for DCS).
- Vehicle:
- propylene glycol
- Details on oral exposure:
- Treatment - Parental Animals
Method
Oral gavage, using a plastic feeding tube. Formulations were placed on a magnetic stirrer during dosing. A dose control system (DCS) was used as additional check to verify the dosing procedure according to Standard Operating Procedures. (Test Facility Study No. 513607 was used for DCS).
Dose volume: 5 mL/kg body weight. Actual dose volumes were calculated according to the latest body weight.
Frequency: Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.
Treatment period: Males were treated for 31 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females that delivered were treated for 50-56 days, i.e. during 2 weeks prior to mating (with the objective of covering at least two complete estrous cycles), the variable time to conception, the duration of the pregnancy and at least 13 days after delivery up to and including the day before scheduled necropsy. Females which failed to deliver healthy offspring were treated for 38-45 days.
Routinely, females that are littering are left undisturbed. In this study, female nos. 52, 55 and 59 (Group 2) and 73 (Group 4) were not dosed on one occasion as they were littering at the time of dosing. The omission of one day of dosing over a period of several weeks was considered not to affect the toxicological evaluation.
Treatment - Pups
Pups were not treated directly but were potentially exposed to the test item in utero, via maternal milk or from exposure to maternal urine/feces. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical verification of doses was conducted using a Liquid chromatography diode array detector (LC-DAD)
Procedural recovery samples
The mean recoveries of the procedural recovery samples fell within the criterion of 90-110%. It demonstrated that the analytical method was adequate for the determination of the test item in the test samples.
Test samples
In the Group 1 formulation, no test item was detected.
The concentrations analyzed in the formulations of Groups 2, 3 and 4 were in agreement with the target concentrations (i.e. mean accuracies between 90% and 110%).
The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%). - Duration of treatment / exposure:
- Males were treated for 31 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females that delivered were treated for 50-56 days, i.e. during 2 weeks prior to mating (with the objective of covering at least two complete estrous cycles), the variable time to conception, the duration of the pregnancy and at least 13 days after delivery up to and including the day before scheduled necropsy. Females which failed to deliver healthy offspring were treated for 38-45 days.
- Frequency of treatment:
- Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 males and 10 females per dosing group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Based on the results of a dose range finding study in which toxicity was noted at 500 mg/kg but not at 250 mg/kg (Test Facility Study No. 513610), the dose levels for this combined 28-day oral gavage study with reproduction/developmental toxicity screening test were selected to be 50, 150 and 500 mg/kg.
- Positive control:
- None.
- Observations and examinations performed and frequency:
- Parental Animals
Mortality / Viability: At least twice daily.
Clinical signs: Clinical observations (detailed clinical signs and arena) were conducted from start of treatment onwards up to the day prior to necropsy at least at 1 hour (± 30 min)) after dosing based on the peak period of anticipated effects. Once prior to start of treatment and at weekly intervals during the treatment period this was also performed outside the home cage in a standard arena.
The time of onset, grade and duration of any observed sign was recorded. Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored. In the data tables, the scored grades were reported, as well as the percentage of animals affected in summary tables.
Functional Observations
The following functional observations tests were performed on each individual animal of the selected 5 animals/sex/group:
• hearing ability (HEARING), pupillary reflex (PUPIL L/R), and static righting reflex (STATIC R) (Score 0 = normal/present, score 1 = abnormal/absent).
• fore- and hind-limb grip strength, recorded as the mean of three measurements per animal (Series M4-10, Mark-10 Corporation, J.J. Bos, Gouda, The Netherlands).
• locomotor activity (recording period: 1-hour under normal laboratory light conditions, using a computerized monitoring system, Kinder Scientific LLC, Poway, USA). Total movements and ambulations are reported. Ambulations represent movements characterized by a relocation of the entire body position like walking, whereas total movements represent all movements made by the animals, including ambulations but also smaller or finer movements like grooming, weaving or movements of the head. The selected males were tested during Week 4 of treatment and the selected females were tested once during the last week of lactation (e.g. PND 6-13). These tests were performed after observation for clinical signs (incl. arena observation, if applicable) and started at 1 hour (± 30 min) after dosing.
Body weights: Males and females were weighed on the first day of treatment (prior to first dosing) and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on PND 1, 4, 7 and 13.
Food consumption: Weekly, except for males and females which were housed together for mating and for females without evidence of mating. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on PND 1, 4, 7 and 13.
Water consumption: Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.
Pups
Each litter was examined to determine the following, if practically possible:
Mortality / Viability: The numbers of live and dead pups were determined on PND 1 and daily thereafter. If possible, defects or cause of death were evaluated.
Clinical signs: At least once daily, detailed clinical observations were made for all animals. Only days on which clinical signs were present between first and last litter check are presented in the respective tables.
Body weights: Live pups were weighed on PND 1, 4, 7 and 13.
Sex: Sex was determined for all pups on PND 1 and 4. Sex ratio (% male pups / % female pups) was calculated per group. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, see "Any other information on materials and methods incl. tables"
HISTOPATHOLOGY: Yes, see "Any other information on materials and methods incl. tables" - Other examinations:
- Parental animals
Estrous cycle determination
Daily vaginal lavage was performed to determine the stage of estrous beginning 14 days prior to treatment (pretest), the first 14 days of treatment and during mating until evidence of copulation was observed. Vaginal lavage continued for those females with no evidence of copulation until termination of the mating period. During pretest, this was done for 48 females. On the day of scheduled necropsy, a vaginal lavage was taken to determine the stage of estrous.
General reproduction data
Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded. Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of pregnant females were examined for evidence of abortion or premature delivery. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.
Pups:
Anogenital distance: Anogenital distance (AGD) was measured for all live pups on PND 1. The AGD was normalized to the cube root of body weight.
Areola/nipple retention: On PND 13, all males in each litter were examined for the number of areola/nipples. - Statistics:
- The following statistical methods were used to analyse the data:
• If the variables could be assumed to follow a normal distribution, the Dunnett-test (Ref. 2; many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
• The Fisher Exact-test was applied to frequency data.
• The Kruskal-Wallis nonparametric ANOVA test was applied to motor activity data to determine intergroup differences.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Parental animals: No treatment-related clinical signs of toxicity were noted during daily clinical observations or during weekly arena observations.
Slight salivation was noted after dosing, starting after about two weeks of treatment, at all dose levels, most frequently at 150 and 500 mg/kg. This salivation was considered to be a physiological response rather than a sign of systemic toxicity considering its slight severity and the time of occurrence (i.e. after dosing).
One female at 500 mg/kg (no. 76) showed lethargy, shallow respiration and piloerection towards the end of the gestation period (on one or two days). Based on the incidental occurrence of these signs of distress and the absence of abnormalities in her body weight development and food consumption, these findings were considered not to be toxicologically relevant.
Any other clinical signs noted incidentally occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and showed no dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.
Pups:
No clinical signs occurred among pups that were considered to be related to treatment.
The nature and incidence of the clinical signs observed incidentally remained within the range considered normal for pups of this age, and were therefore considered to be of no toxicological relevance. - Mortality:
- no mortality observed
- Description (incidence):
- Parental animals: No mortality occurred during the study period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Parental animals: Body weight and body weight gain were not affected by treatment.
Pups: Body weights of pups were considered not to be affected by treatment.
Compared to controls, mean body weights of male and female pups at 500 mg/kg were higher from birth until PND 13. The relative differences gradually decreased from about 20% at PND 1 (statistically significant) to about 10% at PND 13 (no longer statistically significant). The higher means at 500 mg/kg were particularly due to the higher (exceeding normal limits) weights and weight gain of the pups of one small litter (no. 73, two male and two female pups). The higher pup weights in this small litter are consistent with the generally recognized inverse relation between litter size and pup body weight. Pups of the other litters at 500 mg/kg had normal body weights at birth and thereafter (except for those of litter no. 71 which had slightly lower weights at PND 13). For these reasons, the higher mean pup weights at 500 mg/kg were considered to reflect normal biological variation rather than an effect of the test item. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Parental animals: No treatment-related changes in food consumption before or after allowance for body weight were noted.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Parental animals: No toxicologically relevant changes occurred in haematology parameters of treated rats.
Isolated statistically significant variations noted in haematology parameters in males were unrelated to treatment or not toxicologically relevant due to the lack of a dose-related response or a slightly high concurrent control value. - Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Parental animals: No toxicologically relevant changes occurred in clinical biochemistry parameters of treated rats.
The statistically significant variations noted in clinical biochemistry parameters were unrelated to treatment or not toxicologically relevant due to the lack of a dose-related response, slight magnitude of the difference from controls (values in treated rats remained within normal limits), and/or a slightly low concurrent control value.
Thyroid hormone analyses:
Serum levels of T4 in F0 males were not affected by treatment.
Pups: Serum T4 levels in male and female PND 13-15 pups were not affected by treatment. - Urinalysis findings:
- not specified
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Parental animals: Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals.
Grip strength was similar across the groups, except for a statistically significantly lower hind limb grip strength in males at 500 mg/kg. This finding was not accompanied by a decrease in fore limb grip strength and the values at 500 mg/kg were within the normal range for male rats of this strain and age. Therefore, the lower hind limb grip strength in males at 500 mg/kg was considered not to be toxicologically relevant.
The variation in motor activity did not indicate a relation with treatment. All groups showed a similar habituation profile with a decreasing trend in activity over the duration of the test period. - Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Parental animals: There were no treatment-related alterations in organ weights.
The statistically significant variations noted in organ weights of males were unrelated to treatment due to the lack of a dose-related pattern - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Parental animals: There were no treatment-related gross observations.
All of the recorded macroscopic findings were within the range of background gross observations encountered in rats of this age and strain. These necropsy findings were therefore considered to be unrelated to treatment.
Pups: No macroscopic findings were noted among pups that were considered to be related to treatment.
The nature and incidence of the few findings noted (mostly in pups found dead) remained within the range considered normal for pups of this age, and were therefore considered to be unrelated to treatment. - Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the thyroid gland of males, an increased incidence and severity (up to slight) of follicular cell hypertrophy was present starting at 150 mg/kg/day, and colloid alteration was present at 500 mg/kg (up to slight).
The remainder of the recorded microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no test item related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations. This included the recorded findings of control animals which erroneously received the test item. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Description (incidence and severity):
- There were 1/10 couples treated at 50 mg/kg (female/male no. 51/11, total litter loss), 1/10 couples treated at 150 mg/kg (female/male no. 69/29, not mated) and 2/10 couples treated at 500 mg/kg (female/male no. 77/37, not pregnant; no. 79/39, total litter loss) that failed to deliver healthy pups. Histopathology did not reveal any changes in the reproductive organs that could explain the reproductive failure or total litter loss.
There were no morphological findings in the reproductive organs of either sex which could be attributed to the test item, and spermatogenic staging profiles were normal for all males examined.
Length and regularity of the estrous cycle were not affected by treatment.
Most females had regular cycles of 4 days. Control female no. 46 had an irregular cycle and extended di-estrus during paring was noted for female no. 69 at 150 mg/kg. These findings were considered to be unrelated to treatment because their incidence was within normal limits and showed no dose-related trend.
- Details on results:
- Accuracy
The concentrations analyzed in the formulations of Groups 2, 3 and 4 were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%).
No test item was detected in the Group 1 formulation.
Homogeneity
The formulations of Groups 2 and 4 were homogeneous (i.e. coefficient of variation ≤ 10%). - Key result
- Dose descriptor:
- NOEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: non-adverse microscopic changes in the thyroids of males at 500 mg/kg
- Remarks on result:
- not determinable
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- LOWINOX® TBP-6 was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 50, 150 and 500 mg/kg. Males were treated for 2 weeks prior to mating, during mating, and up to termination (for 31 days). The females that delivered were treated for 2 weeks prior to mating, during mating, duringpost-coitum, and at least 13 days of lactation (for 50-56 days). Females which failed to deliver healthy offspring were treated for for 38-45 days.
Formulation analysis showed that the formulations were prepared accurately and homogenously. Stability of formulations under (simulated) experimental conditions was confirmed as part of the analytical method development and validation study.
No toxicologically relevant changes were noted in the in-life parameters examined in this study up to 500 mg/kg (i.e. mortality, clinical appearance, functional observations, body weight and body weight gain, food consumption). Treatment-related in-life findings were limited to slight salivation after dosing at all dose levels, most frequently at 150 and 500 mg/kg. This was considered to be a physiological response rather than a sign of systemic toxicity.
Microscopic examination showed treatment-related changes in the thyroid of male rats, characterized by an increased incidence and severity of follicular cell hypertrophy starting at 150 mg/kg, and alteration of the colloid at 500 mg/kg. There were no other treatment-related microscopic findings. Furthermore, thyroid weight and the serum level of thyroid hormone T4 were not affected by treatment. Based on this and the low degree (up to slight) of the follicular cell hypertrophy and colloid alteration, these findings were regarded as non-adverse.
No treatment-related or toxicologically relevant changes were noted in clinical pathology parameters, organ weights or findings at macroscopic examination.
Based on these results, a parental, reproduction and developmental No Observed Adverse Effect Level (NOAEL) of at least 500 mg/kg was derived.
The parental No Observed Effect Level (NOEL) was established at 150 mg/kg based on non-adverse microscopic changes in the thyroids of males at 500 mg/kg. - Executive summary:
Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of LOWINOX® TBP-6 in rats by oral gavage.
The study was based on the following guidelines:
• OECD 422, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2016.
• OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2000.
• OECD 421, Reproduction/Developmental Toxicity Screening Test, July 2016.
• OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test, July 2000.
• EC No 440/2008 B.7: "Repeated Dose (28 days) Toxicity (oral)", May 2008.
• OECD 407, Repeated Dose 28-day Oral Toxicity Study in Rodents, October 2008.
• OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents, July 2000.
Based on the results of a dose range finding study in which toxicity was noted at 500 mg/kg but not at 250 mg/kg (Test Facility Study No. 513610; see APPENDIX 5), the dose levels for this combined 28-day oral gavage study with reproduction/developmental toxicity screening test were selected to be 50, 150 and 500 mg/kg.
The test item, LOWINOX® TBP-6, formulated in propylene glycol, was administered daily by oral gavage to SPF-bred Wistar Han rats. One control group and three treated groups were tested, each consisting of 10 males and 10 females. Males were treated for 31 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were treated for 50-56 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during 13-15 days of lactation. Females which failed to deliver healthy offspring were treated for 38-45 days.
The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (end of treatment), body weight and food consumption (at least at weekly intervals), estrous cycle determination (14 days prior to treatment, 14 days of treatment and during mating until evidence of mating, and on the day of necropsy), clinical pathology (end of treatment), measurement of thyroid hormone T4 (F0-males at the end of treatment, PND 13-15 pups), macroscopy at termination, organ weights and histopathology on a selection of tissues. In addition, the following reproduction/developmental parameters were determined: mating, fertility and conception indices, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, anogenital distance, areola/nipple retention and macroscopy). Formulations were analyzed once during the study to assess accuracy and homogeneity.
There were no toxicologically relevant changes in the in-life parameters up to 500 mg/kg.
Slight salivation was noted after dosing at all dose levels, most frequently at 150 and 500 mg/kg. This was considered to be a physiological response rather than a sign of systemic toxicity.
Treatment-related microscopic changes were present in the thyroid of male rats, characterized by an increased incidence and severity of follicular cell hypertrophy starting at 150 mg/kg, and alteration of the colloid at 500 mg/kg. These findings were regarded as non-adverse based on their low degree (up to slight) and the absence of other treatment-related findings.
No treatment-related or toxicologically relevant changes were noted in clinical pathology parameters, organ weights or findings at macroscopic examination.
In conclusion:
Based on these results, a parental, reproduction and developmental No Observed Adverse Effect Level (NOAEL) of at least 500 mg/kg was derived.
The parental No Observed Effect Level (NOEL) was established at 150 mg/kg based on non-adverse microscopic changes in the thyroids of males at 500 mg/kg.
Reference
Microscopic Examination
Test item-related microscopic findings were noted in the thyroid gland of males treated at 150 or 500 mg/kg and are summarized in the table below.
|
Males |
|||
Dose level (mg/kg bw): |
0 |
50 |
150 |
500 |
|
|
|
|
|
Thyroid glanda |
5 |
5 |
5 |
5 |
Follicular cell hypertrophy |
|
|
|
|
Minimal |
1 |
1 |
3 |
1 |
Slight |
- |
- |
1 |
4 |
Colloid alteration |
|
|
|
|
Minimal |
- |
- |
- |
1 |
Slight |
- |
- |
- |
3 |
a = Number of tissues examined from each group.
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
|
AT WEEK 4 |
|
|
|
|
|
HEARING |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
PUPIL L |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
PUPIL R |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
STATIC R |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
GRIP FORE |
MEAN |
1288 |
1162 |
1439 |
1373 |
GRAM |
ST.DEV |
176 |
120 |
178 |
187 |
|
N |
5 |
5 |
5 |
5 |
GRIP HIND |
MEAN |
612 |
557 |
581 |
497 * |
GRAM |
ST.DEV |
65 |
57 |
44 |
93 |
|
N |
5 |
5 |
5 |
5 |
FEMALES |
|
||||
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
LACTATION |
|
|
|
|
|
HEARING |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
PUPIL L |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
PUPIL R |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
STATIC R |
MEDIAN |
0 |
0 |
0 |
0 |
SCORE 0/1 |
N |
5 |
5 |
5 |
5 |
GRIP FORE |
MEAN |
840 |
1025 |
870 |
1009 |
GRAM |
ST.DEV |
122 |
206 |
228 |
245 |
|
N |
5 |
5 |
5 |
5 |
GRIP HIND |
MEAN |
613 |
690 |
621 |
680 |
GRAM |
ST.DEV |
88 |
67 |
66 |
81 |
|
N |
5 |
5 |
5 |
5 |
MOTOR ACTIVITY MALES
AT WEEK 4 |
TEST SUMMARY |
|
|
|
|
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
Total Movements |
MEAN1 |
3794 |
2571 |
2772 |
3065 |
|
ST.DEV |
2378 |
182 |
1016 |
669 |
|
N |
5 |
5 |
5 |
5 |
Ambulations |
MEAN1 |
852 |
587 |
625 |
842 |
|
ST.DEV |
594 |
72 |
334 |
280 |
|
N |
5 |
5 |
5 |
5 |
*/** Wilcoxon test significant at 5% (*) or 1% (**) level
1Group mean of all intervals
2combined
|
|
|||
|
||||
MOTOR ACTIVITY TEST SUMMARY |
||||
FEMALES |
||||
AT LACTATION |
||||
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
TotalMovements MEAN1 |
3492 |
3270 |
2229 |
3235 |
ST.DEV |
1449 |
1151 |
413 |
818 |
N |
5 |
5 |
5 |
5 |
Ambulations MEAN1 |
848 |
680 |
545 |
773 |
ST.DEV |
355 |
345 |
140 |
284 |
N |
5 |
5 |
5 |
5 |
*/** Wilcoxon test significant at 5% (*) or 1% (**) level
1Group mean of all intervals combined
BODY WEIGHTS (GRAM) SUMMARY MALES
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
|
PRE MATING DAY 1 |
MEAN |
298 |
297 |
294 |
300 |
WEEK 1 |
ST.DEV |
7.4 |
11.1 |
13.0 |
9.4 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
319 |
320 |
315 |
321 |
WEEK 2 |
ST.DEV |
8.5 |
16.4 |
17.5 |
12.6 |
|
N |
10 |
10 |
10 |
10 |
MATING PERIOD DAY 1 |
MEAN |
339 |
341 |
335 |
343 |
WEEK 1 |
ST.DEV |
9.5 |
20.6 |
21.5 |
16.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
351 |
357 |
347 |
357 |
WEEK 2 |
ST.DEV |
10.4 |
20.4 |
19.3 |
17.7 |
|
N |
10 |
10 |
10 |
10 |
DAY 15 |
MEAN |
368 |
375 |
365 |
374 |
WEEK 3 |
ST.DEV |
12.2 |
22.7 |
21.3 |
20.4 |
|
N |
10 |
10 |
10 |
10 |
FEMALES |
|
||||
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
PRE MATING DAY 1 |
MEAN |
221 |
225 |
222 |
226 |
WEEK 1 |
ST.DEV |
8.2 |
11.5 |
7.6 |
14.3 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
222 |
226 |
224 |
228 |
WEEK 2 |
ST.DEV |
8.9 |
12.5 |
9.5 |
15.8 |
|
N |
10 |
10 |
10 |
10 |
MATING PERIOD DAY 1 |
MEAN |
229 |
232 |
231 |
235 |
WEEK 1 |
ST.DEV |
9.2 |
13.9 |
8.7 |
17.3 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
|
|
263 |
|
WEEK 2 |
ST.DEV N |
|
|
--- 1 |
|
DAY 15 WEEK 3 |
MEAN ST.DEV |
|
|
268 --- |
|
|
N |
|
|
1 |
|
DAY 22 |
MEAN |
|
|
257 |
|
WEEK 4 |
ST.DEV N |
|
|
--- 1 |
|
DAY 29 |
MEAN |
|
|
260 |
|
WEEK 5 |
ST.DEV N |
|
|
--- 1 |
|
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
F0-GENERATION
BODY WEIGHTS (GRAM) SUMMARY FEMALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
POST COITUM DAY 0 |
MEAN |
231 |
235 |
232 |
238 |
|
ST.DEV. |
10.3 |
14.5 |
10.0 |
15.7 |
|
N |
10 |
10 |
9 |
9 |
DAY 4 |
MEAN |
245 |
248 |
248 |
256 |
|
ST.DEV. |
10.9 |
16.1 |
11.2 |
16.0 |
|
N |
10 |
10 |
9 |
9 |
DAY 7 |
MEAN |
253 |
256 |
255 |
264 |
|
ST.DEV. |
10.1 |
16.7 |
12.0 |
18.5 |
|
N |
10 |
10 |
9 |
9 |
DAY 11 |
MEAN |
269 |
271 |
271 |
277 |
|
ST.DEV. |
9.9 |
17.6 |
14.3 |
20.6 |
|
N |
10 |
10 |
9 |
9 |
DAY 14 |
MEAN |
279 |
284 |
283 |
286 |
|
ST.DEV. |
11.3 |
19.7 |
15.5 |
20.9 |
|
N |
10 |
10 |
9 |
9 |
DAY 17 |
MEAN |
299 |
304 |
305 |
309 |
|
ST.DEV. |
11.6 |
25.2 |
16.9 |
22.8 |
|
N |
10 |
10 |
9 |
9 |
DAY 20 |
MEAN |
336 |
341 |
346 |
341 |
|
ST.DEV. |
16.3 |
34.2 |
18.6 |
28.4 |
|
N |
10 |
10 |
9 |
9 |
LACTATION DAY 1 |
MEAN |
260 |
263 |
264 |
272 |
|
ST.DEV. |
9.3 |
20.4 |
16.3 |
21.9 |
|
N |
10 |
10 |
9 |
9 |
DAY 4 |
MEAN |
273 |
276 |
276 |
281 |
|
ST.DEV. |
15.5 |
19.8 |
15.8 |
24.0 |
|
N |
10 |
9 |
9 |
9 |
DAY 7 |
MEAN |
284 |
287 |
289 |
292 |
|
ST.DEV. |
15.6 |
18.7 |
16.5 |
23.2 |
|
N |
10 |
9 |
9 |
8 |
DAY 13 |
MEAN |
302 |
299 |
297 |
306 |
|
ST.DEV. |
16.0 |
21.5 |
17.5 |
21.9 |
|
N |
10 |
9 |
9 |
8 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level Explanations for excluded data are listed in the tables of the individual values
BODY WEIGHT GAIN (%) SUMMARY MALES
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
|
PRE MATING DAY 1 |
MEAN |
0 |
0 |
0 |
0 |
WEEK 1 |
ST.DEV |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
7 |
8 |
7 |
7 |
WEEK 2 |
ST.DEV |
2.0 |
2.2 |
2.1 |
1.6 |
|
N |
10 |
10 |
10 |
10 |
MATING PERIOD DAY 1 |
MEAN |
14 |
15 |
14 |
14 |
WEEK 1 |
ST.DEV |
2.9 |
3.5 |
3.0 |
2.6 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
18 |
20 |
18 |
19 |
WEEK 2 |
ST.DEV |
3.5 |
3.7 |
3.1 |
2.9 |
|
N |
10 |
10 |
10 |
10 |
DAY 15 |
MEAN |
24 |
26 |
24 |
24 |
WEEK 3 |
ST.DEV |
4.2 |
4.2 |
3.4 |
3.5 |
|
N |
10 |
10 |
10 |
10 |
FEMALES |
|
|
|
|
|
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
PRE MATING DAY 1 |
MEAN |
0 |
0 |
0 |
0 |
WEEK 1 |
ST.DEV |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
0 |
0 |
1 |
1 |
WEEK 2 |
ST.DEV |
2.5 |
1.4 |
1.7 |
1.8 |
|
N |
10 |
10 |
10 |
10 |
MATING PERIOD DAY 1 |
MEAN |
3 |
3 |
4 |
4 |
WEEK 1 |
ST.DEV |
2.6 |
2.5 |
2.9 |
3.5 |
|
N |
10 |
10 |
10 |
10 |
DAY 8 |
MEAN |
|
|
15 |
|
WEEK 2 |
ST.DEV N |
|
|
--- 1 |
|
DAY 15 WEEK 3 |
MEAN ST.DEV |
|
|
17 --- |
|
|
N |
|
|
1 |
|
DAY 22 |
MEAN |
|
|
12 |
|
WEEK 4 |
ST.DEV N |
|
|
--- 1 |
|
DAY 29 |
MEAN |
|
|
14 |
|
WEEK 5 |
ST.DEV N |
|
|
--- 1 |
|
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
F0-GENERATION
BODY WEIGHT GAIN (%) SUMMARY FEMALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
POST COITUM DAY 0 |
MEAN |
0 |
0 |
0 |
0 |
|
ST.DEV. |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
9 |
9 |
DAY 4 |
MEAN |
6 |
6 |
7 |
8 |
|
ST.DEV. |
1.8 |
1.8 |
1.8 |
2.8 |
|
N |
10 |
10 |
9 |
9 |
DAY 7 |
MEAN |
9 |
9 |
10 |
11 |
|
ST.DEV. |
1.7 |
1.9 |
2.2 |
3.3 |
|
N |
10 |
10 |
9 |
9 |
DAY 11 |
MEAN |
16 |
15 |
17 |
16 |
|
ST.DEV. |
2.5 |
2.1 |
3.1 |
3.4 |
|
N |
10 |
10 |
9 |
9 |
DAY 14 |
MEAN |
20 |
20 |
22 |
20 |
|
ST.DEV. |
2.1 |
2.5 |
3.4 |
2.8 |
|
N |
10 |
10 |
9 |
9 |
DAY 17 |
MEAN |
30 |
29 |
32 |
30 |
|
ST.DEV. |
3.0 |
4.5 |
3.5 |
4.7 |
|
N |
10 |
10 |
9 |
9 |
DAY 20 |
MEAN |
45 |
45 |
49 |
43 |
|
ST.DEV. |
3.0 |
8.3 |
3.6 |
7.6 |
|
N |
10 |
10 |
9 |
9 |
LACTATION DAY 1 |
MEAN |
0 |
0 |
0 |
0 |
|
ST.DEV. |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
10 |
10 |
9 |
9 |
DAY 4 |
MEAN |
5 |
5 |
5 |
3 |
|
ST.DEV. |
3.1 |
2.9 |
3.0 |
3.4 |
|
N |
10 |
9 |
9 |
9 |
DAY 7 |
MEAN |
10 |
9 |
10 |
8 |
|
ST.DEV. |
3.1 |
3.4 |
4.1 |
2.4 |
|
N |
10 |
9 |
9 |
8 |
DAY 13 |
MEAN |
16 |
14 |
13 |
13 |
|
ST.DEV. |
3.6 |
4.4 |
6.8 |
2.6 |
|
N |
10 |
9 |
9 |
8 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level Explanations for excluded data are listed in the tables of the individual values
FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY MALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
PRE MATING DAYS 1-8 |
MEAN |
22 |
22 |
22 |
23 |
WEEKS 1-2 |
ST.DEV |
0.9 |
0.1 |
0.1 |
0.7 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
21 |
22 |
22 |
23 |
WEEKS 2-3 |
ST.DEV |
0.2 |
0.1 |
0.5 |
1.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER PRE MATI... |
MEAN |
22 |
22 |
22 |
23 |
MATING PERIOD |
|
|
|
|
|
DAYS 1-8 |
MEAN |
23 |
23 |
23 |
23 |
WEEKS 1-2 |
ST.DEV |
0.7 |
0.2 |
0.4 |
1.0 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
22 |
22 |
22 |
23 |
WEEKS 2-3 |
ST.DEV |
0.5 |
0.1 |
0.8 |
1.0 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER MATING P... |
MEAN |
22 |
22 |
22 |
23 |
FEMALES |
|
|
|
|
|
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
PRE MATING DAYS 1-8 |
MEAN |
15 |
15 |
15 |
15 |
WEEKS 1-2 |
ST.DEV |
0.6 |
0.7 |
0.7 |
0.7 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
14 |
14 |
15 |
16 |
WEEKS 2-3 |
ST.DEV |
0.6 |
0.4 |
0.4 |
0.6 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER PRE MATI... |
MEAN |
15 |
15 |
15 |
15 |
F0-GENERATION
FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY FEMALES |
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
POST COITUM DAYS 0-4 |
MEAN |
16 |
16 |
16 |
19 |
|
ST.DEV. |
2.8 |
2.8 |
3.0 |
3.8 |
|
N |
10 |
10 |
9 |
9 |
DAYS 4-7 |
MEAN |
18 |
18 |
18 |
20 |
|
ST.DEV. |
1.6 |
2.2 |
1.7 |
3.4 |
|
N |
10 |
10 |
9 |
9 |
DAYS 7-11 |
MEAN |
19 |
18 |
19 |
20 |
|
ST.DEV. |
1.3 |
2.3 |
2.4 |
3.2 |
|
N |
10 |
10 |
9 |
9 |
DAYS 11-14 |
MEAN |
21 |
21 |
22 |
22 |
|
ST.DEV. |
1.1 |
2.2 |
3.0 |
2.4 |
|
N |
10 |
10 |
9 |
9 |
DAYS 14-17 |
MEAN |
20 |
20 |
20 |
22 |
|
ST.DEV. |
0.6 |
2.4 |
2.2 |
2.9 |
|
N |
10 |
10 |
9 |
9 |
DAYS 17-20 |
MEAN |
23 |
22 |
24 |
24 |
|
ST.DEV. |
2.2 |
2.5 |
2.5 |
2.8 |
|
N |
10 |
10 |
9 |
9 |
MEAN OF MEANS |
|
19 |
19 |
20 |
21 |
LACTATION DAYS 1-4 |
MEAN |
25 |
27 |
25 |
26 |
|
ST.DEV. |
4.1 |
3.0 |
2.8 |
5.3 |
|
N |
6 |
6 |
8 |
9 |
DAYS 4-7 |
MEAN |
37 |
38 |
37 |
37 |
|
ST.DEV. |
4.3 |
3.5 |
3.6 |
5.2 |
|
N |
10 |
9 |
9 |
8 |
DAYS 7-13 |
MEAN |
49 |
46 |
46 |
47 |
|
ST.DEV. |
3.3 |
3.8 |
4.4 |
5.4 |
|
N |
10 |
9 |
9 |
8 |
MEAN OF MEANS |
|
37 |
37 |
36 |
36 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level Explanations for excluded data are listed in the tables of the individual values
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
PRE MATING DAYS 1-8 |
MEAN |
68 |
70 |
69 |
71 |
WEEKS 1-2 |
ST.DEV |
1.9 |
0.2 |
1.1 |
2.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
67 |
69 |
69 |
70 |
WEEKS 2-3 |
ST.DEV |
0.0 |
0.4 |
2.3 |
4.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER PRE MATI... |
MEAN |
68 |
69 |
69 |
71 |
MATING PERIOD |
|
|
|
|
|
DAYS 1-8 |
MEAN |
64 |
64 |
65 |
65 |
WEEKS 1-2 |
ST.DEV |
1.3 |
1.0 |
0.8 |
2.7 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
58 |
58 |
60 |
61 |
WEEKS 2-3 |
ST.DEV |
0.8 |
0.4 |
2.0 |
2.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER MATING P... |
MEAN |
61 |
61 |
63 |
63 |
FEMALES |
|
|
|
|
|
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
PRE MATING DAYS 1-8 |
MEAN |
67 |
66 |
68 |
67 |
WEEKS 1-2 |
ST.DEV |
1.0 |
1.5 |
2.0 |
1.3 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
DAYS 8-15 |
MEAN |
65 |
63 |
67 |
68 |
WEEKS 2-3 |
ST.DEV |
0.9 |
0.3 |
0.7 |
1.1 |
|
N (CAGE) |
2 |
2 |
2 |
2 |
MEAN OF MEANS OVER PRE MATI... |
MEAN |
66 |
64 |
67 |
68 |
F0-GENERATION
RELATIVE FOOD CONSUMPTION (G/KG BODY WEIGHT/DAY) SUMMARY FEMALES |
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
POST COITUM DAYS 0-4 |
MEAN |
66 |
65 |
65 |
73 |
|
ST.DEV. |
10.6 |
9.3 |
12.7 |
14.4 |
|
N |
10 |
10 |
9 |
9 |
DAYS 4-7 |
MEAN |
70 |
69 |
72 |
76 |
|
ST.DEV. |
6.2 |
4.7 |
5.3 |
9.4 |
|
N |
10 |
10 |
9 |
9 |
DAYS 7-11 |
MEAN |
70 |
67 |
71 |
73 |
|
ST.DEV. |
4.4 |
5.2 |
6.5 |
8.5 |
|
N |
10 |
10 |
9 |
9 |
DAYS 11-14 |
MEAN |
74 |
72 |
77 |
76 |
|
ST.DEV. |
4.3 |
4.5 |
8.7 |
5.4 |
|
N |
10 |
10 |
9 |
9 |
DAYS 14-17 |
MEAN |
68 |
66 |
66 |
70 |
|
ST.DEV. |
2.2 |
4.5 |
5.8 |
6.1 |
|
N |
10 |
10 |
9 |
9 |
DAYS 17-20 |
MEAN |
68 |
66 |
69 |
71 |
|
ST.DEV. |
7.0 |
6.4 |
7.2 |
6.8 |
|
N |
10 |
10 |
9 |
9 |
MEAN OF MEANS |
|
69 |
67 |
70 |
73 |
LACTATION DAYS 1-4 |
MEAN |
93 |
98 |
91 |
92 |
|
ST.DEV. |
12.8 |
8.5 |
7.8 |
18.1 |
|
N |
6 |
6 |
8 |
9 |
DAYS 4-7 |
MEAN |
130 |
133 |
126 |
125 |
|
ST.DEV. |
12.1 |
14.5 |
11.1 |
13.4 |
|
N |
10 |
9 |
9 |
8 |
DAYS 7-13 |
MEAN |
161 |
154 |
155 |
154 |
|
ST.DEV. |
9.9 |
10.3 |
12.8 |
16.0 |
|
N |
10 |
9 |
9 |
8 |
MEAN OF MEANS |
|
128 |
128 |
124 |
124 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level Explanations for excluded data are listed in the tables of the individual values
HAEMATOLOGY SUMMARY MALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT WBC |
MEAN |
6.9 |
7.5 |
5.7 |
6.8 |
10E9/L |
ST.DEV |
2.0 |
1.4 |
0.9 |
1.3 |
|
N |
5 |
5 |
5 |
5 |
Neutrophils |
MEAN |
14.3 |
14.6 |
13.6 |
12.1 |
%WBC |
ST.DEV |
3.1 |
3.9 |
3.4 |
1.7 |
|
N |
5 |
5 |
5 |
4 |
Lymphocytes |
MEAN |
82.9 |
82.7 |
83.6 |
85.1 |
%WBC |
ST.DEV |
2.7 |
4.6 |
3.3 |
1.9 |
|
N |
5 |
5 |
5 |
4 |
Monocytes |
MEAN |
1.7 |
1.8 |
1.8 |
1.9 |
%WBC |
ST.DEV |
0.3 |
0.5 |
0.6 |
0.3 |
|
N |
5 |
5 |
5 |
4 |
Eosinophils |
MEAN |
1.0 |
0.9 |
1.0 |
0.9 |
%WBC |
ST.DEV |
0.5 |
0.5 |
0.2 |
0.2 |
|
N |
5 |
5 |
5 |
4 |
Basophils |
MEAN |
0.1 |
0.1 |
0.1 |
0.1 |
%WBC |
ST.DEV |
0.1 |
0.0 |
0.1 |
0.0 |
|
N |
5 |
5 |
5 |
4 |
Red blood cells |
MEAN |
8.88 |
8.71 |
8.78 |
8.62 |
10E12/L |
ST.DEV |
0.21 |
0.29 |
0.32 |
0.34 |
|
N |
5 |
5 |
5 |
5 |
Reticulocytes |
MEAN |
2.2 |
2.5 |
2.7 |
2.7 |
%RBC |
ST.DEV |
0.3 |
0.4 |
0.3 |
0.6 |
|
N |
5 |
5 |
5 |
5 |
RDW |
MEAN |
11.8 |
12.9 |
12.1 |
12.1 |
% |
ST.DEV |
0.6 |
2.1 |
0.7 |
0.3 |
|
N |
5 |
5 |
5 |
5 |
Haemoglobin |
MEAN |
10.0 |
9.8 |
10.0 |
9.7 |
mmol/L |
ST.DEV |
0.2 |
0.2 |
0.3 |
0.2 |
|
N |
5 |
5 |
5 |
5 |
Haematocrit |
MEAN |
0.451 |
0.447 |
0.463 |
0.449 |
L/L |
ST.DEV |
0.013 |
0.007 |
0.018 |
0.013 |
|
N |
5 |
5 |
5 |
5 |
MCV |
MEAN |
50.7 |
51.4 |
52.8 |
52.2 |
fL |
ST.DEV |
1.5 |
1.7 |
2.1 |
1.7 |
|
N |
5 |
5 |
5 |
5 |
MCH |
MEAN |
1.12 |
1.13 |
1.14 |
1.13 |
fmol |
ST.DEV |
0.03 |
0.04 |
0.04 |
0.03 |
|
N |
5 |
5 |
5 |
5 |
MCHC |
MEAN |
22.19 |
22.05 |
21.58 * |
21.67 |
mmol/L |
ST.DEV |
0.33 |
0.52 |
0.30 |
0.22 |
|
N |
5 |
5 |
5 |
5 |
Platelets |
MEAN |
837 |
757 |
755 |
683 * |
10E9/L |
ST.DEV |
136 |
20 |
48 |
50 |
|
N |
5 |
5 |
5 |
5 |
+/++ Steel-test significant at 5% (+) or 1% (++) level
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT PT |
MEAN |
17.9 |
18.6 |
18.1 |
18.4 |
s |
ST.DEV |
0.6 |
0.3 |
0.5 |
0.4 |
|
N |
5 |
5 |
5 |
5 |
APTT |
MEAN |
15.0 |
17.1 |
15.4 |
16.4 |
s |
ST.DEV |
1.3 |
2.3 |
1.4 |
2.4 |
|
N |
5 |
5 |
5 |
5 |
HAEMATOLOGY SUMMARY FEMALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT WBC |
MEAN |
7.3 |
7.2 |
7.6 |
8.1 |
10E9/L |
ST.DEV |
1.0 |
1.3 |
1.3 |
2.1 |
|
N |
5 |
5 |
5 |
5 |
Neutrophils |
MEAN |
52.3 |
45.6 |
43.5 |
45.6 |
%WBC |
ST.DEV |
9.1 |
8.4 |
4.4 |
6.4 |
|
N |
5 |
5 |
5 |
5 |
Lymphocytes |
MEAN |
41.5 |
48.7 |
50.9 |
48.8 |
%WBC |
ST.DEV |
7.8 |
8.2 |
4.2 |
6.0 |
|
N |
5 |
5 |
5 |
5 |
Monocytes |
MEAN |
4.2 |
4.5 |
4.3 |
4.9 |
%WBC |
ST.DEV |
1.4 |
1.3 |
0.7 |
1.2 |
|
N |
5 |
5 |
5 |
5 |
Eosinophils |
MEAN |
2.0 |
1.1 |
1.1 |
0.6 |
%WBC |
ST.DEV |
1.5 |
0.5 |
0.3 |
0.4 |
|
N |
5 |
5 |
5 |
5 |
Basophils |
MEAN |
0.1 |
0.1 |
0.1 |
0.1 |
%WBC |
ST.DEV |
0.0 |
0.0 |
0.0 |
0.0 |
|
N |
5 |
5 |
5 |
5 |
Red blood cells |
MEAN |
7.79 |
7.89 |
7.70 |
7.57 |
10E12/L |
ST.DEV |
0.50 |
0.70 |
0.46 |
0.58 |
|
N |
5 |
5 |
5 |
5 |
Reticulocytes |
MEAN |
3.4 |
3.2 |
2.9 |
3.5 |
%RBC |
ST.DEV |
0.7 |
0.5 |
0.5 |
0.5 |
|
N |
5 |
5 |
5 |
5 |
RDW |
MEAN |
13.1 |
13.7 |
14.7 |
13.4 |
% |
ST.DEV |
1.1 |
1.1 |
1.3 |
0.5 |
|
N |
5 |
5 |
5 |
5 |
Haemoglobin |
MEAN |
9.3 |
9.4 |
9.2 |
9.2 |
mmol/L |
ST.DEV |
0.9 |
1.0 |
0.6 |
0.7 |
|
N |
5 |
5 |
5 |
5 |
Haematocrit |
MEAN |
0.433 |
0.434 |
0.431 |
0.442 |
L/L |
ST.DEV |
0.036 |
0.047 |
0.038 |
0.047 |
|
N |
5 |
5 |
5 |
5 |
MCV |
MEAN |
55.6 |
55.0 |
56.0 |
58.3 |
fL |
ST.DEV |
1.7 |
2.2 |
2.0 |
1.8 |
|
N |
5 |
5 |
5 |
5 |
MCH |
MEAN |
1.19 |
1.19 |
1.19 |
1.21 |
fmol |
ST.DEV |
0.05 |
0.04 |
0.02 |
0.02 |
|
N |
5 |
5 |
5 |
5 |
MCHC |
MEAN |
21.43 |
21.66 |
21.28 |
20.77 |
mmol/L |
ST.DEV |
0.32 |
0.40 |
0.52 |
0.60 |
|
N |
5 |
5 |
5 |
5 |
Platelets |
MEAN |
782 |
793 |
803 |
801 |
10E9/L |
ST.DEV |
78 |
36 |
126 |
184 |
|
N |
5 |
5 |
5 |
5 |
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT PT |
MEAN |
17.3 |
17.4 |
17.7 |
17.3 |
s |
ST.DEV |
0.5 |
1.4 |
0.8 |
0.6 |
|
N |
5 |
5 |
5 |
5 |
APTT |
MEAN |
13.1 |
13.4 |
12.7 |
14.2 |
s |
ST.DEV |
1.7 |
2.5 |
0.7 |
2.0 |
|
N |
5 |
5 |
5 |
5 |
CLINICAL BIOCHEMISTRY SUMMARY MALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT ALAT |
MEAN |
49.8 |
47.7 |
43.1 |
44.6 |
U/L |
ST.DEV |
20.5 |
10.4 |
9.3 |
6.8 |
|
N |
5 |
5 |
5 |
5 |
ASAT |
MEAN |
86.4 |
82.8 |
85.2 |
85.8 |
U/L |
ST.DEV |
4.0 |
4.7 |
10.0 |
13.3 |
|
N |
5 |
5 |
5 |
5 |
ALP |
MEAN |
179 |
162 |
151 |
169 |
U/L |
ST.DEV |
62 |
57 |
59 |
39 |
|
N |
5 |
5 |
5 |
5 |
Total protein |
MEAN |
65.0 |
64.3 |
63.0 |
63.0 |
g/L |
ST.DEV |
2.1 |
1.6 |
1.2 |
2.1 |
|
N |
5 |
5 |
5 |
5 |
Albumin |
MEAN |
34.7 |
34.1 |
33.7 |
33.2 * |
g/L |
ST.DEV |
1.2 |
0.7 |
0.6 |
1.1 |
|
N |
5 |
5 |
5 |
5 |
Total bilirubin |
MEAN |
2.5 |
2.0 * |
2.1 |
2.1 |
umol/L |
ST.DEV |
0.3 |
0.2 |
0.3 |
0.3 |
|
N |
5 |
5 |
5 |
5 |
Urea |
MEAN |
8.1 |
8.0 |
7.9 |
7.7 |
mmol/L |
ST.DEV |
2.5 |
1.1 |
1.5 |
0.2 |
|
N |
5 |
5 |
5 |
5 |
Creatinine |
MEAN |
41.1 |
41.1 |
41.1 |
40.3 |
umol/L |
ST.DEV |
2.9 |
1.2 |
1.5 |
1.3 |
|
N |
5 |
5 |
5 |
5 |
Glucose |
MEAN |
7.94 |
8.26 |
8.55 |
8.19 |
mmol/L |
ST.DEV |
1.07 |
1.27 |
1.19 |
0.82 |
|
N |
5 |
5 |
5 |
5 |
Cholesterol |
MEAN |
1.92 |
1.89 |
1.85 |
2.03 |
mmol/L |
ST.DEV |
0.16 |
0.25 |
0.36 |
0.40 |
|
N |
5 |
5 |
5 |
5 |
Bile Acids |
MEAN |
28.7 |
13.6 * |
16.1 * |
16.1 * |
umol/L |
ST.DEV |
11.8 |
2.6 |
6.5 |
6.7 |
|
N |
5 |
5 |
5 |
5 |
Sodium |
MEAN |
141.0 |
140.6 |
141.5 |
141.2 |
mmol/L |
ST.DEV |
0.2 |
0.3 |
1.5 |
0.4 |
|
N |
5 |
5 |
5 |
5 |
Potassium |
MEAN |
3.59 |
4.02 ** |
3.75 |
3.82 * |
mmol/L |
ST.DEV |
0.11 |
0.13 |
0.16 |
0.13 |
|
N |
5 |
5 |
5 |
5 |
Chloride |
MEAN |
102 |
103 |
102 |
103 |
mmol/L |
ST.DEV |
1 |
1 |
1 |
1 |
|
N |
5 |
5 |
5 |
5 |
Calcium |
MEAN |
2.60 |
2.58 |
2.56 |
2.60 |
mmol/L |
ST.DEV |
0.08 |
0.05 |
0.03 |
0.03 |
|
N |
5 |
5 |
5 |
5 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
- Page 19 -
- Page 19 -
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT Inorg.Phos |
MEAN |
1.99 |
2.05 |
1.94 |
1.99 |
mmol/L |
ST.DEV |
0.20 |
0.20 |
0.18 |
0.21 |
|
N |
5 |
5 |
5 |
5 |
Total T4 |
MEAN |
4.93 |
4.00 |
4.06 |
4.34 |
ug/dL |
ST.DEV |
1.58 |
0.76 |
0.81 |
0.92 |
|
N |
10 |
10 |
10 |
10 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT ALAT |
MEAN |
75.1 |
59.9 |
79.7 |
76.5 |
U/L |
ST.DEV |
17.8 |
11.6 |
29.2 |
13.9 |
|
N |
5 |
5 |
5 |
5 |
ASAT |
MEAN |
118.1 |
100.0 |
112.1 |
112.1 |
U/L |
ST.DEV |
24.7 |
15.0 |
29.2 |
22.4 |
|
N |
5 |
5 |
5 |
5 |
ALP |
MEAN |
108 |
125 |
162 |
129 |
U/L |
ST.DEV |
29 |
38 |
67 |
62 |
|
N |
5 |
5 |
5 |
5 |
Total protein |
MEAN |
59.0 |
61.5 |
62.9 |
60.8 |
g/L |
ST.DEV |
9.7 |
2.1 |
1.3 |
2.3 |
|
N |
5 |
5 |
5 |
5 |
Albumin |
MEAN |
31.7 |
32.8 |
33.0 |
31.8 |
g/L |
ST.DEV |
4.3 |
0.1 |
0.6 |
1.5 |
|
N |
5 |
5 |
5 |
5 |
Total bilirubin |
MEAN |
2.7 |
2.3 |
2.3 |
2.2 |
umol/L |
ST.DEV |
0.3 |
0.6 |
0.4 |
0.4 |
|
N |
5 |
5 |
5 |
5 |
Urea |
MEAN |
14.2 |
10.9 |
11.2 |
10.2 |
mmol/L |
ST.DEV |
4.9 |
0.6 |
0.9 |
2.1 |
|
N |
5 |
5 |
5 |
5 |
Creatinine |
MEAN |
47.5 |
45.8 |
44.4 |
43.2 |
umol/L |
ST.DEV |
3.0 |
2.5 |
3.0 |
3.1 |
|
N |
5 |
5 |
5 |
5 |
Glucose |
MEAN |
7.03 |
7.98 |
7.92 |
7.96 |
mmol/L |
ST.DEV |
1.00 |
1.07 |
0.98 |
0.70 |
|
N |
5 |
5 |
5 |
5 |
Cholesterol |
MEAN |
1.80 |
2.15 |
2.30 |
2.18 |
mmol/L |
ST.DEV |
0.17 |
0.35 |
0.39 |
0.56 |
|
N |
5 |
5 |
5 |
5 |
Bile Acids |
MEAN |
60.7 |
58.0 |
39.3 |
32.6 |
umol/L |
ST.DEV |
60.7 |
72.3 |
26.1 |
7.8 |
|
N |
5 |
5 |
5 |
5 |
Sodium |
MEAN |
134.6 |
137.8 ** |
136.8 * |
137.2 ** |
mmol/L |
ST.DEV |
0.9 |
1.7 |
1.2 |
0.9 |
|
N |
5 |
5 |
5 |
5 |
Potassium |
MEAN |
3.62 |
3.53 |
3.98 |
3.79 |
mmol/L |
ST.DEV |
0.29 |
0.46 |
0.58 |
0.50 |
|
N |
5 |
5 |
5 |
5 |
Chloride |
MEAN |
94 |
96 |
97 |
97 |
mmol/L |
ST.DEV |
2 |
3 |
1 |
2 |
|
N |
5 |
5 |
5 |
5 |
Calcium |
MEAN |
2.53 |
2.63 |
2.70 |
2.61 |
mmol/L |
ST.DEV |
0.23 |
0.12 |
0.10 |
0.04 |
|
N |
5 |
5 |
5 |
5 |
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT Inorg.Phos |
MEAN |
3.08 |
2.91 |
2.83 |
2.68 |
mmol/L |
ST.DEV |
0.38 |
0.55 |
0.53 |
0.34 |
|
N |
5 |
5 |
5 |
5 |
Total T4 |
MEAN |
--- |
--- |
--- |
--- |
ug/dL |
ST.DEV |
--- |
--- |
--- |
--- |
|
N |
0 |
0 |
0 |
0 |
MACROSCOPIC FINDINGS SUMMARY MALES
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT Animals examined |
10 |
10 |
10 |
10 |
Animals without findings |
7 |
7 |
9 |
10 |
Animals affected |
3 |
3 |
1 |
0 |
Epididymides |
|
|
|
|
Nodule(s) Cowper's gland |
1 |
1 |
0 |
0 |
Agenesis |
0 |
1 |
0 |
0 |
Thymus Focus/foci |
1 |
1 |
1 |
0 |
Mandibular lymph n |
|
|
|
|
Discolouration |
1 |
0 |
0 |
0 |
FEMALES |
|
|
|
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
INTERCURRENT DEATH |
|
|
|
|
Animals examined |
|
1 |
|
1 |
Animals affected |
|
1 |
|
1 |
General observations |
|
|
|
|
Total litter loss |
|
1 |
|
1 |
END OF TREATMENT Animals examined |
10 |
9 |
10 |
9 |
Animals without findings |
7 |
4 |
5 |
5 |
Animals affected |
3 |
5 |
5 |
4 |
Stomach Focus/foci |
3 |
1 |
1 |
1 |
Uterus Contains fluid |
0 |
0 |
1 |
1 |
Clitoral glands |
|
|
|
|
Focus/foci |
0 |
2 |
3 |
1 |
Thyroid gland Reduced in size |
0 |
1 |
0 |
0 |
Thymus Focus/foci |
0 |
1 |
0 |
0 |
Reduced in size |
0 |
1 |
0 |
0 |
Discolouration |
0 |
1 |
1 |
0 |
Skin Alopecia |
0 |
1 |
1 |
1 |
# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level
ORGAN WEIGHTS (GRAM) SUMMARY MALES
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
|
END OF TREATMENT BODY W. |
MEAN |
349 |
356 |
345 |
354 |
(GRAM) |
ST.DEV |
12 |
24 |
19 |
19 |
|
N |
10 |
10 |
10 |
10 |
BRAIN |
MEAN |
2.07 |
2.05 |
2.01 |
2.04 |
(GRAM) |
ST.DEV |
0.09 |
0.07 |
0.05 |
0.04 |
|
N |
5 |
5 |
5 |
5 |
HEART |
MEAN |
0.928 |
1.011 |
0.895 |
1.003 |
(GRAM) |
ST.DEV |
0.069 |
0.069 |
0.023 |
0.092 |
|
N |
5 |
5 |
5 |
5 |
LIVER |
MEAN |
9.22 |
9.22 |
9.05 |
9.34 |
(GRAM) |
ST.DEV |
0.93 |
0.93 |
0.73 |
1.19 |
|
N |
5 |
5 |
5 |
5 |
THYROIDS |
MEAN |
0.015 |
0.015 |
0.018 * |
0.016 |
(GRAM) |
ST.DEV |
0.002 |
0.002 |
0.003 |
0.003 |
|
N |
10 |
10 |
10 |
10 |
THYMUS |
MEAN |
0.334 |
0.409 |
0.353 |
0.365 |
(GRAM) |
ST.DEV |
0.071 |
0.052 |
0.042 |
0.125 |
|
N |
5 |
5 |
5 |
5 |
KIDNEYS |
MEAN |
2.40 |
2.46 |
2.39 |
2.43 |
(GRAM) |
ST.DEV |
0.06 |
0.12 |
0.19 |
0.15 |
|
N |
5 |
5 |
5 |
5 |
ADRENALS |
MEAN |
0.060 |
0.064 |
0.072 |
0.058 |
(GRAM) |
ST.DEV |
0.008 |
0.008 |
0.006 |
0.007 |
|
N |
5 |
5 |
5 |
5 |
SPLEEN |
MEAN |
0.586 |
0.672 |
0.640 |
0.639 |
(GRAM) |
ST.DEV |
0.055 |
0.091 |
0.110 |
0.089 |
|
N |
5 |
5 |
5 |
5 |
TESTES |
MEAN |
3.46 |
3.57 |
3.59 |
3.47 |
(GRAM) |
ST.DEV |
0.28 |
0.32 |
0.27 |
0.19 |
|
N |
10 |
10 |
10 |
10 |
PROSTATE GLAND |
MEAN |
0.893 |
0.942 |
1.043 |
0.916 |
(GRAM) |
ST.DEV |
0.140 |
0.183 |
0.111 |
0.104 |
|
N |
10 |
10 |
10 |
10 |
EPIDIDYMIDES |
MEAN |
1.134 |
1.096 |
1.091 |
1.077 |
(GRAM) |
ST.DEV |
0.085 |
0.118 |
0.065 |
0.028 |
|
N |
10 |
10 |
10 |
10 |
SEMINAL VESICLES |
MEAN |
1.638 |
1.415 * |
1.424 * |
1.514 |
(GRAM) |
ST.DEV |
0.155 |
0.164 |
0.215 |
0.210 |
|
N |
10 |
10 |
10 |
10 |
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT BODY W. |
MEAN |
349 |
356 |
345 |
354 |
(GRAM) |
ST.DEV |
12 |
24 |
19 |
19 |
|
N |
10 |
10 |
10 |
10 |
BRAIN |
MEAN |
0.59 |
0.58 |
0.58 |
0.58 |
(%) |
ST.DEV |
0.04 |
0.04 |
0.03 |
0.03 |
|
N |
5 |
5 |
5 |
5 |
HEART |
MEAN |
0.264 |
0.285 |
0.258 |
0.282 |
(%) |
ST.DEV |
0.025 |
0.021 |
0.011 |
0.007 |
|
N |
5 |
5 |
5 |
5 |
LIVER |
MEAN |
2.62 |
2.59 |
2.61 |
2.62 |
(%) |
ST.DEV |
0.17 |
0.12 |
0.12 |
0.15 |
|
N |
5 |
5 |
5 |
5 |
THYROIDS |
MEAN |
0.004 |
0.004 |
0.005 * |
0.004 |
(%) |
ST.DEV |
0.001 |
0.001 |
0.001 |
0.001 |
|
N |
10 |
10 |
10 |
10 |
THYMUS |
MEAN |
0.094 |
0.116 |
0.102 |
0.101 |
(%) |
ST.DEV |
0.017 |
0.016 |
0.008 |
0.028 |
|
N |
5 |
5 |
5 |
5 |
KIDNEYS |
MEAN |
0.68 |
0.69 |
0.69 |
0.68 |
(%) |
ST.DEV |
0.03 |
0.03 |
0.04 |
0.02 |
|
N |
5 |
5 |
5 |
5 |
ADRENALS |
MEAN |
0.017 |
0.018 |
0.021 * |
0.016 |
(%) |
ST.DEV |
0.002 |
0.002 |
0.003 |
0.002 |
|
N |
5 |
5 |
5 |
5 |
SPLEEN |
MEAN |
0.167 |
0.189 |
0.184 |
0.180 |
(%) |
ST.DEV |
0.020 |
0.020 |
0.025 |
0.023 |
|
N |
5 |
5 |
5 |
5 |
TESTES |
MEAN |
0.99 |
1.01 |
1.04 |
0.98 |
(%) |
ST.DEV |
0.07 |
0.09 |
0.10 |
0.06 |
|
N |
10 |
10 |
10 |
10 |
PROSTATE GLAND |
MEAN |
0.257 |
0.264 |
0.302 * |
0.259 |
(%) |
ST.DEV |
0.045 |
0.046 |
0.033 |
0.026 |
|
N |
10 |
10 |
10 |
10 |
EPIDIDYMIDES |
MEAN |
0.325 |
0.309 |
0.317 |
0.305 |
(%) |
ST.DEV |
0.026 |
0.037 |
0.027 |
0.018 |
|
N |
10 |
10 |
10 |
10 |
SEMINAL VESICLES |
MEAN |
0.471 |
0.399 * |
0.412 * |
0.427 |
(%) |
ST.DEV |
0.051 |
0.052 |
0.051 |
0.053 |
|
N |
10 |
10 |
10 |
10 |
ORGAN WEIGHTS (GRAM) SUMMARY FEMALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT BODY W. |
MEAN |
266 |
266 |
263 |
267 |
(GRAM) |
ST.DEV |
12 |
17 |
15 |
28 |
|
N |
10 |
9 |
10 |
10 |
BRAIN |
MEAN |
1.91 |
1.91 |
1.96 |
1.94 |
(GRAM) |
ST.DEV |
0.02 |
0.05 |
0.10 |
0.07 |
|
N |
5 |
5 |
5 |
5 |
HEART |
MEAN |
0.805 |
0.841 |
0.805 |
0.874 |
(GRAM) |
ST.DEV |
0.076 |
0.072 |
0.051 |
0.097 |
|
N |
5 |
5 |
5 |
5 |
LIVER |
MEAN |
8.79 |
9.22 |
9.20 |
9.99 |
(GRAM) |
ST.DEV |
0.34 |
0.82 |
0.78 |
1.02 |
|
N |
5 |
5 |
5 |
5 |
THYROIDS |
MEAN |
0.014 |
0.013 |
0.015 |
0.015 |
(GRAM) |
ST.DEV |
0.002 |
0.003 |
0.003 |
0.002 |
|
N |
10 |
9 |
10 |
10 |
THYMUS |
MEAN |
0.214 |
0.182 |
0.199 |
0.236 |
(GRAM) |
ST.DEV |
0.038 |
0.052 |
0.049 |
0.042 |
|
N |
5 |
5 |
5 |
5 |
KIDNEYS |
MEAN |
1.80 |
1.98 |
1.98 |
2.03 |
(GRAM) |
ST.DEV |
0.10 |
0.14 |
0.28 |
0.23 |
|
N |
5 |
5 |
5 |
5 |
ADRENALS |
MEAN |
0.075 |
0.078 |
0.069 |
0.076 |
(GRAM) |
ST.DEV |
0.009 |
0.005 |
0.015 |
0.004 |
|
N |
5 |
5 |
5 |
5 |
SPLEEN |
MEAN |
0.518 |
0.527 |
0.521 |
0.570 |
(GRAM) |
ST.DEV |
0.089 |
0.056 |
0.088 |
0.078 |
|
N |
5 |
5 |
5 |
5 |
OVARIES |
MEAN |
0.111 |
0.121 |
0.111 |
0.119 |
(GRAM) |
ST.DEV |
0.010 |
0.024 |
0.012 |
0.010 |
|
N |
5 |
5 |
5 |
5 |
UTERUS |
MEAN |
0.386 |
0.503 |
0.464 |
0.559 |
(GRAM) |
ST.DEV |
0.052 |
0.111 |
0.084 |
0.211 |
|
N |
5 |
5 |
5 |
5 |
ORGAN/BODY WEIGHT RATIOS (%) SUMMARY FEMALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
END OF TREATMENT BODY W. |
MEAN |
266 |
266 |
263 |
267 |
(GRAM) |
ST.DEV |
12 |
17 |
15 |
28 |
|
N |
10 |
9 |
10 |
10 |
BRAIN |
MEAN |
0.72 |
0.72 |
0.76 |
0.69 |
(%) |
ST.DEV |
0.03 |
0.04 |
0.02 |
0.04 |
|
N |
5 |
5 |
5 |
5 |
HEART |
MEAN |
0.305 |
0.317 |
0.310 |
0.308 |
(%) |
ST.DEV |
0.025 |
0.015 |
0.009 |
0.024 |
|
N |
5 |
5 |
5 |
5 |
LIVER |
MEAN |
3.33 |
3.47 |
3.55 |
3.52 |
(%) |
ST.DEV |
0.12 |
0.25 |
0.25 |
0.27 |
|
N |
5 |
5 |
5 |
5 |
THYROIDS |
MEAN |
0.005 |
0.005 |
0.006 |
0.006 |
(%) |
ST.DEV |
0.001 |
0.001 |
0.001 |
0.001 |
|
N |
10 |
9 |
10 |
10 |
THYMUS |
MEAN |
0.080 |
0.068 |
0.077 |
0.083 |
(%) |
ST.DEV |
0.011 |
0.018 |
0.021 |
0.010 |
|
N |
5 |
5 |
5 |
5 |
KIDNEYS |
MEAN |
0.68 |
0.74 |
0.76 |
0.71 |
(%) |
ST.DEV |
0.03 |
0.04 |
0.08 |
0.03 |
|
N |
5 |
5 |
5 |
5 |
ADRENALS |
MEAN |
0.028 |
0.029 |
0.027 |
0.027 |
(%) |
ST.DEV |
0.004 |
0.000 |
0.005 |
0.002 |
|
N |
5 |
5 |
5 |
5 |
SPLEEN |
MEAN |
0.197 |
0.199 |
0.201 |
0.201 |
(%) |
ST.DEV |
0.038 |
0.019 |
0.031 |
0.025 |
|
N |
5 |
5 |
5 |
5 |
OVARIES |
MEAN |
0.042 |
0.045 |
0.043 |
0.042 |
(%) |
ST.DEV |
0.005 |
0.006 |
0.005 |
0.002 |
|
N |
5 |
5 |
5 |
5 |
UTERUS |
MEAN |
0.146 |
0.188 |
0.178 |
0.195 |
(%) |
ST.DEV |
0.016 |
0.031 |
0.030 |
0.066 |
|
N |
5 |
5 |
5 |
5 |
REPRODUCTIONDATASUMMARY
|
GROUP 1CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
Females paired |
10 |
10 |
10 |
10 |
Females mated |
10 |
10 |
9 |
10 |
Pregnant females |
10 |
10 |
9 |
9 |
Females with total litter loss on Day 1 |
0 |
1 |
0 |
0 |
Females with living pups on Day 1 |
10 |
9 |
9 |
9 |
Mating index (%) |
100 |
100 |
90 |
100 |
(Females mated / Females paired) * 100 |
|
|
|
|
Fertility index (%) |
100 |
100 |
90 |
90 |
(Pregnant females / Females paired) * 100 |
|
|
|
|
Conception index (%) |
100 |
100 |
100 |
90 |
(Pregnant females / Females mated) * 100 |
|
|
|
|
Gestation index (%) |
100 |
90 |
100 |
100 |
(Females with living pups on Day 1 / Pregnant females) * 100 |
|
|
|
|
F0-GENERATION - POSTCOITUM
DAY OF THE PAIRING PERIOD |
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
NUMBER OF FEMALES MATED 1 |
2 |
1 |
2 |
4 |
2 |
3 |
1 |
3 |
2 |
3 |
3 |
4 |
3 |
1 |
4 |
2 |
4 |
1 |
3 |
MEDIAN PRECOITAL TIME |
3 |
3 |
2 |
2 |
MEAN PRECOITAL TIME |
2.5 |
3.1 |
2.3 |
2.3 |
N |
10 |
10 |
9 |
10 |
IMPLANTATION SITES FEMALES |
SUMMARY |
|
|||
|
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
NECROPSY Implantations |
MEAN |
12.5 |
12.1 |
13.4 |
10.0 |
|
ST.DEV |
2.4 |
4.4 |
1.6 |
4.2 |
|
N |
10 |
10 |
9 |
9 |
F0-GENERATION - LACTATION |
||||
GROUP 1 CONTROL |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
50 MG/KG |
150 MG/KG |
500 MG/KG |
||
LITTERS TOTAL |
10 |
10 |
9 |
9 |
DURATION OF GESTATION MEAN (+) |
21.2 |
21.6 |
21.1 |
21.7 |
ST.DEV. |
0.4 |
0.5 |
0.3 |
0.7 |
N |
10 |
10 |
9 |
9 |
DEAD PUPS AT FIRST LITTER CHECK |
||||
LITTERS AFFECTED (#) |
3 |
1 |
2 |
1 |
TOTAL |
4 |
1 |
3 |
1 |
MEAN (+) |
0.4 |
0.1 |
0.3 |
0.1 |
ST.DEV. |
0.7 |
0.3 |
0.7 |
0.3 |
N |
10 |
10 |
9 |
9 |
LIVING PUPS AT FIRST LITTER CHECK |
||||
% OF MALES / FEMALES (#) |
51 / 49 |
52 / 48 |
45 / 55 |
53 / 47 |
TOTAL |
113 |
108 |
109 |
85 |
MEAN (+) |
11.3 |
10.8 |
12.1 |
9.4 |
ST.DEV. |
2 |
4.6 |
2.3 |
4.2 |
N |
10 |
10 |
9 |
9 |
POSTNATAL LOSS |
||||
% OF LIVING PUPS |
5.3 |
1.9 |
5.5 |
3.5 |
LITTERS AFFECTED (#) |
4 |
2 |
4 |
2 |
TOTAL (#) |
6 |
2 |
6 |
3 |
MEAN (+) |
0.6 |
0.2 |
0.7 |
0.3 |
ST.DEV. |
1 |
0.4 |
0.9 |
0.7 |
N |
10 |
10 |
9 |
9 |
CULLED PUPS |
||||
TOTAL |
28 |
35 |
32 |
22 |
LIVING PUPS DAY 4 P.P. |
||||
TOTAL |
79 |
71 |
71 |
60 |
MEAN (+) |
7.9 |
7.1 |
7.9 |
6.7 |
ST.DEV. |
0.3 |
2.5 |
0.3 |
2.8 |
N |
10 |
10 |
9 |
9 |
BREEDING LOSS DAYS 5 - 13 P.P. |
||||
% OF LIVING PUPS AT DAY 4 P.P. |
0 |
0 |
1.4 |
0 |
LITTERS AFFECTED (#) |
0 |
0 |
1 |
0 |
TOTAL (#) |
0 |
0 |
1 |
0 |
MEAN (+) |
0 |
0 |
0.1 |
0 |
ST.DEV. |
0 |
0 |
0.3 |
0 |
N |
10 |
10 |
9 |
9 |
LIVING PUPS DAY 13 P.P. |
||||
% OF MALES / FEMALES (#) |
48 / 52 |
51 / 49 |
49 / 51 |
53 / 47 |
TOTAL |
79 |
71 |
70 |
60 |
MEAN (+) |
7.9 |
7.1 |
7.8 |
6.7 |
ST.DEV. |
0.3 |
2.5 |
0.4 |
2.8 |
N |
10 |
10 |
9 |
9 |
Steel-test significant at 5% (+) or 1% (++) level
DEVELOPMENTAL DATA |
|
|||
|
GROUP 1 |
GROUP 2 |
GROUP 3 |
GROUP 4 |
|
CONTROL |
50 MG/KG |
150 MG/KG |
500 MG/KG |
Total number of offspring born |
117 |
109 |
112 |
86 |
Total number of uterine implantation sites |
125 |
121 |
121 |
90 |
Number of live offspring on Day 1 after littering |
113 |
108 |
109 |
85 |
Number of live offspring on Day 4 (before culling) |
107 |
106 |
103 |
82 |
Number of live offspring on Day 4 (after culling) |
79 |
71 |
71 |
60 |
Number of live offspring on Day 13 after littering |
79 |
71 |
70 |
60 |
Post-implantation survival index (%) |
94 |
90 |
93 |
96 |
(Total number of offspring born/Total number of uterine implantation sites) * 100 |
|
|
|
|
Live birth index (%) |
97 |
99 |
97 |
99 |
(Number of live offspring on Day 1 after littering/Total number of offspring born) * 100 |
|
|
|
|
Viability index (%) |
95 |
98 |
94 |
96 |
(Number of live offspring on Day 4 (before culling)/Number of live offspring on Day 1 after littering)*100 |
|
|
|
|
Lactation index (%) |
100 |
100 |
99 |
100 |
(Number of live offspring on Day 13 after littering/Number of live offspring on Day 4 (after culling)) * 100 |
|
|
|
|
BODY WEIGHTS OF PUPS(GRAM)
F0-GENERATION -LACTATION
DAY |
SEX |
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
1 |
M |
MEAN |
6.0 |
6.5 |
6.0 |
7.1 * |
|
|
ST.DEV. |
0.7 |
0.6 |
0.9 |
1.3 |
|
|
N |
10 |
9 |
9 |
9 |
|
F |
MEAN |
5.7 |
6.2 |
5.6 |
6.8 * |
|
|
ST.DEV. |
0.8 |
0.7 |
0.9 |
1.4 |
|
|
N |
10 |
9 |
9 |
9 |
|
M+F |
MEAN |
5.9 |
6.4 |
5.8 |
7.0 * |
|
|
ST.DEV. |
0.7 |
0.6 |
0.9 |
1.4 |
|
|
N |
10 |
9 |
9 |
9 |
4 |
M |
MEAN |
8.7 |
9.4 |
8.7 |
10.5 |
|
|
ST.DEV. |
1.3 |
1.0 |
1.3 |
2.4 |
|
|
N |
10 |
9 |
9 |
8 |
|
F |
MEAN |
8.4 |
8.9 |
8.1 |
10.2 * |
|
|
ST.DEV. |
1.3 |
1.2 |
1.3 |
2.3 |
|
|
N |
10 |
9 |
9 |
8 |
|
M+F |
MEAN |
8.5 |
9.2 |
8.4 |
10.4 * |
|
|
ST.DEV. |
1.2 |
1.0 |
1.3 |
2.4 |
|
|
N |
10 |
9 |
9 |
8 |
7 |
M |
MEAN |
14.4 |
15.1 |
14.3 |
16.6 * |
|
|
ST.DEV. |
1.5 |
1.1 |
1.6 |
3.1 |
|
|
N |
10 |
9 |
9 |
8 |
|
F |
MEAN |
14.0 |
14.5 |
13.3 |
16.2 |
|
|
ST.DEV. |
1.3 |
1.2 |
1.7 |
3.3 |
|
|
N |
10 |
9 |
9 |
8 |
|
M+F |
MEAN |
14.2 |
14.8 |
13.8 |
16.4 |
|
|
ST.DEV. |
1.3 |
1.1 |
1.7 |
3.2 |
|
|
N |
10 |
9 |
9 |
8 |
13 |
M |
MEAN |
28.5 |
28.5 |
27.7 |
30.9 |
|
|
ST.DEV. |
1.6 |
1.2 |
2.1 |
5.1 |
|
|
N |
10 |
9 |
9 |
8 |
|
F |
MEAN |
27.7 |
27.7 |
26.3 |
29.8 |
|
|
ST.DEV. |
1.6 |
1.4 |
2.4 |
5.2 |
|
|
N |
10 |
9 |
9 |
8 |
|
M+F |
MEAN |
28.1 |
28.1 |
26.9 |
30.4 |
|
|
ST.DEV. |
1.5 |
1.3 |
2.2 |
5.1 |
|
|
N |
10 |
9 |
9 |
8 |
*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level
F0-GENERATION -LACTATION
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
|
anogenital dist M mm |
MEAN |
2.48 |
2.59 |
2.60 |
2.70 |
|
ST. DEV. |
0.14 |
0.09 |
0.13 |
0.27 |
|
N |
10 |
9 |
9 |
9 |
anogenital dist F mm |
MEAN |
1.05 |
0.97 |
0.94 |
1.11 |
|
ST.DEV. |
0.17 |
0.02 |
0.18 |
0.21 |
|
N |
10 |
9 |
9 |
9 |
Number of nipples |
MEAN |
0.00 |
0.00 |
0.00 |
0.00 |
|
MEDIAN (+) |
0.00 |
0.00 |
0.00 |
0.00 |
|
N |
10 |
9 |
9 |
8 |
# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level
CORRECTED ANOGENITAL DISTANCE SUMMARY FEMALES
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
|
PND 1 norm anog dist M |
MEAN |
1.37 |
1.39 |
1.43 |
1.41 |
mm |
ST.DEV |
0.07 |
0.03 |
0.10 |
0.06 |
|
N |
10 |
9 |
9 |
9 |
norm anog dist F |
MEAN |
0.59 |
0.53 |
0.53 |
0.58 |
mm |
ST.DEV |
0.10 |
0.02 |
0.10 |
0.09 |
|
N |
10 |
9 |
9 |
9 |
CLINICAL BIOCHEMISTRY SUMMARY MALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
PUPS (PND 13-15) Total T4 |
MEAN |
6.60 |
7.36 |
5.76 |
6.65 |
ug/dL |
ST.DEV |
1.36 |
2.01 |
1.13 |
0.83 |
|
N |
10 |
9 |
9 |
8 |
CLINICAL BIOCHEMISTRY SUMMARY FEMALES
|
|
GROUP 1 CONTROL |
GROUP 2 50 MG/KG |
GROUP 3 150 MG/KG |
GROUP 4 500 MG/KG |
PUPS (PND 13-15) Total T4 |
MEAN |
6.09 |
6.32 |
5.62 |
5.88 |
ug/dL |
ST.DEV |
1.31 |
1.03 |
1.05 |
1.01 |
|
N |
10 |
9 |
9 |
8 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- K1
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of LOWINOX® TBP-6 in rats by oral gavage.
The study was based on the following guidelines:
• OECD 422, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2016.
• OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2000.
• OECD 421, Reproduction/Developmental Toxicity Screening Test, July 2016.
• OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test, July 2000.
• EC No 440/2008 B.7: "Repeated Dose (28 days) Toxicity (oral)", May 2008.
• OECD 407, Repeated Dose 28-day Oral Toxicity Study in Rodents, October 2008.
• OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents, July 2000.
Based on the results of a dose range finding study in which toxicity was noted at 500 mg/kg but not at 250 mg/kg, the dose levels for this combined 28-day oral gavage study with reproduction/developmental toxicity screening test were selected to be 50, 150 and 500 mg/kg.
The test item, LOWINOX® TBP-6, formulated in propylene glycol, was administered daily by oral gavage to SPF-bred Wistar Han rats. One control group and three treated groups were tested, each consisting of 10 males and 10 females. Males were treated for 31 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were treated for 50-56 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during 13-15 days of lactation. Females which failed to deliver healthy offspring were treated for 38-45 days.
The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (end of treatment), body weight and food consumption (at least at weekly intervals), estrous cycle determination (14 days prior to treatment, 14 days of treatment and during mating until evidence of mating, and on the day of necropsy), clinical pathology (end of treatment), measurement of thyroid hormone T4 (F0-males at the end of treatment, PND 13-15 pups), macroscopy at termination, organ weights and histopathology on a selection of tissues. In addition, the following reproduction/developmental parameters were determined: mating, fertility and conception indices, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, anogenital distance, areola/nipple retention and macroscopy). Formulations were analyzed once during the study to assess accuracy and homogeneity.
There were no toxicologically relevant changes in the in-life parameters up to 500 mg/kg. Slight salivation was noted after dosing at all dose levels, most frequently at 150 and 500 mg/kg. This was considered to be a physiological response rather than a sign of systemic toxicity.
Treatment-related microscopic changes were present in the thyroid of male rats, characterized by an increased incidence and severity of follicular cell hypertrophy starting at 150 mg/kg, and alteration of the colloid at 500 mg/kg. These findings were regarded as non-adverse based on their low degree (up to slight) and the absence of other treatment-related findings.
No treatment-related or toxicologically relevant changes were noted in clinical pathology parameters, organ weights or findings at macroscopic examination.
Based on these results, a parental, reproduction and developmental No Observed Adverse Effect Level (NOAEL) of at least 500 mg/kg was derived.
The parental No Observed Effect Level (NOEL) was established at 150 mg/kg based on non-adverse microscopic changes in the thyroids of males at 500 mg/kg.
Justification for classification or non-classification
Under the conditions of the study, no treatment-related or toxicologically relevant changes were noted in clinical pathology parameters, organ weights or findings at macroscopic examination. In accordance with CLP Regulation (EC) 1272/2008, 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol test item is not classified for repeated dose toxicity.
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