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EC number: 233-215-5 | CAS number: 10081-67-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu./o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 12 February 2021 to 15 April 2021
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 021
- Report date:
- 2021
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- OECD guideline no. 414 “Prenatal Developmental Toxicity Study” of 25 June 2018.
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
Test material
- Reference substance name:
- 4-(1-methyl-1-phenylethyl)-N-[4-(1-methyl-1-phenylethyl)phenyl]aniline
- EC Number:
- 233-215-5
- EC Name:
- 4-(1-methyl-1-phenylethyl)-N-[4-(1-methyl-1-phenylethyl)phenyl]aniline
- Cas Number:
- 10081-67-1
- Molecular formula:
- C30H31N
- IUPAC Name:
- 4-(2-phenylpropan-2-yl)-N-[4-(2-phenylpropan-2-yl)phenyl]aniline
- Test material form:
- solid
- Details on test material:
- Test substance name: 4-(1-methyl-1-phenylethyl)-N-[4-(1-methyl-1-phenylethyl)phenyl]aniline
Scymaris reference number: 1108TS001
CAS number: 10081-67-1
Batch/Lot number: EL0D14H276
Purity: 97%
Physical state and appearance: White to off-white powder
Expiry/re-test date: 14 April 2023
Storage conditions: Room Temperature
Constituent 1
- Specific details on test material used for the study:
- No further details specified in the study report.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- Animal supply and acclimatisation
A total of 116 Sprague Dawley SD virgin female rats, 9 weeks old (200-225 g) were ordered from Charles River Italia S.p.A., Calco (Lecco), Italy. The male rats used were from the same supplier, and were at least 11 weeks old (at least 350 g). After arrival the weight range was determined and the females were uniquely identified by tattoo on the hind feet. A health check was then performed by a veterinarian. An acclimatisation period of approximately 2 weeks was allowed before the start of treatment, during which time the health status of the animals was assessed by thorough observations.
Animal husbandry
The rats were housed in a limited access rodent facility. Animal room controls were set to maintain temperature and relative humidity at 22°C ± 2°C and 55% ± 15% respectively; actual conditions were monitored, recorded and the records retained. No relevant deviations from these ranges were recorded during the study. There were approximately 15-20 air changes per hour and the rooms were lit by artificial light for 12 hours each day.
Before mating for all animals and after mating for males, the animals were housed no more than 5 of one sex to a cage in clear polysulfone cages measuring 59.5×38×20 cm (Tecniplast Gazzada S.a.r.l., Buguggiate, Varese). During the mating period, one male rat was housed with one female rat in clear polysulfone cages measuring 42.5×26.6×18 cm (Tecniplast Gazzada S.a.r.l., Buguggiate, Varese) with a stainless steel mesh lid and floor. Each cage tray held absorbent material which was inspected and changed daily. After mating, the mated females were housed in clear polysulfone cages measuring 42.5×26.6×18 cm (Tecniplast Gazzada S.a.r.l., Buguggiate, Varese).
Nesting material was provided inside suitable bedding bags. In addition, suitable nesting material (Scobis 0Mucedola) was provided as necessary. Nesting material was changed at least 2 times a week.
Drinking water was supplied ad libitum to each cage via water bottles.
A commercially available laboratory rodent diet (4 RF 21,Mucedola S.r.l., Via G. Galilei 4, 20019 SettimoMilanese (MI), Italy) was offered ad libitum throughout the study.
There was no information available to indicate that any non-nutrient substance likely to influence the effect of the test item was present in the drinking water or the diet. Records of analyses of water and diet are kept on file at ERBC.
Dated and signed records of activities relating to the day to day running and maintenance of the study in the animal house were recorded.
Allocation to groups
On the day of allocation (Day 0 post coitum) all females were weighed and allocated to the groups by computerised stratified randomisation to give approximately equal initial group mean body weights. Each female was identified within the study by ear notch and housed no more than 5 per cage.
The cages were identified by a label recording the study number, animal numbers and details of treatment. The arrangement of cages in batteries was such that cages from each treatment group were evenly distributed across the battery to minimise possible environmental effects.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5%
- Details on exposure:
- The required amount of the test item was suspended in the vehicle to reach the required concentrations of 5, 25 and 100 mg/mL. The formulation was prepared up to weekly interval based on the stability data measurements. Concentrations were calculated and expressed in terms of test item as supplied.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis was performed in a separate study in order to validate the analytical method and the formulation procedure and to verify the stability of the formulations (ERBC Study no. A4101). A 28 hour stability at room temperature and a 8 day stability at +4°C were verified in the range from 5 to 100 mg/mL.
Samples of the formulations prepared during the current study (the first and the last week of treatment) were analysed to check the homogeneity and concentration. The results were within the acceptability limits stated in ERBC protocols for suspensions. - Details on mating procedure:
- The females were paired with male rats. Females were paired one to one in the home cage of the male and left overnight. Vaginal smears were taken daily in themorning from the day after pairing until a positive identification of mating was made. The day of mating, as judged by the presence of spermin the vaginal smear or by the presence of a copulation plug, was considered as Day 0 of gestation (or Day 0 post coitum). Full mating records were maintained.
On the day of allocation (Day 0 post coitum) all females were weighed and allocated to the groups by computerised stratified randomisation to give approximately equal initial group mean body weights. Each female was identified within the study by ear notch and housed no more than 5 per cage.
The cages were identified by a label recording the study number, animal numbers and details of treatment. The arrangement of cages in batteries was such that cages from each treatment group were evenly distributed across the battery to minimise possible environmental effects. - Duration of treatment / exposure:
- All animals were dosed from Day 3 through Day 19 post coitum.
- Frequency of treatment:
- All animals were dosed once a day.
- Duration of test:
- 20 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control Level
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- Low Level
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- Medium Level
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- High Level
- No. of animals per sex per dose:
- Each group comprised 24 mated female rats.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Choice of the species, administration route and dose levels
The Sprague Dawley SD rat was the species and strain of choice because it is accepted by many regulatory authorities and there are ample experience and background data on this species and strain.
The oral route was selected as it is a possible route of exposure of the test item in man.
Dose levels were selected by the Sponsor.
Administration of test item
The test item was administered orally by gavage at a dose volume of 10 mL/kg body weight.
Control animals received the vehicle alone at the same dose volume. The dose was administered to each animal on the basis of the most recently recorded body weight and the volume administered was recorded for each animal.
Examinations
- Maternal examinations:
- Mortality
Throughout the study, all animals were checked early in each working day and again in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.
Clinical signs
All clinical signs were recorded for individual animals. Each animal was observed daily and any clinical signs recorded starting from allocation until sacrifice.
Body weight
All animals were weighed on Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum.
Food consumption
Food consumption was measured on Days 3, 6, 9, 12, 15, 18 and 20 post coitum starting from Day 0 post coitum.
Terminal studies
Euthanasia
All animals at termination were killed by carbon dioxide inhalation on Day 20 post coitum and necropsied as detailed below. All foetuses were sacrificed by intraperitoneal injection of Sodium Thiopental followed by hypothermia.
Necropsy
The clinical history of the animal was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices). Changes were noted and the abnormalities preserved in 10% neutral buffered formalin.
Organ weight, fixation and preservation
From all females completing the scheduled test period, the thyroid and the brain were weighed, fixed and preserved in 10% neutral buffered formalin. The thyroid weight was determined after fixation. The ratio of thyroid weight to brain weight was calculated for each animal.
Thyroid histopathological examination
After dehydration and embedding in paraffin wax, sections of the tissue were cut at 5 micrometre thickness and stained with haematoxylin and eosin. Sections were examined for evaluation of pathological changes. - Ovaries and uterine content:
- The ovaries and uteri were examined to determine:
– Gravid uterine weight (not obtained from animals found dead or killed during the study);
– number of corpora lutea;
– number of implantation sites;
– number, sex and weight of all live foetuses;
– number and sex of dead foetuses (foetuses at termwithout spontaneous movements and breathing);
– number of intra-uterine deaths;
– gross evaluation of placentae.
Intra-uterine deaths were classified as:
– early resorptions: only placental remnants visible.
– late resorptions: placental and foetal remnants visible.
Uteri or individual uterine horns without visible implantations were immersed in a 20% solution of ammonium sulphide to reveal evidence of embryonic death at very early stages of implantation. - Blood sampling:
- On Day 20 post coitum, blood samples for thyroid hormones determination (approximately 1 mL), were collected, randomizing (equalised) between treatment groups, from the sublingual vein of all females, under slight isoflurane anaesthesia. This procedure was performed within a short time frame (e.g. two hours, if possible) on the morning of the day of necropsy.
Samples were transferred into tubes containing no anticoagulant and centrifuged at room temperature. The serum obtained was divided in two aliquots (300 µL in the aliquot A, the remaining in the aliquot B, if possible) and stored at -20°C, pending analysis.
Immunoanalysis was carried out by the Test Site, BioVetim (Study Phase number: BIOVX1610),
according to immunoanalytical methods validated at the Test Site:
– RV-T3/R/S-BKM/RIA-002 for T3
– RV-T4/R/S-BKM/RIA-002 for T4
– RV-TSH/R/S-IZO/RIA-002 for TSH
Samples were assayed to determine the serum levels of Total triiodothyronine (total T3), Total thyroxine (total T4) and Thyroid stimulating hormone (TSH) by RadioImmunoAssay (RIA).
Total number of samples: 96 × 2 aliquots
The aliquots were maintained at -20°C until transfer to the Test Site indicated below, where the immunoanalysis was carried out:
BIOVETIM
VetAgro Sup, aile 1 niveau 3
1 avenue Bourgelat
69280Marcy l’Etoile
France
Prior to shipment, the Principal Investigator was notified by e-mail.
Samples were labelled as follows: study number, animal number, group and sex, sampling date. Samples were transported in dry ice, by a dedicated courier and were subject to the latter’s standard insurance policy. In the first instance, only the aliquots A were despatched to the Test Site. The backup samples (aliquots B) will disposed of after Study Director’s authorisation and following Sponsor’s approval.
A Final Delegated Phase Report with the results of these analyses was sent to ERBC for inclusion in the Final Study Report. The results were presented as individual data (mean of duplicates, where applicable), group mean and group standard deviation. Evaluation of the data and the statistical analysis was performed in ERBC. - Fetal examinations:
- Examination of foetuses
All live foetuses were examined externally. Approximately one-half of the foetuses (i.e., routinely, every second live foetus) in each litter was preserved in Bouin’s solution for subsequent fixed-visceral examination. The remaining foetuses were eviscerated after which the carcasses were fixed in 95% (v/v) ethanol for subsequent skeletal examination.
Skeletal and fixed-visceral examinationswere performed in all groups. Structural deviations were classified as follows:
Malformations
Major abnormalities that are rare and/or affect the survival or health of the species under investigation.
Anomalies
Minor abnormalities that are detected relatively frequently.
Variants
A change that occurs within the normal population under investigation and is unlikely to adversely affect survival or health. This might include a delay in growth or morphogenesis that would have otherwise followed a normal pattern of development.
Anogenital distance (AGD):
The AGD of each live foetuses was measured on Day 20 post coitum. The AGD was normalized to the cube root of foetal body weight collected on Day 20 post coitum. Individual and mean data was reported. - Statistics:
- For continuous variables the significance of the differences amongst group means was
assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data.
Statistical analysis of non-continuous variables was carried out by means of the Kruskal-
Wallis test and intergroup differences between the control and treated groups assessed by a
non-parametric version of theWilliams test. The criterion for statistical significance was
p<0.05. The mean values, standard deviations and statistical analysis were calculated from
the actual values in the computer without rounding off. - Indices:
- Pre-implantation loss was calculated as a percentage from the formula:
Pre impl. Loss % = [(no. of corpora lutea – no. of implantations) / no. of corpora lutea] x 100
Post-implantation loss was calculated as a percentage from the formula:
Post impl. Loss% = [(no. of implantations – no. of foetuses) / no. of implantations] x 100
Total implantation loss was calculated as a percentage from the formula:
Total impl. Loss % = [(no. of corpora lutea – no. of live foetuses) / no. of corpora lutea] x 100
Sex ratios of the foetuses were calculated as the percentage of males.
All derived values (e.g., means, percentages, ratios) first were calculated within the litter and the group values derived as a mean of individual litter values. Foetal structural deviations were expressed as the percentage of affected foetuses relative to all foetuses examined per group, as well as in terms of the mean litter percentage of affected litters. - Historical control data:
- No specified in the study report
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related clinical signs were detected throughout the study. A palpable subcutaneous mass was recorded in one lowdose female (no. 73) during the last day of study. This formation did not show microscopically changes. Other signs like hairloss or scabs were occasionally recorded during the study in single animals, with no correlation with the dose.
Thus they were considered as minor clinical signs and not related to the administration with the test item. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All females survived to the final sacrifice on gestation Day 20 and were found pregnant with the exception of two controls (no. 31, 33) and one low dose female (no. 81).
The final number of females with live foetuses on gestation day 20 was of:
– 22 in the control group (0 mg/kg/day)
– 23 in the low dose group (50 mg/kg/day)
– 24 in the mid-dose group (250 mg/kg/day)
– 24 in the high dose group (1000 mg/kg/day) - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects were seen in maternal body weight/body weight gain throughout the study.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No treatment-related effects were seen in food consumption throughout the study.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- no effects observed
- Description (incidence and severity):
- Serum levels of T3, T4 and TSH did not differ between treated and control groups.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Body weight at termination, uterus weight and the absolute weight gain of females were unaffected by treatment.
No effects were seen in thyroid weight between treated and control groups. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- At post mortem examination, no treatment-related macroscopic observations were noted in treated females receiving test item at ≥ 50 mg/kg/day, when compared to controls. Any macroscopic observations were within the range of expected spontaneous findings in SD rats of the same age considered incidental and unrelated to the test item.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were noted in thyroid gland of females receiving 4-(1-methyl-1-phenylethyl)-N-[4-(1-methyl-1-phenylethyl)phenyl]aniline at ≥ 50 mg/kg/day, when compared to controls. The microscopic observations in control and treated females were consistent with those known to occur spontaneously in untreated SD rats of the same age and were considered incidental and unrelated to treatment.
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no differences in the number of implantations, corpora lutea and the intrauterine
deaths between control and treated groups. - Total litter losses by resorption:
- not examined
- Early or late resorptions:
- not examined
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- The number of live foetuses, the mean litter and body weights and the percentage of males respect to females did not differ between control and treated groups.
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The number of live foetuses, the mean litter and body weights and the percentage of males respect to females did not differ between control and treated groups.
- Details on maternal toxic effects:
- Treatment with the test item did not cause changes in body weight or food consumption at all dose levels when compared to controls throughout the study. In addition, the animals did not showtreatment-related clinical signs. The serumlevels of TSH, T3 and T4 hormones were comparable between control and treated groups. No treatment-related changes were noted at necropsy of females or at thyroid weight. The microscopic analysis of thyroid did not reveal findings at any dose level.
Effect levels (maternal animals)
- 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
- food consumption and compound intake
- gross pathology
- histopathology: neoplastic
- maternal abnormalities
- mortality
- necropsy findings
- organ weights and organ / body weight ratios
- pre and post implantation loss
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The body weights did not differ between control and treated groups.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The number of live foetuses did not differ between control and treated groups.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The the percentage of males respect to females did not differ between control and treated groups.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- The mean litter and body weights did not differ between control and treated groups.
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Description (incidence and severity):
- No treatment-related findings were recorded at external examination of foetuses. One single small foetus (body weight below 2.7g) was found in Group 3 as abnormality.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Minor abnormalities or variations occurred in all groups and included for example altered ossification (asymmetrical, incomplete or no ossification) of several bones of the skull, sternebrae, thoracic/sacral vertebrae and the presence supernumerary ribs (14th). The incidence of the affected litters in treated groups was similar or even lower than observed in the control group or without dose relation. Therefore, the findings were considered unrelated to treatment.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A total of three major abnormalities were found in the study. Two were related to the heart (incomplete septum and/or persistent truncus arteriosus) and observed in one control foetus (foetus no. 10; Dam no. 9) and in one foetus of group 3 (foetus 10; Dam no. 125).
The other major abnormality was related to brain (extreme enlarged lateral ventricles) and it was found in one foetus of group 3 (Dam no. 139). These malformations occurred in single instances and in the absence of a dose dependency. Therefore, they were considered incidental and unrelated to treatment.
The incidences of foetuses or litters with minor abnormalities or variations did not suggest any test item effect.
The overall data confirm that there were no treatment-related findings at fixed visceral examination of foetuses. - Details on embryotoxic / teratogenic effects:
- The number of corpora lutea, implantations, viable foetuses, intrauterine deaths and sex ratios were comparable between control and treated groups. No treatment-related effects were seen in the mean foetal weight. The external examination of foetuses including the measurement of the anogenital distance did not show differences in treated animals at all dose levels when compared to the control group.
No treatment-related findings were noted at skeletal and visceral examinations. Indeed, no evidence of teratogenicity was noted up to and including the dose level of 1000 mg/kg/day.
Effect levels (fetuses)
- 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:
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- external malformations
- skeletal malformations
- visceral malformations
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Treatment related:
- no
Any other information on results incl. tables
SUMMARY OF REPRODUCTION DATA – GROUP DATA
| Dosage Levels mg/kg/day | |||
Observations | 0 | 50 | 250 | 1000 |
No. Dams Inseminated No. Dams That Conceived Percent Dams Conceived No. Dams Died During Study No. Dams with Resorptions only No. of Litters Mean Absolute Weight Gain Total No. Corpora Lutea Mean No. Corpora Lutea/Pregnancy Total No. Implantation Mean No. Implants/Pregnancy Total No. Live Fetuses Mean No. Live Fetuses/Pregnancy Total No. Dead Fetuses Mean No. Dead Fetuses/Pregnancy No. Dams with Resorptions Total No. Resorptions Mean No. Resorptions/Pregnancy Preimplantation Loss (%) Post Implantation Loss (%) Mean Live Foetal Weight (g) | 24 22 91.7 0 0 22 66.9 326 14.8 320 14.5 317 14.4 0 0.0 3 3 0.1 2.1 1.0 3.97 | 24 23 95.8 0 0 23 63.6 345 15.0 339 14.7 333 14.5 0 0.0 5 6 0.3 1.7 1.8 3.96 | 24 24 100.0 0 0 24 80.5 349 14.5 347 14.5 336 14.0 0 0.0 4 11 0.5 0.8 3.2 4.03 | 24 24 100.0 0 0 24 63.2 368 15.3 362 15.1 357 14.9 0 0.0 4 5 0.2 1.4 1.3 3.98 |
CLINICAL SIGNS OF FEMALES – GROUP INCIDENCE
Interval: 0 – 20 Days Group Observation | 1 (24) | 2 (24) | 3 (24) | 4 (24) | ||||
| A | B | A | B | A | B | A | B |
APPERANCE Scab(s) Presence if palpable mass |
2 0 |
8.3 0.0 |
1 1 |
4.2 4.2 |
0 0 |
0.0 0.0 |
0 0 |
0.0 0.0 |
Key:
() = Number of animals alive at start of interval
A = Number of animals affected
B = Percent of animals with observations during interval
BODY WEIGHT (g) OF PREGNANT FEMALES – GROUP DATA
Group(s) |
| Day of Phase | |||||||
0! | 3” | 6 | 9 | 12 | 15 | 18 | 20 | ||
1 | (n) Mean SD | 22 274.20 19.12 | 22 291.48 19.07 | 22 301.78 20.33 | 22 317.60 21.07 | 22 336.15 22.98 | 22 355.70 23.20 | 22 399.69 28.91 | 22 436.66 31.84 |
2 | (n) Mean SD | 23 272.39 12.58 | 23 285.38 12.44 | 23 300.41 13.42 | 23 312.48 13.97 | 23 331.93 14.84 | 23 351.01 17.37 | 23 392.40 20.65 | 23 430.58 24.53 |
3 | (n) Mean SD | 24 272.90 16.51 | 24. 294.75 18.34 | 24 308.83 17.96 | 24 323.23 18.55 | 24 342.84 19.29 | 24 363.27 22.68 | 24 409.54 26.36 | 24 448.51 30.88 |
4 | (n) Mean SD | 24 273.76 12.25 | 24 292.71 15.88 | 24 303.76 14.66 | 24 316.81 14.18 | 24 334.43 17.86 | 24 355.05 18.86 | 24 397.54 24.80 | 24 434.91 30.01 |
Note: ! = Gestation phase; “ = Dosing/Gestation phase
* = mean value of group is significantly different from control at p < 0.05
** = mean value of group is statistically different from control at p < 0.01
Statistical analysis: Dunnett’s test if group variances are homogenous; Modified t test if group variances are inhomogenous ($)
BODY WEIGHT GAIN PER DAY° (g) OF PREGNANT FEMALES – GROUP MEAN DATA
Group(s) |
| Day of Phase | ||||||
3 | 6 | 9 | 12 | 15 | 18 | 20 | ||
1 | (n) Mean SD | 22 5.762 2.126 | 22 3.431 2.144 | 22 5.274 2.985 | 22 6.184 1.561 | 22 6.518 1.651 | 22 14.662 2.579 | 22 18.485 2.957 |
2 | (n) Mean SD | 23 4.333 2.875 | 23 5.008 2.997 | 23 4.024 1.611 | 23 6.484 1.554 | 23 6.359 1.548 | 23 13.798 2.233 | 23 19.091 3.190 |
3 | (n) Mean SD | 24 7.284 1.749 | 24 4.6914 2.049 | 24 4.801 1.795 | 24 6.539 1.735 | 24 6.810 2.109 | 24 15.422 2.629 | 24 19.485 3.184 |
4 | (n) Mean SD | 24 6.319 2.705 | 24 3.683 1.848 | 24 4.350 1.814 | 24 5.871 2.015 | 24 6.875 1.897 | 24 14.162 2.729 | 24 18.685 3.493 |
Note: Data for Dosing/Gestation phase
* = mean value of group is significantly different from control at p < 0.05
** = mean value of group is statistically different from control at p < 0.01
Statistical analysis: Dunnett’s test if group variances are homogenous; Modified t test if group variances are inhomogenous ($)
°= mean daily body weight gain over the previous period starting from gestation day 0
FOOD CONSUMPTION° (g/animal/day) OF FEMALES – GROUP MEAN CAGE DATA
Group(s) |
| Day of Phase | ||||||
3 | 6 | 9 | 12 | 15 | 18 | 20 | ||
1 | (n) Mean SD | 9 22.47 2.50 | 9 25.08 1.70 | 9 26.59 1.99 | 9 26.85 1.89 | 9 27.61 2.53 | 9 29.97 3.20 | 9 30.58 2.99 |
2 | (n) Mean SD | 9 20.57 4.56 | 9 25.43 1.92 | 9 26.39 1.64 | 9 28.04 2.14 | 9 27.84 3.29 | 9 30.09 2.49 | 9 30.54 3.98 |
3 | (n) Mean SD | 9 23.96 1.37 | 9 25.99 1.70 | 9 27.30 1.28 | 9 27.94 1.38 | 9 29.05 1.79 | 9 31.70 2.06 | 9 32.29 2.58 |
4 | (n) Mean SD | 9 23.66 1.19 | 9 25.28 1.33 | 9 26.54 1.65 | 9 27.28 2.56 | 9 28.30 1.89 | 9 30.65 2.80 | 9 31.29 2.03 |
Note: Data for Dosing/Gestation phase
* = mean value of group is significantly different from control at p < 0.05
** = mean value of group is statistically different from control at p < 0.01
Statistical analysis: Dunnett’s test if group variances are homogenous; Modified t test if group variances are inhomogenous ($)
°= food consumed over the previous period starting from Day 0 post coitum
TERMINAL BODY WEIGHT, GRAVID UTERUS WEIGHT AND ABSOLUTE WEIGHT GAIN (g) OF PREGNANT FEMALES – GROUP MEAN DATA
Group |
| Terminal body weight (g) | Gravid uterus weight (g) | Absolute weight gain# (g) |
1 | Mean SD N | 427.77 32.18 22 | 86.72 15.79 22 | 66.85 18.32 22 |
2 | Mean SD N | 423.44 25.60 23 | 87.50 13.16 23 | 63.56 24.12 23 |
3 | Mean SD N | 439.63 30.86 24 | 86.28 20.79 24 | 80.45* 16.53 24 |
4 | Mean SD N | 426.77 30.71 24 | 89.84 17.13 24 | 63.18 19.95 24 |
# = Body weight at necropsy minus gravid uterus weight, minus body weight at Day 0 of pregnancy
* = mean value of group is significantly different from control
Statistical analysis: Kruskall Wallis test; Williams test if group means are different from control at p < 0.05
THYROID HORMONE DETERMINATION ON DAY 20 POST COITUM – GROUP MEAN DATA
Parameter/units | Group | 1 | 2 | 3 | 4 |
Triiodothyronine nmol/L | Mean SD n | 1.310 0.185 24 | 1.298 0.190 24 | 1.276 0.174 24 | 1.287 0.205 24 |
Thyroxine nmol/L | Mean SD | 20.4 4.2 24 | 19.8 4.1 24 | 19.0 1.9 24 | 18.5 1.9 24 |
THYROID STIMULATING HORMONE ng/ml | Mean SD n | 7.93 1.79 24 | 7.49 1.31 24 | 7.58 1.81 24 | 7.12 1.25 24 |
Controls from group(s): 1 Subgroup(s): 1
* = mean value of group is significantly different from control at p < 0.05
+ = mean value of group is significantly different from control at p < 0.01
LITTER DATA AND SEX RATIO OF FEMALES – GROUP MEAN DATA
Group |
| Corpora Lutea | Implan-tations | Uterine Deaths | Viable Young | % males | Implantation loss (%) | Litter Weight (g) | Mean Foetal Weight (g) | ||||||||
By sex | Combined | ||||||||||||||||
Early | Late | Total | Total | M | F | Pre | Post | Total | M | F | |||||||
1 | Mean SD (n) | 14.82 2.40 22 | 14.55 2.67 22 | 0.14 0.35 22 | 0.00 0.00 22 | 0.14 0.35 22 | 14.41 2.70 22 | 7.18 2.28 22 | 7.23 1.93 22 | 49.43 12.29 22 | 2.06 5.38 22 | 0.99 2.59 22 | 3.04 5.60 22 | 57.27 11.74 22 | 4.09 0.21 22 | 3.85 0.23 22 | 3.97 0.21 22 |
2 | Mean SD (n) | 15.00 2.30 23 | 14.74 2.30 23 | 0.22 0.52 23 | 0.04 0.21 23 | 0.26 0.54 23 | 14.48 2.33 23 | 6.87 2.01 23 | 7.61 1.90 23 | 47.26 11.23 23 | 1.67 3.92 23 | 1.76 3.59 23 | 3.41 5.10 23 | 57.30 9.46 23 | 4.05 0.29 23 | 3.89 0.22 23 | 3.96 0.24 23 |
3 | Mean SD (n) | 14.54 2.92 24 | 14.46 3.05 24 | 0.46 1.64 24 | 0.00 0.00 24 | 0.46 1.64 24 | 14.00 3.44 24 | 7.67 2.87 24 | 6.33 2.41 24 | 54.50 13.51 24 | 0.81 2.77 24 | 3.16 10.98 24 | 3.97 11.10 24 | 56.25 14.09 24 | 4.11 0.23 24 | 3.93 0.26 24 | 4.03 0.24 24 |
4 | Mean SD (n) | 15.33 3.13 24 | 15.08 2.95 24 | 0.21 0.51 24 | 0.00 0.00 24 | 0.21 0.51 24 | 14.88 2.91 24 | 7.71 2.61 24 | 7.17 2.51 24 | 51.94 13.65 24 | 1.41 3.32 24 | 1.31 3.21 24 | 2.70 4.48 24 | 58.96 10.91 24 | 4.07 0.21 24 | 3.90 0.20 24 | 3.98 0.19 24 |
* = mean value of group is significantly different from control
Statistical analysis: Kruskall Wallis test; William’s test of group means are different from control at p < 0.05
ANOGENITAL DISTANCE ON DAY 20 POST COITUM – GROUP MEAN DATA
MALES
Parameter/units | Group | 1 | 2 | 3 | 4 |
ANOGENITAL DISTANCE (mm) | Mean SD n | 4.30 0.26 22 | 4.24 0.30 23 | 4.36 0.28 24 | 4.37 0.25 24 |
Foetus weight (g) | Mean SD n | 4.10 0.21 22 | 4.05 0.29 23 | 4.11 0.23 24 | 4.07 0.21 24 |
ANOGENITAL DISTANCE ^ (NORMALISED) mm/g1/3 | Mean SD n | 2.69 0.16 22 | 2.66 0.18 23 | 2.72 0.16 24 | 2.74 0.16 24 |
^ = normalised for the cube root of the body weight collected on Day 20 post coitum (mm/g)
Statistical analysis: Kruskall Wallis test; T test if group mean differences are different from control at p < 0.05
* = mean value of group is significantly different from control
ANOGENITAL DISTANCE ON DAY 20 POST COITUM – GROUP MEAN DATA
FEMALES
Parameter/units | Group | 1 | 2 | 3 | 4 |
ANOGENITAL DISTANCE (mm) | Mean SD n | 2.54 0.53 22 | 2.48 0.60 23 | 2.53 0.55 24 | 2.69 0.50 24 |
Foetus weight (g) | Mean SD n | 3.85 0.23 22 | 3.89 0.22 23 | 3.93 0.26 24 | 3.90 0.20 24 |
ANOGENITAL DISTANCE ^ (NORMALISED) mm/g1/3 | Mean SD n | 1.62 0.35 22 | 1.58 0.38 23 | 1.60 0.34 24 | 1.71 0.32 24 |
^ = normalised for the cube root of the body weight collected on Day 20 post coitum (mm/g)
Statistical analysis: Kruskall Wallis test; T test if group mean differences are different from control at p < 0.05
* = mean value of group is significantly different from control
ABSOLUTE ORGAN WEIGHTS (g) – GROUP MEAN DATA
FEMALES
Organ: Brain | Controls from group: 1 | Data homogenous by Bartlett’s test (Dunnett’s test) | ||
Group Number/group Mean Standard deviation Group diff. at p > 0.05 Group diff. at p < 0.01 | Control 24 1.969 0.105 | 2 24 1.944 0.083 0.065 0.081 | 3 24 1.976 0.104 0.065 0.081 | 4 24 1.967 0.078 0.065 0.081 |
Analysis of variance: F ratio = 0.52 Df = 3/92 F probability = 0.677
Note: a * indicates group mean is significantly different from control at level of significance shown.
Organ: Thyroid | Controls from group: 1 | Data homogenous by Bartlett’s test (Dunnett’s test) | ||
Group Number/group Mean Standard deviation Group diff. at p > 0.05 Group diff. at p < 0.01 | Control 24 0.0241 0.0048 | 2 24 0.0241 0.0056 0.0031 0.0039 | 3 24 0.0222 0.0042 0.0031 0.0039 | 4 24 0.0215 0.0032 0.0031 0.0039 |
Analysis of variance: F ratio = 2.13 Df = 3/92 F probability = 0.100
Note: a * indicates group mean is significantly different from control at level of significance shown.
ORGAN WEIGHTS° TO BRAIN WEIGHT – GROUP MEAN DATA
FEMALES
Organ: Thyroid | Controls from group: 1 | Data homogenous by Bartlett’s test (Modified t test) | ||
Group Number/group Mean Standard deviation Group diff. at p > 0.05 Group diff. at p < 0.01 | Control 24 1.228 0.248 | 2 24 1.241 0.299 0.164 0.223 | 3 24 1.122 0.193 0.133 0.180 | 4 24 1.092 0.165 0.126* 0.171 |
Analysis of variance: F ratio = 2.49 Df = 3/92 F probability = 0.064
Note: a * indicates group mean is significantly different from control at level of significance shown.
° = expressed as % organ to brain weight ratio
MACROSCOPIC OBSERVATIONS OF FEMALES – FINAL SACRIFICE – GROUP INCIDENCE
| -- Females -- | |||
Group: Number in group: | 1 24 | 2 24 | 3 24 | 4 24 |
Skin Subcutaneous mass(es) |
0 |
1 |
0 |
0 |
Uterus Not pregnant |
2 |
1 |
0 |
0 |
Whole animal No abnormalities detected |
22 |
22 |
24 |
24 |
EXTERNAL EXAMINATION OF FOETUSES – GROUP INCIDENCE
Group | Organ | Cat | Observation(s) | No. Foetuses | No. Litters | ||||
Observed | Affected | % | Observed | Affected | % | ||||
1 | Whole foetus |
| No abnormalities detected | 317 | 317 | 100.00 | 22 | 22 | 100.00 |
2 | Whole foetus |
| No abnormalities detected | 333 | 333 | 100.00 | 23 | 23 | 100.00 |
3 | Whole foetus Whole foetus |
AN | No abnormalities detected Small | 336 336 | 335 1 | 99.70 0.30 | 24 24 | 23 1 | 95.83 4.17 |
4 | Whole foetus |
| No abnormalities detected | 357 | 357 | 100.00 | 24 | 24 | 100.00 |
SKELETAL EXAMINATION OF FOETUSES – GROUP INCIDENCE
Group | Organ | Cat | Observation(s) | No. Foetuses | No. Litters | ||||
Obs | Aff | % | Obs | Aff | % | ||||
1 | Forepaw(s) Forepaw(s) Pelvic girdle Ribs Ribs Ribs Sacral vertebrae Skull Skull Skull Skull Skull Skull Skull Skull Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Thoracic vertebrae Thoracic vertebrae Thoracic vertebrae | AN AN AN AN AN VA AN AN AN AN VA VA VA VA VA AN AN AN VA VA VA VA AN VA VA | Metacarpal(s) no ossification 4th Metacarpal(s) incomplete ossification Pubis incomplete ossification Short Rudimentary Short 14th Arch(es) incomplete ossification General incomplete ossification Hyoid no ossification Temporal incomplete ossification Nasal incomplete ossification Parietal incomplete ossification Supraoccipital incomplete ossification Hyoid incomplete ossification Interparietal incomplete ossification Asymmetrical ossification Fused No ossification 6th Incomplete ossification 6th Incomplete ossification No ossification 5th Incomplete ossification 5th Centrum asymmetrical ossification Centrum incomplete ossification Centrum dumb-bell shaped | 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 165 | 68 1 1 4 1 6 8 2 17 6 1 2 18 16 49 6 1 28 51 1 38 32 1 19 1 | 41.21 0.61 0.61 2.42 0.61 3.64 4.85 1.21 1.30 3.64 0.61 1.21 10.91 9.70 29.70 3.64 0.61 16.97 30.91 0.61 23.03 19.39 0.61 11.52 0.61 | 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 | 19 1 1 3 1 4 4 1 8 4 1 2 10 11 16 5 1 13 19 1 16 14 1 10 1 | 86.36 4.55 4.55 13.64 4.55 18.18 18.18 4.55 36.36 18.18 4.55 9.09 45.45 50.00 72.73 22.73 4.55 59.09 86.36 4.55 72.73 63.64 4.55 45.45 4.55 |
2 | Forepaw(s) Ribs Ribs Sacral vertebrae Skull Skull Skull Skull Skull Skull Skull Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Thoracic vertebrae Thoracic vertebrae Thoracic vertebrae Thoracic vertebrae | AN AN VA AN AN AN AN VA VA VA VA AN AN AN VA VA VA VA AN AN VA VA | Metacarpal(s) no ossification 4th Rudimentary Short 14th Arch(es) incomplete ossification Frontal incomplete ossification Hyoid no ossification Temporal incomplete ossification Interparietal incomplete ossification Parietal incomplete ossification Supraoccipital incomplete ossification Hyoid incomplete ossification Asymmetrical ossification No ossification 6th Bipartite 5th No ossification 5th Incomplete ossification 6th Incomplete ossification Incomplete ossification 5th Centrum no ossification Centrum bipartite Centrum incomplete ossification Centrum dumb-bell shaped | 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 171 | 58 3 3 5 1 15 1 33 1 13 9 11 17 2 43 41 3 53 1 2 15 1 | 33.92 1.75 1.75 2.92 0.58 8.77 0.58 19.30 0.58 7.60 5.26 6.43 9.94 1.17 25.15 23.98 1.75 30.99 0.58 1.17 8.77 0.58 | 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 | 20 3 3 5 1 9 1 16 1 6 6 10 8 1 16 18 2 19 1 2 9 1 | 86.96 13.04 13.04 21.74 4.35 39.13 4.35 69.57 4.35 26.09 26.09 43.48 34.78 4.35 69.57 78.26 8.70 82.61 4.35 8.70 39.13 4.35 |
3 | Forepaw(s) Ribs Ribs Ribs Sacral vertebrae Skull Skull Skull Skull Skull Skull Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Thoracic vertebrae Thoracic vertebrae | AN AN AN VA AN AN AN VA VA VA VA AN AN AN VA VA VA VA AN VA | Metacarpal(s) no ossification 4th Short Rudimentary Short 14th Arch(es) incomplete ossification Temporal incomplete ossification Hyoid no ossification Hyoid incomplete ossification Interparietal incomplete ossification Parietal incomplete ossification Supraoccipital incomplete ossification No ossification 6th No ossification Asymmetrical ossification No ossification 6th Incomplete ossification 6th Incomplete ossification 5th Incomplete ossification Centrum bipartite Centrum incomplete ossification | 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 | 60 1 1 1 6 1 7 7 38 2 9 13 1 9 32 49 46 1 3 21 | 34.48 0.57 0.57 0.57 3.45 0.57 4.02 4.02 21.84 1.15 5.17 7.47 0.57 4.02 18.39 28.16 26.44 0.57 1.72 12.07 | 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 | 20 1 1 1 5 1 4 6 15 2 9 8 1 4 13 16 16 1 3 11 | 83.33 4.17 4.17 4.17 20.83 4.17 16.67 25.00 62.50 8.33 37.50 33.33 4.17 16.67 56.17 66.67 66.67 4.17 12.50 45.83 |
4 | Forepaw(s) Ribs Ribs Sacral vertebrae Skull Skull Skull Skull Skull Skull Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Sternebrae Thoracic vertebrae Thoracic vertebrae Thoracic vertebrae | AN AN VA AN AN AN VA VA VA VA AN AN AN VA VA VA VA AN VA VA | Metacarpal(s) no ossification 4th Rudimentary Short 14th Arch(es) incomplete ossification Temporal incomplete ossification Hyoid no ossification Interparietal incomplete ossification Hyoid incomplete ossification Supraoccipital incomplete ossification Parietal incomplete ossification Asymmetrical ossification Bipartite 5th No ossification 6th Incomplete ossification Incomplete ossification 5th No ossification 5th Incomplete ossification 6th Centrum bipartite Centrum incomplete ossification Centrum dumb-bell shaped | 183 183 183 183 183 183 183 183 183 183 183 183 183 183 183 183 183 183 183 183 | 43 6 2 3 1 9 43 12 16 3 3 3 23 1 45 31 53 2 19 2 | 23.50 3.28 1.09 1.64 0.55 4.92 23.50 6.56 8.74 1.64 1.64 1.64 12.57 0.55 24.59 16.94 28.96 1.09 10.38 1.09 | 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 | 16 5 2 2 1 7 17 9 11 3 2 3 9 1 18 17 17 2 11 2 | 66.67 20.83 8.33 8.33 4.17 29.17 70.83 37.50 45.83 12.50 8.33 12.50 37.50 4.17 75.00 70.83 70.83 8.33 45.83 8.33 |
FIXED VISCERAL EXAMINATION OF FOETUSES – GROUP INCIDENCE
Group | Organ | Cat | Observation(s) | No. Foetuses | No. Litters | ||||
Obs | Aff | % | Obs | Aff | % | ||||
1 | Abdomen Brain Heart Heart Heart Heart Kidneys Kidneys Testis Ureter | VA AN AN AN MA VA AN VA AN VA | Umbelical vein left Ventricle enlarged moderate Ventricle enlarged Atrium enlarged Septum incomplete Ventricle enlarged Ectopic Pelvic dilation slight Displaced Enlarged slight | 152 152 152 152 152 152 152 152 152 152 | 1 1 1 1 1 2 2 1 10 7 | 0.66 0.66 0.66 0.66 0.66 1.32 1.32 0.66 6.58 4.64 | 22 22 22 22 22 22 22 22 22 22 | 1 1 3 1 1 3 2 1 9 4 | 4.55 4.55 13.64 4.55 4.55 13.64 9.09 4.55 40.91 18.18 |
2 | Abdomen Abdomen Great vessels Heart Kidneys Kidneys Testis Thoracic cavity Ureter | VA VA VA AN AN VA AN VA VA | Umbelical vein left Haemorrhagic Long innominate artery Atrium enlarged Ectopic Pelvic dilation slight Displaced Haemorrhage Enlarged slight | 162 162 162 162 162 162 162 162 162 | 2 2 1 4 4 1 5 2 5 | 1.23 1.23 0.62 2.47 2.47 0.62 3.09 1.23 3.09 | 23 23 23 23 23 23 23 23 23 | 2 2 1 2 3 1 2 2 5 | 8.70 8.70 4.35 8.70 13.04 4.35 8.70 8.70 21.74 |
3 | Abdomen Abdomen Brain Great vessels Heart Heart Heart Heart Kidneys Kidneys Testis Testis Thoracic cavity Ureter Ureter | VA VA MA VA AN MA MA VA AN VA AN AN VA AN VA | Haemorrhagic Umbelical vein left Ventricles enlarged extreme Long innominate artery Atrium enlarged Septum incomplete Persistant truncus areriosus Pericardium Haemorragic Ectopic Pelvic dilation slight Malpositioned Displaced Haemorrhage Kinked moderate Enlarged slight | 162 162 162 162 162 162 162 162 162 162 162 162 162 162 162 | 3 1 1 1 2 1 1 1 4 2 1 5 5 1 4 | 1.85 0.62 0.62 0.62 1.23 0.62 0.62 0.62 2.47 1.23 0.62 3.09 3.09 0.62 2.47 | 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 | 3 1 1 1 2 1 1 1 3 2 1 5 3 1 4 | 12.50 4.17 4.17 4.17 8.33 4.17 4.17 4.17 12.50 8.33 4.17 20.83 12.50 4.17 16.67 |
4 | Abdomen Great vessels Heart Heart Kidneys Kidneys Testis Testis Thoracic cavity Thoracic cavity Ureter Ureter Ureter | VA VA AN VA AN VA AN AN AN VA AN AN VA | Haemorrhagic Long innominate artery Atrium enlarged Pericardium Haemorragic Ectopic Pelvic dilation slight Hypoplasia Displaced Haemorrhage Haemorrhage Enlarged moderate Kinked moderate Enlarge slight | 173 173 173 173 173 173 173 173 173 173 173 173 173 | 7 3 6 2 1 1 1 10 2 1 1 1 3 | 4.05 1.73 3.47 1.16 0.58 0.58 0.58 5.78 1.16 0.58 0.58 0.58 1.73 | 24 24 24 24 24 24 24 24 24 24 24 24 24 | 5 2 4 1 1 1 1 9 2 1 1 1 3 | 20.83 8.33 16.67 47.17 4.17 4.17 4.17 37.50 8.33 4.17 4.17 4.17 12.50 |
Applicant's summary and conclusion
- Conclusions:
- Based on the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for maternal and developmental toxicity can be set at 1000 mg/kg/day.
- Executive summary:
Study design
The effects of 4-(1-methyl-1-phenylethyl)-N-[4-(1-methyl-1-phenylethyl)phenyl]aniline were investigated in female Sprague Dawley SD rats during pregnancy and embryo-foetal development according to OECD guideline no. 414 “Prenatal Developmental Toxicity Study”. Females were in-house mated with sexually mature males of the same strain and then assigned to 4 groups of 24 females each as indicated below:
Group Number
Treatment
(mg/kg/day)+
Level
Female Numbers
(odd only)
1
2
3
4
0
50
250
1000
Control
Low
Medium
High
1-47
49-95
97-143
145-191
+: in terms of test item supplied
The test item was suspended in 0.5 % methyl cellulose (0.5% MC) and administered by oral gavage at 50, 250 and 1000 mg/kg/day with the dose volume set at 10 mL/kg body weight.
The animals were treated throughout the gestation period from Day 3 up to Day 19 post coitum. Control females received the vehicle (0.5 % MC) at the same dose volume during the same treatment period.
Parameters assessed included clinical observations, body weight and food consumption during the in-life phase. Blood collection for hormones determination (T3, T4 and TSH) was performed on Day 20 post coitum before dispatch to necropsy.
All females were caesarean-sectioned on Day 20 post coitum and subjected to post mortem examination along with thyroid and brain weights. The ovaries were examined and the corpora lutea counted. Gravid uterus was weighed and the uterine content examined for the number of implantations, intrauterine deaths and live foetuses.
Live foetuses were weighed, sexed and observed for external abnormalities. In addition, the anogenital distance (AGD) was recorded in all live foetuses.
Approximately one half of the foetuses in each litter was examined for fixed-visceral and skeletal abnormalities.
Histopathology of thyroid was performed in all groups.
Fate of females
All females survived to the final sacrifice on gestation Day 20 and were found pregnant with the exception of two controls and one low dose female.
The final number of females with live foetuses on gestation Day 20 was as follows:
– 22 in the control group (0 mg/kg/day)
– 23 in the low dose group (50 mg/kg/day)
– 24 in the mid-dose group (250 mg/kg/day)
– 24 in the high dose group (1000 mg/kg/day)
Clinical signs
No treatment-related findings were recorded.
Maternal body weight and body weight gain
No treatment-related effects were seen in maternal body weight/body weight gain throughout the study.
Food consumption
No treatment-related effects were seen in food consumption throughout the study.
Thyroid hormone determination
Serum levels of T3, T4 and TSH did not differ between treated and control groups.
Terminal body weight, uterus weight and absolute weight gain
Body weight at termination, uterus weight and the absolute weight gain of females were unaffected by treatment.
Organ weight
No effects were seen in thyroid weight between treated and control groups.
Litter data and sex ratios
Litter data and sex ratios were unaffected by treatment.
Anogenital distance
No differences were seen in the anogenital distance between treated and control groups both in male and females foetuses.
Macroscopic and microscopic examinations
At post mortem examination, no treatment-related macroscopic observations were noted in treated females receiving test item at ≥ 50 mg/kg/day, when compared to controls. Any macroscopic observations were within the range of expected spontaneous findings in SD rats of the same age considered incidental and unrelated to the test item.
External examinations of foetuses
No treatment-related effects were seen at external examination of foetuses.
Skeletal examinations of foetuses
No treatment-related effects were seen at external examination of foetuses.
Visceral examination of foetuses
No treatment-related effects were seen at external examination of foetuses.
Conclusion
Based on the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for maternal and developmental toxicity can be set at 1000 mg/kg/day.
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