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EC number: 288-307-8 | CAS number: 85711-47-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Well documented and reported study fully adequate for assessment. The study was conducted according to an internationally accepted technical guideline and in compliance with GLP in a recognized contract research organization.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- of 1996
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Test material form:
- liquid: viscous
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Sprague Dawley rats, strain: Crl:CD(SD) with appropriate range of bodyweight at study start.
- Source: Charles River (UK) Ltd.
- Age at treatment start: 72 days.
- Weight at treatment start: Males: minimum 337 g, maximum 417 g,
Females: minimum 227 g, maximum 293 g.
- Housing Inside a barriered rodent facility:
all animals pre-pairing + toxicity subgroups: In groups up to 5 by sex in solid floor polycarbonate cages.
during pairing (1 male+1 female/cage): In RB3 modified polycarbonate cages with stainless steel grid-floor over absorbent paper-lined trays.
males after pairing: In groups up to 5 in solid floor polycarbonate cages.
females during gestation and lactation: Females housed individually (+litter) in solid floor polycarbonate cages.
- Bedding material (in solid floor cages): Wood based bedding, sterilised by autoclaving before use.
- Cage enrichment: Aspen chew block + plastic shelter (except during pairing or post Gestation Day 20).
- Diet (ad libitum): Standard rodent diet (SDS VRF1 Certified) without antibiotic, chemotherapeutic or prophylactic agent.
- Fasting (diet withheld): Main phase males and Toxicity phase females overnight before blood sampling for clinical pathology.
- Water (ad libitum): Potable drinking water from the public supply.
- Acclimation period: 7 days before treatment start, under laboratory conditions.
Routine analysis of the batch of diet used and water, chew blocks and bedding material did not provide evidence of contamination that might have prejudiced the study.
IN-LIFE DATES:
- Duration of test, males & toxicity phase females: Five weeks
Duration of test, main phase females (i.e. reproductive subgroup): From 14 days prior to pairing to day 7 of lactation.
Duration of test, offspring: From birth to day 7 of lactation.
ENVIRONMENTAL CONDITIONS
Air conditioned room kept at positve pressure without re-circulation of the filtered fresh air supplied to the room.
Controlled environment, environmental conditions were set at:
- Temperature (°C): 21 ± 2°C
- Relative Humidity (%): 40 to 70%
- Photoperiod (artificial lighting): 12 hrs day / 12 hrs night
- Rate of air exchange: At least 15 changes/h
Deviations from the target ranges for temperature and relative humidity were not evident.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Treatment of parental animals by oral gavage administration. Test substance was not directly administered to F1 animals.
- Concentration in vehicle: The concentration of the test material in vehicle varied between dose groups thus allowing constant dosage volume in terms of mL/kg bw/day.
- Amount (dose volume by gavage): 5 mL/kg bw/day.
Actual dose volumes were calculated at about weekly or shorter intervals accounting for the latest bodyweight.
- For concentrations of test material in vehicle at different dose levels, see Table 1 in "Any other information on materials and methods incl. tables"
- Justification for choice of vehicle:
The suitability of corn oil as a vehicle was established during the 14-day range-finding study. In addition, in the present main study, concentrations of dose formulations were chemically analysed. - Details on mating procedure:
- - Male/female ratio per cage: 1/1
- Length of cohabitation: At the most 8 days (1 high dose female), until proof of successful mating was confirmed.
(1 control female had an acyclic oestrous and failed to mate)
- Proof of successful mating: Formation of at least one copulation plug and a sperm positive vaginal smear.
The day this was found was referred to as day 0 of gestation.
(During cohabitation, females were checked every morning for pregnancy). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Chemical analysis of test material formulations by high performance liquid chromatography coupled with a mass spectrometer (HPLC-MS/MS).
- Mean concentrations of the test material formulations (verified for first and 7th treatment week) were confirmed at each dose level.
Chemical analysis confirmed that the mean concentrations of WS400107 in prepared formulations were within 93% to 100% of the corresponding
nominal concentration, thus confirming acceptable accuracy of formulation for dosing of the animals.
- Homogeneity and stability of test material formulations at 2 and 200 mg/L and at storage and handling conditions similar to those adopted for dosing of the animals were confirmed. - Duration of treatment / exposure:
- - Treatment period, males & toxicity phase females: Daily, for five consecutive weeks, in males commencing 14 days prior to pairing
- Treatment period, main phase females (i.e. reproductive subgroup): 44 to 51 days (from 14 days prior to pairing to Day 6 of lactation)
- Offspring were not dosed - Frequency of treatment:
- Daily, 7 days/week (during parturition, dosing omitted as appropriate)
- Details on study schedule:
- - Age at mating of the mated animals in the study: 12 to 14 weeks
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0 (vehicle control), 150, 400, 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- Toxicity phase animals: */ 5 females
Main phase animals (i.e. reproductive subgroups): 10 males / 10 females
*Explanatory note by the notifier:
Examinations assigned to the toxicity phase females to meet the requirements of a 28-day repeat dose oral toxicity study were also assigned to 5 (for some examinations to 10) main phase males per dose group. Therefore, these 5 main phase males per dose group are called also "toxicity subgroup" in the present robust study summary for clarification. After pairing with main phase females, all males were killed at the same time (Week 6). - Control animals:
- yes, concurrent vehicle
- Details on study design:
- This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study
(OECD 422 test guideline). Therefore, animals initially entering the study were divided into toxicity subgroup animals (toxicity phase) and reproductive subgroup animals (main phase), whereby 5 of the 10 F0 males (used for pairing) per dose group formed the toxicity male subgroups.
Dose selection was based on the results of a 14-day preliminary oral (gavage) toxicity study in the rat in which dose levels of 100, 300 or 1000 mg/kg/day did not have any severe toxic effects on young adult animals (females nulliparous and non-pregnant) preventing the choice of up to 1000 mg/kg/day in the present OECD 422 toxicity study. - Positive control:
- Not included in the study.
Examinations
- Parental animals: Observations and examinations:
- Clinical observations performed and frequency:
- Clinical signs : At least twice a day
- Detailed physical examination
and arena observations: Before treatment start and at least once a treatment week (except possibly 1 female taking 5 to 8 days for pairing).
- Functional Observation Battery: During treatment week 5 (before dosing) on all toxicity subgroup animals (5 parental males/group inclusively)*.
- Body weight, all males: About weekly throughout the study.
Body weight, Toxicity Females: About weekly throughout the study.
Body weight, Repro. Females: Weekly for pre-pairing period; on gestation days 0, 6, 13, 20; on lactation days 1, 4 & 7.
- Food consumption, all males: Weekly for pre-pairing period and for the period after mating.
Food cons., Toxicity Females: About weekly throughout the study.
Food cons., Repro. Females: Weekly for pre-pairing period, during gestation for days 0-6, 6-13, 13-20, during lactation for days 1-4 & 4-7.
- Hematology: During treatment week 5 after functional observation battery*
- Blood (plasma) chemistry: During treatment week 5 after functional observation battery*
* Examinations confined to toxicity subgroup animals are marked above with an asterisk*
and are detailed in the separate endpoint study record "7.5.1 Repeated dose toxicity: oral - Repeat dose tox combined_gavage_rat_HLS_GAH0152"
Explanatory note
This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study
(OECD 422 test guideline). Therefore, animals initially entering the study were divided into toxicity subgroup animals (toxicity phase) and reproductive subgroup animals (main phase), whereby 5 of the 10 F0 males (used for pairing) per dose group formed the toxicity male subgroups. - Oestrous cyclicity (parental animals):
- Frequency of vaginal oestrus was determined by examination of vaginal smears taken daily from all main phase (i.e. reproductive subgroup) females from the beginning of the treatment period to the day of confirmed copulation.
- Regular: All observed cycles of 4 or 5 days
- Irregular: At least one cycle of 2, 3 or 6 to 10 days
- Acyclic: At least 10 days without oestrus - Sperm parameters (parental animals):
- Parameters examined in male parental animals:
- testis weight,
- epididymis weight
- detailed qualitative histopathology examination of the testes taking into account the tubular stages of the spermatogenic cycle. This was to identify treatment related effects such as missing germ cell layers or types, retained spermatids, multinucleate or apoptotic germ cells and sloughing of spermatogenic cells in the lumen. Any cell- or stage-specificity of testicular findings was noted. - Litter observations:
- STANDARDISATION OF LITTERS: Not performed. The study ended on Lactation Day 7.
LITTER PARAMETERS EXAMINED
- From Day 20 post copulation 3 times a day checks for evidence of parturition, any difficulties and numbers of live and dead offspring.
- Total litter size on day 1 of age and mortality/live litter size on each day until 7 days after littering.
- Sex ratio expressed as percentage males and calculated for total offspring on Day 1 and for live offspring on Days 1, 4 & 7
(No. of male pups in litter/No. of offspring in litter) x 100
- Clinical signs, recorded daily
- Body weight of live pups (on days 1, 4 and 7 after littering) and weight change from Days 1-4, 4-7 and 1-7. - Postmortem examinations (parental animals):
- GROSS PATHOLOGY: Yes, see below
WEIGHING OF ORGANS: Yes, see below
HISTOPATHOLOGY: Yes, see below
Terminal sacrifice
- all males (F0) and toxicity subgr. females: Killed in Week 6, after completion of the Treatment Week 5 investigations.
- reproductive subgr. females & offspring: Killed on Day 7 post partum.
(1 high dose female was killed after mating in poor clinical condition. It was confirmed to be non-pregnant)
(1 control female failed to mate and therefore was killed in Week 8 following 7 weeks of treatment)
Gross pathology:
- adult/parental animals: Full macroscopic examination.
Organs Weights:
- all males (F0) +
toxicity subgroup females: Adrenals, brain, epididymides, heart, kidneys, liver, ovaries, prostate, seminal vesicles with coagulation gland,
spleen, testes, thymus, uterus with cervix & oviducts.
- dams: Ovaries
Histopathology:
- toxicity subgroups: The following organs were microscopically observed for the control and 1000 mg/kg bw/day toxicity subgroups:
Brain, eyes, pituitary gland, thyroid with parathyroids, heart, thymus, liver, spleen, adrenals, kidneys, testes,
epididymides, ovaries, lung, trachea, oesophagus, stomach, duodenum, jejunum, ileum, caecum, rectum, colon,
Peyer's patch, lymph node (axillary, mesenteric), urinary bladder, uterus (with cervix & oviducts), vagina,
spinal cord, sciatic nerve, skeletal muscle, sternum with marrow, seminal vesicle & coagulation gland, prostate.
In addition, the duodenum, jejunum, ileum, mesenteric lymph nodes, seminal vesicles and prostate
were also examined by light microscopy for the remaining F0 males of the control and 1000 mg/kg bw/day
groups and all adult males and toxicity subgroup females of the 150 and 400 mg/kg bw/day groups and any
gross lesions for all adult animals.
- reproductive subgroups All above organs/tissues from a premature death (1 high dose female). Gross lesions from adult dams comprised only focal hairloss not necessating any examination by light microscopy. - Postmortem examinations (offspring):
- Pup survivors were killed on Day 7 post partum and had a careful external macroscopic examination for gross abnormalities.
Externally abnormal offspring and premature deaths had an internal macroscopic examination including assessment of the presence of milk in the stomach, where possible. (Missing or grossly autolysed or cannibalised offspring could not be examined). - Statistics:
- As detailed in Endpoint study record "7.5.1 Repeated dose toxicity: oral - Repeat dose tox combined_gavage_rat_HLS_GAH0152"
- Reproductive indices:
- - Pre-coital interval (pairing days until detection of mating)
- No. of animals mating (evidence of successful copulation, i.e. at least one copulation plug or a sperm positive vaginal smear)
- No. of animals achieving pregnancy
- Percentage mating (No. of animals mating/No. of animals paired) x 100
- Fertility index (No. of animals achieving pregnancy/ No. of animals paired) x 100
- Conception rate (No. of animals achieving pregnancy/No. of animals mated) x 100
- Gestation length (time elapsing between detection of mating and commencement of parturition)
- Gestation index (No. of live litters born/No. of living animals having achieved pregnancy)
- No. of living pregnant females
- For further reproductive parameters, see also the above section "Litter observations" and section "Offspring viability indices" below. - Offspring viability indices:
- - Post-implantation survival index (Total no. of pups born/Total no. of uterine implantation sites) x 100
- Live birth index (No. of live pups on Day 1 after littering/Total no. of pups born) x 100
- Viability index (No. of live pups on Day 4 after littering /No. of live pups on Day 1 after littering) x 100
- Lactation index (No. of live pups on Day 7 after littering /No. of live pups on Day 1 after littering) x 100
- For further parameters indicative of the viability of the offspring, see also the above section "Litter observations"
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- one high dose female was killed for animal welfare reasons; it had very low eight gain and was not pregnant.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- body weight gain was affected in males and females
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- body weight gain was affected in males and females
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- but not representing toxicity or toxicological significance unclear
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
There were no premature deaths, clinical signs or adverse effects on neurobehaviour attributable to treatment with the test material. One high dose female of the reproductive subgroup was killed during the gestation phase, because of its poor clinical condition (thin built, hunched posture, piloerection, ungroomed fur and 13 g bodyweight loss over 14 days, confirmed to be not pregnant at necropsy). One control female of the reproductive subgroup failed to mate and therefore was killed after 7 weeks of treatment (Week 8).
BODYWEIGHT GAIN AND FOOD CONSUMPTION
A dose related adverse effect on bodyweight gain was evident in males over the 5 weeks of treatment attaining statistical significance at 400 and 1000 mg/kg bw/day. Nulliparous females were unaffected by treatment, but in dams treated with 1000 mg/kg bw/day bodyweight gain was statistically significantly lower than in concurrent controls during gestation Days 6 to 13 and overall during gestation Days 0 to 20. Food consumption was lower than in concurrent controls in males at 1000 mg/kg/day during the 5-week treatment period and in dams at 1000 mg/kg/day on lactation Days 4 to 7.
ORGAN WEIGHTS
After 5 weeks of treatment at 1000 mg/kg/day, prostate and seminal vesicle weights were statistically significantly lower than in concurrent controls. The toxicological significance of this finding remained unclear.
GROSS PATHOLOGY AND HISTOPATHOLOGY (NON-NEOPLASTIC)
The effects on prostate and seminal vesicle weights were consistent with small prostates and small seminal vesicles macroscopically apparent and reduced colloid microscopically seen in these tissues in four of ten high dose males. The toxicological significance of this finding remained unclear. Testes, ovaries and epididymides were unaffected by treatment. Evaluation of the seminiferous testicular tubules regarding their stage in the spermatogenic cycle and regarding the integrity of the various cell types present within the different stages did not reveal any cell or stage abnormalities. Main phase females (reproductive subgroup) killed on Lactation Day 7 were not histopathologically examined.
Thickening of the jejunum, ileum and duodenum was macroscopically apparent in a number of animals from all test item treated groups and thickening of the colon in two of ten males of the high dose group (1000 mg/kg/day) after 5 weeks of treatment, and were attributed to treatment with the test material. Histopathology revealed foamy macrophages within the villi of the illeum and jejunum (at 150, 400 and 1000 mg/kg/day) and of the duodenum (at 400 and 1000 mg/kg/day). Macrophage aggregates in the mesenteric lymph nodes in all treated groups were considered to be secondary deposits of the foamy macrophages seen in the intestines. These pathology findings were considered not to represent toxicity, but to result from test material ingestion by macrophages.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- > 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: A dose related adverse effect on bodyweight gain was evident in males over the 5 weeks of treatment attaining statistical significance at 400 and 1000 mg/kg bw/day.
- Dose descriptor:
- NOAEL
- Effect level:
- > 400 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Nulliparous females were unaffected by treatment, but in dams treated with 1000 mg/kg bw/day bodyweight gain was statistically significantly lower than in concurrent controls during gestation Days 6 to 13 and overall during gestation Days 0 to 20.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- on bodyweight or bodyweight gain to Day 7, the day of scheduled sacrifice of the pups.
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- disclosed by careful external macroscopic examination of all pups surviving to Day 7 and by necropsy of externally abnormal pups and decedents
- Histopathological findings:
- not examined
Details on results (F1)
Effect levels (F1)
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- > 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: NOEL = highest dose tested. Offspring development up to Day 7 of age.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 2: No. of Implantations and Litter Size - Group Mean Values for Main Phase Females during Lactation |
||||||||||
Group |
1 |
2 |
3 |
4 |
||||||
Compound |
Vehicle Control |
WS400107 |
WS400107 |
WS400107 |
||||||
Dose (mg/kg/day) |
0 |
150 |
400 |
1000 |
||||||
|
||||||||||
Group |
Implantations |
Total litter size |
Live litter size |
|||||||
|
|
Day |
Day |
Day |
Day |
|||||
|
|
1≠ |
1 |
4 |
7 |
|||||
Statistical test: |
Sh |
Wi |
Wi |
Wi |
Wi |
|||||
1 |
Mean |
16.8 |
16.1 |
16.0 |
15.3 |
15.2 |
||||
|
SD |
1.4 |
1.7 |
1.7 |
1.6 |
1.6 |
||||
|
N |
9 |
9 |
9 |
9 |
9 |
||||
|
|
|
|
|
|
|
||||
2 |
Mean |
15.9 |
14.8 |
14.5 |
14.3 |
14.3 |
||||
|
SD |
1.5 |
2.0 |
2.3 |
2.1 |
2.1 |
||||
|
N |
10 |
10 |
10 |
10 |
10 |
||||
|
|
|
|
|
|
|
||||
3 |
Mean |
16.2 |
15.2 |
15.1 |
14.9 |
14.8 |
||||
|
SD |
1.7 |
1.7 |
1.5 |
1.4 |
1.4 |
||||
|
N |
10 |
10 |
10 |
10 |
10 |
||||
|
|
|
|
|
|
|
||||
4 |
Mean |
14.0* |
12.8** |
12.4** |
12.1** |
12.0** |
||||
|
SD |
4.2 |
3.7 |
3.5 |
3.4 |
3.3 |
||||
|
N |
9 |
9 |
9 |
9 |
9 |
||||
|
Wi |
Wi |
Wi |
Wi |
Wi |
|||||
4a |
Mean |
15.3 |
13.9* |
13.5** |
13.1* |
13.0* |
||||
|
SD |
1.9 |
1.9 |
1.6 |
1.6 |
1.4 |
||||
|
N |
8 |
8 |
8 |
8 |
8 |
||||
Statistical test Wi = Treated groups compared to Control using Williams’ test, * p<0.05, ** p<0.01
Statistical test Sh = Treated groups compared to Control using Shirley’s test, * p<0.05, ** p<0.01
≠ Includes offspring that died prior to designated Day 1 of age
a Excludes Litter 4F, 41 which was atypically small
Applicant's summary and conclusion
- Conclusions:
- Reduced mean numbers of implantations and live litter sizes on Days 1-7 of age were observed at the highest dose level of 1000 mg/kg/day. However, this reduction of mean values could be traced back to a sub-population of females in the high dose group (4/10) which showed weight loss or retarded weight gain in the first two weeks of dosing. Thus, the observed effects are due to maternal toxicity, and not to a specific effect on reproductive parameters. Survival and growth of the offspring of all dose groups, their clinical condition and macropathology findings were comparable with control values.
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