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EC number: 258-053-2 | CAS number: 52628-03-2
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP/Guideline Study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: USEPA OPPTS 870.3050 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- yes
Test material
- Reference substance name:
- 2-Propenoic acid, 2-methyl-, 2-hydroxyethyl ester, phosphate
- EC Number:
- 258-053-2
- EC Name:
- 2-Propenoic acid, 2-methyl-, 2-hydroxyethyl ester, phosphate
- Cas Number:
- 52628-03-2
- Molecular formula:
- C6 H10 O3 . x H3 O4 P
- IUPAC Name:
- 2-(methacryloyloxy)ethyl phosphate
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): HEMA phosphate
- Composition of test material, percentage of components: the sum of six major components PEM-dimer, phosphoethyl methacrylate (PEM), phospho-di(ethyl methacrylate) (PEM diester), methyl methacrylate (MMA), HEMA dimer, and ethylene glycol dimethacrylate (EGDMA)
- Lot/batch No.: A022C73001
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: F344/DuCrl
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (Kingston, New York)
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: Males: 114.3-138.2 g; Females: 86.1-100.5 g
- Fasting period before study: no
- Housing: one per cage in stainless steel cages. Cages had solid floors with corncob bedding and shredded Aspen bedding
- Diet (e.g. ad libitum): LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in meal form ad libitum
- Water (e.g. ad libitum): municipal water was provided ad libitum
- Acclimation period: approximately one week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C with a tolerance of ± 1°C (and a maximum permissible excursion of ± 3°C)
- Humidity (%): 40-70%
- Air changes (per hr): 10-15 times/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark (on at 6:00 a.m. and off at 6:00 p.m.)
IN-LIFE DATES: From: October 11, 2012 To: November 8, 2012
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
All dosing solutions were prepared by mixing the test material in propylene glycol (PG) at concentrations of 0, 16.7, 50, or 166.7 mg/ml and administered at a dose volume of 6 ml/kg body weight to achieve the targeted dose levels. Dose solutions were not corrected for purity. Dose volumes were adjusted at least weekly based on individual body weights.
VEHICLE
- Concentration in vehicle: 0, 16.7, 50, or 166.7 mg/ml
- Amount of vehicle (if gavage): 6 ml/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose confirmation analyses of all dose solutions were determined pre-exposure. The homogeneity of the low-dose and the high-dose solutions were determined concurrent with dose confirmation. The method used for analyzing the test material in propylene glycol was high performance liquid chromatography with ultraviolet detection (HPLC/UV).
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 100, 300, or 1000 MKD
Basis:
actual ingested
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels selected are shown in Text Table 1. The high dose was the limit dose of 1000 mg/kg/day. The mid- and low-dose levels were expected to provide dose response data for any treatment-related effects observed in the high-dose group. The low-dose was expected to be a no-observed-effect level (NOEL).
- Positive control:
- none
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table 1 were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: pre-exposure and once per week throughout the study
BODY WEIGHT: Yes
- Time schedule for examinations: pre-exposure, twice during the first week and at least weekly during the dosing period
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-exposure and pre-terminal
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: terminal
- Anaesthetic used for blood collection: Yes (CO2/O2)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table [2] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: terminal
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table [3] were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: the week prior to the scheduled necropsy
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters checked in table [4] were examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 5)
HISTOPATHOLOGY: Yes (see table 6) - Statistics:
- Means and standard deviations were calculated for all continuous data. All parameters examined statistically (feed consumption is addressed below) were first tested for equality of variance using Bartlett's test. In-life body weights were evaluated using a repeated measures (RM) analysis of variance (ANOVA), the multivariate approach, for time (the repeated factor), sex, and dose. The first examination in the RM-ANOVA was of the time-sex-dose interaction. If significant at alpha = 0.02, the analysis was repeated separately for each sex without examining the results of other factors. Terminal body weight, organ weight (absolute and relative, excluding epididymides, testes, prostate+seminal vesicles with coagulating glands (and fluids), and prostate weights), urine volume, urine specific gravity, hematologic parameters (excluding RBC indices and differential WBC counts), coagulation and clinical chemistry parameters (excluding globulin and albumin/globulin ratio), were evaluated using a two-way ANOVA. Results for epididymides, testes, prostate + seminal vesicles with coagulating glands (and fluids), and prostate weights (absolute and relative) were analyzed using a one-way ANOVA. Feed consumption data were evaluated by Bartlett's test for equality of variances. Descriptive statistics only (means and standard deviations) were reported for body weight gains, globulin, albumin/globulin ratio, RBC indices, and differential WBC counts. Because numerous measurements were statistically compared in the same group of animals, the overall false positive rate (type I errors) was greater than the nominal alpha levels.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See Table 2
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See Table 3
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See Table 4
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- See Table 7
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See Table 5
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- See Table 6
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
All rats survived the full duration of the study.
Examinations performed on all animals revealed no treatment-related findings.
BODY WEIGHT AND WEIGHT GAIN
There were no statistically identified or treatment-related differences in the body weights or body weight gains of male or female rats at any dose level as compared to their respective controls.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no statistically identified or treatment-related differences in the feed consumption of male or female rats at any dose level as compared to their respective controls.
OPHTHALMOSCOPIC EXAMINATION
Pre-exposure examination on all animals placed on study indicated all but two rats were within normal limits. These two males assigned to the 300 mg/kg/day group had cloudy corneas during the pre-exposure examination, but were considered suitable for study purposes.
In addition to pre-exposure observations, cloudy cornea was noted in four male rats one in the 100 mg/kg/day group, two in the 300 mg/kg/day group, and one in the 1000 mg/kg/day group) and three female rats (two in the 100 mg/kg/day group, and one in the 300 mg/kg/day group) prior to study termination. These observations were interpreted to be unrelated to treatment due to their low incidence and lack of a dose-response relationship.
HAEMATOLOGY
Treatment-related effects on hematology in both sexes of the 1000 mg/kg/day group consisted of statistically significant, marginal decreases in red blood cell counts, hemoglobin concentration, and hematocrit levels with a corresponding treatment-related increase in reticulocyte counts that was consistent with compensatory response to lower hemoglobin and hematocrit levels. However, there were no associated histopathological effects in the bone marrow or spleen of males and females given 1000 mg/kg/day.
CLINICAL CHEMISTRY
There was a statistically identified increase in total bile acids for males in the 1000 mg/kg/day group, which was interpreted to be treatment-related; however, this effect was of questionable toxicological significance as this finding was not observed in high-dose females and there were no associated histopathological effects in the liver or alterations in liver enzymes that would be expected in the presence of a toxicologically significant increase in bile acids.
URINALYSIS
Males given 1000 mg/kg/day had a higher incidence of acidic urine (pH 6.5) as compared to the controls (4/5 given 1000 mg/kg/day versus 0/5 controls). The change in the urine pH was interpreted to be treatment related, possibly due to excretion of the test material and/or its metabolites in the urine. Urine samples from some of the females in all treatment-groups were noted to be acidic (pH 6.5 or 6.0), however, due to absence of a clear dose-response relationship, it was interpreted to be unrelated to treatment.
ORGAN WEIGHTS
Males and females given 1000 mg/kg/day had statistically significant, treatment-related increases in relative kidney weights compared to controls. The exact reason(s) for the increased relative kidney weights are not clear, although kidneys of males and females at this dose level had a marginal treatment-related increase in the severity of tubular mineralization, relative to controls.
Females in the 1000 mg/kg/day group had a statistically higher mean relative spleen weight compared to controls which was interpreted to be treatment-related as this value was outside recent historical control range; however, this change was not associated with any treatment-related histopathological effect.
There were statistically identified decreases in absolute (males at 100 mg/kg/day; females at 300 and 1000 mg/kg/day) and relative (females at 300 and 1000 mg/kg/day) heart weights; however, these alterations were unrelated to treatment as these values were within recent historical control ranges, and there was a lack of a dose-response relationship. Moreover, there were no histopathological correlates to the lower heart weights at 1000 mg/kg/day.
GROSS PATHOLOGY
Treatment-related gross observations at necropsy were limited to the stomach and consisted of a slight thickening of the limiting ridge (a fold of the stomach mucosa that demarcates the border between the forestomach and the glandular stomach) in males and females given 1000 mg/kg/day as compared to the respective controls. All other gross findings were interpreted to be spontaneous changes unassociated with exposure to the test material.
HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment-related histopathological changes were limited to the stomach and kidneys of males and females given 300 or 1000 mg/kg/day. Treatment-related stomach effects were noted in the glandular mucosa as well as at the limiting ridge of the non-glandular mucosa of the forestomach. Males and females given 300 or 1000 mg/kg/day had a treatment-related, dose-dependent, very slight or slight hyperplasia of the neck mucous cells of the glandular mucosa.
There were no treatment-related histopathological changes in the stomachs of males and females given 100 mg/kg/day.
In the kidneys of males and females given 300 or 1000 mg/kg/day, there was a marginal treatment-related increase in the degree of background mineralization of medullary tubules as compared to that observed in the controls.
There were no treatment-related histopathological changes in the kidneys of males and females given 100 mg/kg/day.
HISTORICAL CONTROL DATA (if applicable)
Sex Males
Historical Control@
Red Blood Cell Count (E6/ul) 8.68-9.07
Hemoglobin Concentration (g/dl) 15.7-17.5
Hematocrit (%) 48.0-50.4
Reticulocytes (109/l) 143.3-180.4
Sex Females
Historical Control@
Red Blood Cell Count (E6/ul) 8.67-8.73
Hemoglobin Concentration (g/dl) 16.0-17.0
Hematocrit (%) 47.8-48.8
Reticulocytes (109/l) 138.6-165.1
Sex Males
Historical Control@
Total Bile Acids (umol/l) 3.70-17.18
Total protein (g/dl) 6.6-6.8
Albumin (g/dl) 4.5-4.6
Sex Females
Historical Control@
Total protein (g/dl) 6.4-6.6
Albumin (g/dl) 4.5-4.6
Sex Males
Historical Control@
Final Body wt (g) 198.5-212.2
Heart (g) 0.646-0.694
Kidneys (g/100) 0.663-0.729
Sex Females
Historical Control@
Final Body wt (g) 129.6-140.3
Heart (g) 0.472-0.522
Heart (g/100) 0.336-0.403
Kidneys (g/100) 0.790-0.810
Spleen (g/100) 0.267-0.273
@Historical control data obtained from four 28-day gavage studies conducted in this laboratory in 2012
using PG as the vehicle.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Clinical Observations Summary
MALES |
DOSE | 0 | 100 | 300 | 1000 | |
Within Normal limits | |||||
DAYS | 1 -6 | 5/5 | 5/5 | 5/5 | 5/5 |
DAY | 7 | 5/5 | 4/5 | 5/5 | 5/5 |
DAYS | 8 -10 | 5/5 | 4/5 | 4/5 | 5/5 |
DAYS | 11 -22 | 5/5 | 4/5 | 5/5 | 5/5 |
DAYS | 23 -27 | 5/5 | 4/5 | 4/5 | 5/5 |
DAY | 28 | 3/5 | 4/5 | 4/5 | 5/5 |
Injury, Apparent Mechanical | |||||
DAYS | 8 -10 | 0/5 | 0/5 | 1/5 | 0/5 |
DAY | 28 | 1/5 | 0/5 | 0/5 | 0/5 |
Posture, Head-Tilt | |||||
DAYS | 7 -28 | 0/5 | 1/5 | 0/5 | 0/5 |
Skin/Fur/Mucous Membranes, Excessive Hairloss | |||||
DAYS | 23 -27 | 0/5 | 0/5 | 1/5 | 0/5 |
DAY | 28 | 1/5 | 0/5 | 1/5 | 0/5 |
FEMALES | |||||
DOSE | 0 | 100 | 300 | 1000 | |
Within Normal Limits | |||||
DAYS | 1 -22 | 5/5 | 5/5 | 5/5 | 5/5 |
DAYS | 23 -28 | 5/5 | 5/5 | 5/5 | 4/5 |
Skin/Fur/Mucous Membranes, Excessive Hairloss | |||||
DAYS | 23 -28 | 0/5 | 0/5 | 0/5 | 1/5 |
Table 2: Hematology Summary
MALES |
Dose(mkd) | WBC(E3/ul) | RBC(E6/ul) | HGB(g/dl) | HCT(pcnt) | MCV(fl) | MCH(pg) | MCHC(g/dl) | PLT(E3/ul) | RET(E9/l) | |
0 | Mean | 6.48 | 8.66 | 15.8 | 48.7 | 56.2 | 18.3 | 32.5 | 804 | 190.3 |
S.D. | 1.36 | 0.14 | 0.2 | 0.6 | 0.9 | 0.2 | 0.5 | 91 | 17.8 | |
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
100 | Mean | 7.10 | 8.70 | 15.8 | 48.2 | 55.4 | 18.1 | 32.8 | 736 | 172.6 |
S.D. | 1.29 | 0.17 | 0.3 | 1.1 | 1.1 | 0.3 | 0.4 | 67 | 23.6 | |
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
300 | Mean | 6.82 | 8.67 | 15.8 | 48.4 | 55.9 | 18.2 | 32.5 | 834 | 190.8 |
S.D. | 1.25 | 0.29 | 0.3 | 1.4 | 0.6 | 0.2 | 0.4 | 37 | 5.9 | |
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
1000 | Mean | 7.29 | 8.48 | 15.6 | 48.1 | 56.6 | 18.4 | 32.5 | 784 | 231.8 |
S.D. | 1.28 | 0.17 | 0.4 | 0.7 | 0.5 | 0.4 | 0.7 | 78 | 40.1 | |
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
FEMALES | ||||||||||
Dose(mkd) | WBC(E3/ul) | RBC(E6/ul) | HGB(g/dl) | HCT(pcnt) | MCV(fl) | MCH(pg) | MCHC(g/dl) | PLT(E3/ul) | RET(E9/l) | |
0 | Mean | 8.32 | 8.85 | 16.5 | 48.4 | 54.7 | 18.7 | 34.1 | 711 | 141.7 |
S.D. | 1.72 | 0.11 | 0.2 | 1.1 | 0.7 | 0.1 | 0.4 | 117 | 5.3 | |
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
100 | Mean | 7.81 | 8.67 | 16.3 | 47.9 | 55.3 | 18.8 | 34.1 | 795 | 140.2 |
S.D. | 1.24 | 0.10 | 0.4 | 0.7 | 0.5 | 0.3 | 0.8 | 96 | 22.6 | |
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
300 | Mean | 8.18 | 8.94 | 16.4 | 49.3 | 55.1 | 18.3 | 33.2 | 814 | 141.8 |
S.D | 1.51 | 0.38 | 0.5 | 2.1 | 0.1 | 0.4 | 0.6 | 54 | 10.8 | |
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | |
1000 | Mean | 7.94 | 8.24 | 15.6 | 46.0 | 55.8 | 19.0 | 34.0 | 844 | 156.8 |
S.D. | 1.29 | 0.23 | 0.2 | 1.4 | 0.3 | 0.3 | 0.6 | 87 | 9.7 |
WBC=TOTAL LEUKOCYTE COUNT, RBC=ERYTHROCYTE COUNT, HGB=HEMOGLOBIN CONCENTRATION,
HCT=HEMATOCRIT, MCV=MEAN CORPUSCULAR VOLUME, MCH=MEAN CORPUSCULAR HEMOGLOBIN,
MCHC=MEAN CORPUSCULAR HEMOGLOBIN CONCENTRATION, PLT=PLATELET COUNT, RET=RETICULOCYTE COUNT
Table 3: Clinical Chemistry Summary
MALES | ||||||||||||||
Dose(mkd) | ALT(u/l) | ALP(u/l) | AST(u/l) | GGT(u/l) | TBIL(mg/dl) | TBA(umol/l) | TP(g/dl) | ALB(g/dl) | GLOB(g/dl) | A/GRatio | CHOL(mg/dl) | TRIG(mg/dl) | ||
0 | Mean | 39 | 164 | 84 | 1.5 | 0.05 | 4.51 | 6.7 | 4.6 | 2.1 | 2.2 | 62 | 61 | |
S.D. | 4 | 9 | 6 | 0.0 | 0.00 | 1.98 | 0.2 | 0.2 | 0.1 | 0.1 | 3 | 11 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
100 | Mean | 38 | 156 | 81 | 1.5 | 0.05 | 8.64 | 6.6 | 4.5 | 2.1 | 2.2 | 60 | 49 | |
S.D. | 2 | 16 | 6 | 0.0 | 0.00 | 8.78 | 0.2 | 0.1 | 0.1 | 0.1 | 7 | 9 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
300 | Mean | 39 | 166 | 90 | 1.5 | 0.05 | 6.66 | 6.6 | 4.5 | 2.0 | 2.2 | 60 | 52 | |
S.D. | 4 | 9 | 13 | 0.0 | 0.00 | 2.94 | 0.2 | 0.2 | 0.1 | 0.2 | 4 | 9 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
1000 | Mean | 41 | 166 | 87 | 1.5 | 0.05 | 21.34 | 6.2 | 4.3 | 1.9 | 2.3 | 55 | 62 | |
S.D. | 6 | 8 | 12 | 0.0 | 0.00 | 12.28 | 0.1 | 0.1 | 0.1 | 0.1 | 5 | 8 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
GGT LOWEST DETECTION LIMIT IS 3.0. INDIVIDUAL VALUES <3.0 WERE REPORTED AS 1.5 (ONE-HALF THE DETECTION LIMIT) FORSTATISTICAL ANALYSIS.TBIL LOWEST DETECTION LIMIT IS 0.10. INDIVIDUAL VALUES <0.10 WERE REPORTED AS 0.05 (ONE-HALF THE DETECTION LIMIT) FORSTATISTICAL ANALYSIS.ALT=ALANINE AMINOTRANSFERASE, ALP=ALKALINE PHOSPHATASE, AST=ASPARTATE AMINOTRANSFERASE,GGT=GAMMA GLUTAMYL TRANSPEPTIDASE TBIL=TOTAL BILIRUBIN, TBA = TOTAL BILE ACIDS, TP=TOTAL PROTEIN,ALB=ALBUMIN, GLOB=GLOBULIN, A/G=RATIO OF ALBUMIN/GLOBULIN, CHOL=CHOLESTEROL, TRIG=TRIGLYCERIDES
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Dose(mkd) | UN(mg/dl) | CREA(mg/dl) | GLUC(mg/dl) | NA(mmol/l) | K(mmol/l) | CL(mmol/l) | CA(mg/dl) | PHOS(mg/dl) | |
|||||
0 | Mean | 19 | 0.3 | 125 | 149 | 5.8 | 97 | 12.8 | 12.9 | |||||
S.D. | 2 | 0.0 | 12 | 1 | 0.3 | 1 | 0.2 | 1.4 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||||||
100 | Mean | 17 | 0.2 | 130 | 149 | 5.9 | 97 | 12.8 | 12.9 | |||||
S.D. | 1 | 0.1 | 23 | 1 | 0.5 | 1 | 0.5 | 0.8 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||||||
300 | Mean | 18 | 0.3 | 122 | 148 | 5.9 | 97 | 12.8 | 12.8 | |||||
S.D. | 1 | 0.1 | 18 | 1 | 0.2 | 2 | 0.3 | 0.7 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||||||
1000 | Mean | 17 | 0.2 | 131 | 148 | 6.4 | 96 | 12.9 | 13.8 | |||||
S.D. | 2 | 0.1 | 24 | 1 | 0.4 | 1 | 0.5 | 1.0 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||||||
UN=UREA NITROGEN, CREA=CREATININE, GLUC=GLUCOSE, NA=SODIUM, K=POTASSIUM, CL=CHLORIDE,CA=CALCIUM, PHOS=PHOSPHORUS
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Dose(mkd) | ALT(u/l) | ALP(u/l) | AST(u/l) | GGT(u/l) | TBIL(mg/dl) | TBA(umol/l) | TP(g/dl) | ALB(g/dl) | GLOB(g/dl) | A/GRatio | CHOL(mg/dl) | TRIG(mg/dl) | ||
0 | Mean | 33 | 134 | 90 | 1.5 | 0.05 | 16.32 | 6.3 | 4.5 | 1.9 | 2.4 | 74 | 51 | |
S.D | 3 | 5 | 5 | 0.0 | 0.00 | 17.98 | 0.3 | 0.1 | 0.2 | 0.2 | 3 | 8 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
100 | Mean | 29 | 131 | 82 | 3.4 | 0.05 | 7.92 | 6.1 | 4.4 | 1.7 | 2.5 | 68 | 49 | |
S.D. | 2 | 6 | 8 | 4.3 | 0.00 | 3.77 | 0.2 | 0.2 | 0.1 | 0.2 | 5 | 10 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
300 | Mean | 33 | 136 | 87 | 1.5 | 0.05 | 5.25 | 6.4 | 4.5 | 1.9 | 2.4 | 72 | 57 | |
S.D. | 5 | 16 | 11 | 0.0 | 0.00 | 1.58 | 0.4 | 0.2 | 0.2 | 0.2 | 8 | 7 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
1000 | Mean | 30 | 128 | 84 | 1.5 | 0.05 | 12.31 | 6.0 | 4.3 | 1.7 | 2.5 | 68 | 45 | |
S.D. | 1 | 8 | 3 | 0.0 | 0.00 | 10.59 | 0.2 | 0.1 | 0.1 | 0.2 | 9 | 4 | ||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||
GGT LOWEST DETECTION LIMIT IS 3.0. INDIVIDUAL VALUES <3.0 WERE REPORTED AS 1.5 (ONE-HALF THE DETECTION LIMIT) FORSTATISTICAL ANALYSIS.TBIL LOWEST DETECTION LIMIT IS 0.10. INDIVIDUAL VALUES <0.10 WERE REPORTED AS 0.05 (ONE-HALF THE DETECTION LIMIT) FORSTATISTICAL ANALYSIS.ALT=ALANINE AMINOTRANSFERASE, ALP=ALKALINE PHOSPHATASE, AST=ASPARTATE AMINOTRANSFERASE,GGT=GAMMA GLUTAMYL TRANSPEPTIDASE TBIL=TOTAL BILIRUBIN, TBA = TOTAL BILE ACIDS, TP=TOTAL PROTEIN,ALB=ALBUMIN, GLOB=GLOBULIN, A/G=RATIO OF ALBUMIN/GLOBULIN, CHOL=CHOLESTEROL, TRIG=TRIGLYCERIDES
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Dose(mkd) | UN(mg/dl) | CREA(mg/dl) | GLUC(mg/dl) | NA(mmol/l) | K(mmol/l) | CL(mmol/l) | CA(mg/dl) | PHOS(mg/dl) | ||||||
0 | Mean | 15 | 0.3 | 92 | 149 | 6.6 | 97 | 13.0 | 14.6 | |||||
S.D. | 1 | 0.1 | 14 | 3 | 0.5 | 2 | 0.4 | 1.5 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||||||
100 | Mean | 21 | 0.4 | 98 | 148 | 6.6 | 98 | 12.4 | 14.0 | |||||
S.D. | 10 | 0.5 | 10 | 1 | 0.9 | 2 | 0.3 | 2.4 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||||||
300 | Mean | 16 | 0.2 | 108 | 151 | 6.4 | 99 | 12.9 | 13.4 | |||||
S.D. | 1 | 0.1 | 13 | 7 | 0.5 | 5 | 0.6 | 0.6 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | ||||||
1000 | Mean | 19 | 0.2 | 111 | 148 | 6.4 | 98 | 12.5 | 13.6 | |||||
S.D. | 1 | 0.0 | 9 | 1 | 0.6 | 0 | 0.4 | 1.2 | ||||||
N= | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
UN=UREA NITROGEN, CREA=CREATININE, GLUC=GLUCOSE, NA=SODIUM, K=POTASSIUM, CL=CHLORIDE,
CA=CALCIUM, PHOS=PHOSPHORUS
Table 4: Urinalysis Summary
FEMALES | |||||||||||||
Dose(mkd) | UrineVolume(ml) | SpecificGravity | Color | Appear | pH | Protein | Glucose | Ketones | Bilirubin | Blood | Urobilinogen(eu/dl) | ||
0 | Mean | 2.5 | 1.069 | yellow (4) | clear (4) | 7.0 (1) | + (3) | Neg | TRC (4) | + (4) | Neg (5) | 1.0 (1) | |
S.D. | 0.8 | 0.009 | DK. YE (1) | cloudy (1) | 7.5 (1) | ++ (2) | + (1) | ++ (1) | 2.0 (3) | ||||
N= | 5 | 5 | 8.5 (3) | 4.0 (1) | |||||||||
100 | Mean | 4.1 | 1.051 | yellow (5) | clear (5) | 6.5 (3) | Neg (1) | Neg (5) | Neg (2) | Neg (2) | Neg (5) | 0.2 (1) | |
S.D. | 2.2 | 0.014 | 7.0 (1) | TRC (3) | TRC (3) | + (3) | 1.0 (4) | ||||||
N= | 5 | 5 | 7.5 (1) | + (1) | |||||||||
300 | Mean | 2.7 | 1.064 | yellow (5) | clear (5) | 6.0 (1) | TRC (1) | Neg (5) | Neg (1) | Neg (1) | Neg (5) | 1.0 (3) | |
S.D. | 0.6 | 0.012 | 7.0 (2) | + (4) | TRC (4) | + (3) | 2.0 (2) | ||||||
N= | 5 | 5 | 7.5 (2) | ++ (1) | |||||||||
1000 | Mean | 4.5 | 1.051 | yellow (5) | clear (4) | 6.0 (2) | Neg (1) | Neg (5) | Neg (5) | Neg (2) | Neg (5) | 0.2 (1) | |
S.D. | 2.6 | 0.014 | SL CL (1) | 6.5 (2) | TRC (3) | + (3) | 1.0 (4) | ||||||
N= | 5 | 5 | 7.0 (1) | + (1) | |||||||||
URINE VOLUME AND SPECIFIC GRAVITY VALUES ARE MEAN AND S.D. FOR THE SPECIFIED NUMBER (N) OF ANIMALS.ALL OTHER DATA TABULATED AS NUMBER OF ANIMALS (N) WITH THE STATED VALUE.DK.YE=DARK YELLOW SL CL=SLIGHTLY CLOUDY EU/DL=EHRLICH UNITS/DECILITERNEG=NEGATIVE TRC=TRACE +=SMALL ++=MODERATE +++=LARGE
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Dose(mkd) | UrineVolume(ml) | SpecificGravity | Color | Appear | pH | Protien | Glucose | Ketones | Bilirubin | Blood | Urobilinogen(eu/dl) | ||
0 | Mean | 5.4 | 1.048 | yellow (5) | clear (5) | 7.0 (1) | + (5) | Neg (5) | TRC (4) | Neg (4) | Neg (5) | 1.0 (5) | |
S.D. | 1.0 | 0.009 | 7.5 (1) | + (1) | + (1) | ||||||||
N= | 5 | 5 | 8.0 (3) | ||||||||||
100 | Mean | 4.1 | 1.056 | yellow (5) | clear (4) | 7.5 (3) | + (5) | Neg (5) | TRC (2) | Neg (2) | Neg (5) | 1.0 (4) | |
S.D. | 1.0 | 0.006 | SL CL (1) | 8.0 (2) | + (3) | + (3) | 2.0 (1) | ||||||
N= | 5 | 5 | |||||||||||
300 | Mean | 4.3 | 1.055 | yellow (5) | clear (3) | 7.0 (4) | + (4) | Neg (5) | TRC (5) | Neg (4) | Neg (5) | 1.0 (5) | |
S.D. | 0.8 | 0.008 | SL CL (2) | 7.5 (1) | ++ (1) | + (1) | |||||||
N= | 5 | 5 | |||||||||||
1000 | Mean | 6.1 | 1.050 | yellow (5) | clear (5) | 6.5 (4) | + (5) | Neg (5) | Neg (4) | Neg (5) | Neg (5) | 1.0 (5) | |
S.D. | 1.3 | 0.008 | 7.0 (1) | TRC (1) | |||||||||
N= | 5 | 5 |
MALES | FEMALES | |||||||
0 | 100 | 300 | 1000 | 0 | 100 | 300 | 1000 | |
MKD | MKD | MKD | MKD | MKD | MKD | MKD | MKD | |
Number of Animals on Study | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
Number of Animals Completed | (5) | (5) | (5) | (5) | (5) | (5) | (5) | (5) |
STOMACH | ||||||||
Submitted | (5) | (5) | (5) | (5) | (5) | (5) | (5) | (5) |
No Visible Lesions | 5 | 5 | 5 | 0 | 5 | 5 | 5 | 0 |
Thickened; Limiting Ridge | 0 | 0 | 0 | 5 | 0 | 0 | 0 | 5 |
Table 6: Histopathological Observations
MALES | FEMALES | |||||||
0 | 100 | 300 | 1000 | 0 | 100 | 300 | 1000 | |
Number of Animals on Study | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
Number of Animals Completed | (5) | (5) | (5) | (5) | (5) | (5) | (5) | (5) |
KIDNEYS | ||||||||
Examined | (5) | (5) | (5) | (5) | (5) | (5) | (5) | (5) |
Within Normal Limits | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Degeneration; Tubule; Focal | (1) | (1) | (1) | (0) | (0) | (0) | (0) | (0) |
very slight | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
Degeneration; Tubule; Mulitfocal | (1) | (0) | (2) | (0) | (0) | (0) | (0) | (2) |
very slight | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 2 |
Dilatation; Tubule; Medulla; Focal | (0) | (0) | (1) | (0) | (0) | (2) | (0) | (0) |
very slight | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 0 |
Inflammation; Subacute to chronic; Interstitium; Focal | (0) | (0) | (0) | (1) | (0) | (1) | (0) | (0) |
very slight | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
Inflammation; Subacute to chronic; Interstitium; Mulitfocal | (0) | (0) | (0) | (0) | (0) | (0) | (0) | (1) |
very slight | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Mineralization; Tubule; Medulla; Multifocal | (5) | (5) | (5) | (5) | (5) | (5) | (5) | (5) |
very slight | 5 | 5 | 3 | 0 | 5 | 5 | 4 | 1 |
slight | 0 | 0 | 2 | 5 | 0 | 0 | 1 | 4 |
STOMACH | ||||||||
Examined | (5) | (5) | (5) | (5) | (5) | (5) | (5) | (5) |
Within Normal Limits | 5 | 5 | 0 | 0 | 4 | 5 | 2 | 0 |
Dilatation; gland; glandular mucosa; focal | (0) | (0) | (0) | (1) | (0) | (0) | (0) | (0) |
very slight | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Edema; limiting ridge; nonglandular mucosa | (0) | (0) | (3) | (5) | (1) | (0) | (0) | (3) |
very slight | 0 | 0 | 3 | 2 | 0 | 0 | 0 | 2 |
slight | 0 | 0 | 0 | 3 | 1 | 0 | 0 | 1 |
Hyperplasia; neck mucous cell; glandular mucosa | (0) | (0) | (5) | (5) | (0) | (0) | (3) | (5) |
very slight | 0 | 0 | 5 | 0 | 0 | 0 | 3 | 0 |
slight | 0 | 0 | 0 | 5 | 0 | 0 | 0 | 5 |
Hyperplasia; epithelial; limiting ridge; nonglandular mucosa | (0) | (0) | (2) | (5) | (0) | (0) | (0) | (5) |
very slight | 0 | 0 | 2 | 5 | 0 | 0 | 0 | 3 |
slight | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Inflammation; subacute; glandular mucosa; multifocal | (0) | (0) | (0) | (3) | (0) | (0) | (0) | (2) |
very slight | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 2 |
Inflammation; subacute; limiting ridge; nonglandular mucosa | (0) | (0) | (2) | (5) | (1) | (0) | (0) | (3) |
very slight | 0 | 0 | 2 | 4 | 1 | 0 | 0 | 2 |
slight | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
Table 7:Text Table 5. Selected Final Body and Organ Weights
Sex | MALES | |||
Dose (mg/kg/day) | 0 | 100 | 300 | 1000 |
Final Body wt (g) | 216.4 | 208.1 | 211.4 | 210.2 |
Heart (g) | 0.737 | 0.664a | 0.682 | 0.732 |
Kidneys (g/100) | 0.715 | 0.724 | 0.751 | 0.775* |
Sex | FEMALES |
|||
Dose (mg/kg/day) | 0 | 100 | 300 | 1000 |
Final Body wt (g) | 134.5 | 135.4 | 136.0 | 131.9 |
Heart (g) | 0.519 | 0.505 | 0.487a | 0.483a |
Heart (g/100) | 0.386 | 0.373 | 0.358a | 0.366a |
Kidneys (g/100) | 0.793 | 0.777 | 0.789 | 0.833* |
Spleen (g/100) | 0.277 | 0.273 | 0.276 | 0.298a |
*Statistically different from control mean, males and females analyzed together, by Dunnett’s test,
alpha = 0.05.
a Statistically different from control mean, males and females analyzed separately, by Dunnett’s test, alpha
=0.05
Bold type indicates the effects judged to be treatment related.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, based on histopathological changes in the stomach and kidney of males and females given 300 and 1000 mg/kg/day, the no-observed-effect level (NOEL) for HEMA phosphate in F344/DuCrl rats of either sex was 100 mg/kg/day.
- Executive summary:
The purpose of this study was to evaluate the potential toxicity of reaction product of 2 -hydroxyethyl methacrylate (HEMA) and polyphosphoric acid (PPA), hereafter referred to as HEMA phosphate, in rats following oral gavage administration for 28 days. Five male and five female F344/DuCrl rats per group were administered 0, 100, 300, or 1000 milligrams HEMA phosphate per kilogram body weight per day (mg/kg/day, mkd) in propylene glycol (PG) via gavage. Parameters evaluated were daily cage-side and clinical observations, weekly detailed clinical observations, ophthalmic examinations, body weights/body weight gains, feed consumption, hematology, prothrombin time, urinalysis, clinical chemistry, selected organ weights, gross and histopathological examinations.
There were no treatment-related effects in clinical signs, body weights, feed consumption, ophthalmic examinations, or prothrombin time for any treatment group. Males and females given 1000 mg/kg/day had marginal treatment-related decreases in hematocrit, red blood cell counts and hemoglobin levels along with associated increases in reticulocyte counts. In addition there were slight treatment-related decreases in total protein and albumin levels in these dose groups. Serum total bile acid levels in males given 1000 mg/kg/day were higher than the controls and statistically identified; however, this was interpreted to be of questionable toxicological significance due to lack of any associated treatment-related liver histopathological effects or change in liver enzymes. Males given 1000 mg/kg/day had a treatment-related higher incidence of lower urine pH (6.5) as compared to the controls, possibly due to the excretion of the test material and/or its metabolites in the urine.
There were no treatment-related effects on hematology, clinical chemistry or urinalysis parameters for males or females in the 100 or 300 mg/kg/day dose groups. Treatment-related organ weight effects were limited to the 1000 mg/kg/day group and consisted of increased relative kidney weights in both sexes, and an increased relative spleen weight in females only. There were no treatment-related organ weight effects in either sex in the 100 or 300 mg/kg/day dose groups.
Treatment-related gross pathological observations were limited to the stomach of males and females given 1000 mg/kg/day and consisted of a slight thickening of the limiting ridge. Treatment-related histopathological effects were limited to the stomach and kidneys of males and females given 300 or 1000 mg/kg/day. In the stomach, treatment-related histopathological changes consisted of very slight or slight hyperplasia of the neck mucous cells of the glandular mucosa, for males and females in the 300 or 1000 mg/kg/day groups. A very slight subacute multifocal inflammation was also observed in the glandular mucosa of some of the males and females given 1000 mg/kg/day. Males and females given 1000 mg/kg/day and males given 300 or 1000 mg/kg/day had very slight or slight epithelial hyperplasia of the limiting ridge which was also accompanied by very slight or slight subacute inflammation and a very slight edema in the lamina propria underlying the epithelium. Histopathological changes in the stomach were interpreted to be due to localized, point of contact irritant effects due to the repeated oral gavage of the test material. In the kidneys of males and females given 300 or 1000 mg/kg/day, there was a marginal treatment-related increase in the degree of background mineralization of medullary tubules as compared to that observed in the controls.
There were no treatment-related gross or histopathological alterations for males and females given 100 mg/kg/day.
Under the conditions of this study, based on histopathological changes in the stomach and kidney of males and females given 300 and 1000 mg/kg/day, the no-observed-effect level (NOEL) for HEMA phosphate in F344/DuCrl rats of either sex was 100 mg/kg/day.
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