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EC number: 220-482-8 | CAS number: 2781-11-5
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- publication
- Title:
- Hepatic changes in rats following subchronic administration of fyrol 6, an organophosphorus ester flame retardent
- Author:
- Katz AC et al.
- Year:
- 1 988
- Bibliographic source:
- J. Toxicol. Environ. Health 23: 295-301
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted in 1981
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Diethyl bis(2-hydroxyethyl)aminomethylphosphonate
- EC Number:
- 220-482-8
- EC Name:
- Diethyl bis(2-hydroxyethyl)aminomethylphosphonate
- Cas Number:
- 2781-11-5
- Molecular formula:
- C9H22NO5P
- IUPAC Name:
- diethyl {[bis(2-hydroxyethyl)amino]methyl}phosphonate
- Test material form:
- not specified
- Details on test material:
- - Purity: 90.7 %
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source of test material: Stauffer Chemical Company, Westport, USA
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability under test conditions: stable at room temperature
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Not reported
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, USA
- Age at study initiation: 6 weeks
- Housing: individually in suspended polycarbonate cages (20.3 x 17.8 x 17.8 cm) with hardwood chip bedding
- Diet: Purina Certified Rodent Chow 5002 ad libitum (except when fasted overnight prior to taking blood samples)
- Water: ad libitum
- Acclimation period: 2 weeks
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Not reported
- Vehicle:
- corn oil
- Details on oral exposure:
- - Dose volume: 5 mL/kg bw
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- No details reported
- Duration of treatment / exposure:
- 13 weeks (control and test groups)
- Frequency of treatment:
- once daily, 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 22 rats per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: not reported
- Rationale for animal assignment (if not random): random
- Fasting period before blood sampling for clinical biochemistry: none
- Dose range finding studies: not reported
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: during quarantine, at study midpoint and study termination
- Animals fasted: Yes
- How many animals: 20 animals (10 rats per sex) for midpoint analysis; all 176 animals (88 rats per sex) during quarantine and at study termination
- Complete hematology profiles were determined
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study midpoint and study termination
- Animals fasted: Yes
- How many animals: 20 animals (10 rats per sex) for midpoint analysis; all 176 animals (88 rats per sex) during quarantine and at study termination
- Complete clinical chemistry profiles (incl. plasma and erythrocyte cholinesterase assays) were determined
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No
OTHER:
- - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- Brain acetylcholinesterase activity was measured for 10 rats in each group. Absolute and relative organ weights of liver, kidneys, heart, gonads, brain and adrenals of all animals were determined.
- Statistics:
- Body weight, food consumption, absolute and relative organ weights, hematology and clinical chemistry were analyzed statistically by a one-way analysis of variance and Dunnett's t-test. Results between groups were considered statistically significant when p < 0.05.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Dehydration, diarrhea, skin abrasions, minor hair loss, chromodacryorrhea and chromorhinorrhea were observed. The incidences of these symptoms were similar in control and treated rats.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Necropsy findings showed deaths to be dosing accidents related to gavage administration.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg bw: relative kidney and liver weights were significantly increased in females
500 mg/kg bw: absolute and relative kidney and liver weights were increased in males and females
See table 1 in "any other information on results incl. tables" for details - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg bw: hepatocellular hypertrophy (3/17 males and 1/20 females), increased eosinophilia of centrilobular hepatocytes (1/17 males)
500 mg/kg bw: hepatocellular hypertrophy (10/21 males and 6/16 females); increased eosinophilia in centrilobular hepatocytes (12/21 males); hepatocellular hypertrophy (48% of males and 38% of females); 40% increase in cross-sectional area of male livers compared to controls (see table 2 in "any other information on results incl. tables" for details) - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Details on results:
- No treatment-related mortality and few signs of toxicity were noted during the study. The test material did not inhibit plasma, erythrocyte, or brain cholinesterase activities and treatment-related necropsy and microscopic alterations were restricted to the liver. Increased liver weights, hepatocellular hypertrophy, and eosinophilia of centrilobular hepatocytes were evident in 100 mg/kg females and in both sexes at 500 mg/kg. Morphometric analysis revealed a 40% increase in cross-sectional area of individual hepatocytes in 500 mg/kg males compared to controls. Morphologic evidence of hepatic necrosis or clinical evidence of liver dysfunction was not observed.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Dose descriptor:
- LOAEL
- Effect level:
- > 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1: Effect of test material on absolute and relative kidney and liver weights
|
|
Liver weight* |
Kidney weight* |
||
Test material conc. (mg/kg bw) |
Sex |
Abs. (g) |
Rel. |
Abs. (g) |
Rel. |
0 |
M |
16.05 ± 2.32 |
3.02 ± 0.30 |
2.89 ± 0.24 |
0.55 ± 0.05 |
F |
7.57 ± 0.96 |
2.70 ± 0.19 |
1.62 ± 0.18 |
0.60 ± 0.06 |
|
20 |
M |
15.84 ± 2.07 |
2.95 ± 0.30 |
2.94 ± 0.29 |
0.55 ± 0.05 |
F |
7.41 ± 0.83 |
2.76 ± 0.16 |
1.68 ± 0.15 |
0.63 ± 0.06 |
|
100 |
M |
16.19 ± 1.91 |
3.05 ± 0.31 |
3.05 ± 0.35 |
0.58 ± 0.06 |
F |
8.01 ± 1.01 |
2.93 ± 0.31** |
1.84 ± 0.18 |
0.67 ± 0.08** |
|
500 |
M |
18.45 ± 2.99** |
3.44 ± 0.32** |
3.26 ± 0.45** |
0.61 ± 0.07 |
F |
9.41 ± 1.80** |
3.47 ± 0.24** |
2.09 ± 0.24** |
0.78 ± 0.07** |
*: mean ± standard deviation (n = 16-21)
**: significantly different from mean of untreated control (0 mg/kg bw) for the same sex (p < 0.05)
Relative weight = organ weight/body weight x 100
Table 2: Comparison of cross-sectional area measured for individual liver cells in rats treated with test material and control rats
Treatment |
Animal no. |
Number of cells measured |
Mean cross-sectional area |
Group mean± SD |
Control (corn oil) |
1 |
50 |
494.4 |
424.2 ± 41.8 |
2 |
50 |
425.8 |
||
3 |
50 |
412.4 |
||
4 |
50 |
387.0 |
||
5 |
50 |
401.4 |
||
test material (500 mg/kg) |
6 |
50 |
587.1 |
595.8* ± 35.6 |
7 |
50 |
631.1 |
||
8 |
50 |
568.3 |
||
9 |
50 |
635.1 |
||
10 |
50 |
557.6 |
*: p < 0.05
Applicant's summary and conclusion
- Conclusions:
- In conclusion, test item treatment resulted in measurable effects upon rat liver and kidney. These effects were indicative of an adaptive rather than a toxic response (NOAEL = 500 mg/kg bw/day; highest dose tested). No evidence of a treatment-related alteration was found in rats given the lowest dose (NOEL = 20 mg/kg bw/day).
- Executive summary:
The subchronic oral toxicity was determined using 22 rats/sex/group treated by gavage daily for three months at doses of 0, 20, 100 or 500 mg/kg bw/day.
No treatment-related changes were found with respect to body weights, food consumption, clinical signs or urinalysis. Certain hematological and clinical chemistry changes occurred in mid and/or high dose groups.
The hematology changes included reductions in red blood cell count, hemoglobin concentration and hematocrit, as well as altered total and differential white blood cell counts. Clinical chemistry changes were altered electrolyte (Ca and K) levels and increased albumin and total protein. Although these changes were statistically significant, they were mild and considered to be within the range of normal variation.
Liver changes noted at mid and/or high dose levels were reported. These included very slight hepatocellular hypertrophy (males and females), cytoplasmic eosinophilia of centrolobular hepatocytes (males) and increased relative liver weights (males and females). These changes were considered to be minimal, reversible, and not representative of degenerative processes; this interpretation is supported by the fact that liver function in treated rats appeared normal based on serum enzyme levels. These morphologic findings are compatible with an adaptive response.
Relative kidney weights were increased in high dose males and mid and high dose females. However, no gross or microscopic kidney changes were noted. Based on serum BUN and creatinine levels, kidney function appeared normal in all treated groups. The findings with respect to the kidneys were not considered indicative of degeneration.
In conclusion, test item treatment resulted in measurable effects upon rat liver and kidney. These effects were indicative of an adaptive rather than a toxic response (NOAEL = 500 mg/kg bw/day; highest dose tested). No evidence of a treatment-related alteration was found in rats given the lowest dose (NOEL = 20 mg/kg bw/day).
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