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EC number: 204-506-4 | CAS number: 121-91-5
- 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
- Study period:
- 1971-08-09
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 972
- Report date:
- 1972
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Repeated dose oral toxicity; administered in the diet.
- GLP compliance:
- no
- Remarks:
- Study performed prior to the inception of the Principles of GLP
- Limit test:
- no
Test material
- Reference substance name:
- Isophthalic acid
- EC Number:
- 204-506-4
- EC Name:
- Isophthalic acid
- Cas Number:
- 121-91-5
- Molecular formula:
- C8H6O4
- IUPAC Name:
- isophthalic acid
- Test material form:
- solid: crystalline
- Details on test material:
- - Name of test material (as cited in study report): Isophthalic acid
- Molecular formula (if other than submission substance): C6H4(COOH)2
- Physical state: white crystalline solid
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Isophthalic acid
- Molecular formula (if other than submission substance): C6H4(COOH)2
- Physical state: white crystalline solid
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Laboratory Derived Stock: The rats (Wistar derived) were selected from litters weaned at 28 days of age from the breeding colony. They were assigned to achieve equal sex and weight distribution.
- Housing: Individually in mesh bottom cages
- Diet ( ad libitum): Purina Laboratory Chow, prepared biweekly.
- Water (ad libitum): fresh tap water
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- Isophthalic acid was added to Purina Laboratory Chow at levels of 0.5, 1.6 and 5%. Diets were prepared biweekly and offered ad libitum.
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- no data
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily/continous - ad libitum in diet.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.5 other: % nomianl in diet
- Dose / conc.:
- 1.6 other: % nominal in diet
- Dose / conc.:
- 3 other: % nominal in diet
- Remarks:
- 5% nominal in the diet for the first week.
- No. of animals per sex per dose:
- 25 males and 25 females per dose
- Control animals:
- yes, plain diet
- Details on study design:
- Dose levels were initially chosen based on previously obtained data. The highest concentration was lowered from 5 % to 3 % after a one week exposure as it was felt that the rats would not survive for the full 13 week study at that dose.
After 30 and 60 days on test, 3 animals per sex per group were terminated and gross pathological examinations were performed. At 90 days of the study, all surviving animals were euthanized and submitted to detailed necropsies - Positive control:
- A positive control was not included - the study included two test compounds for a comparison of the results (dimethyl terephthalate and isophthalic acid).
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
Animals observed daily for any deviations from normal appearance or behaviour which would indicate an adverse effect of the treatments.
BODY WEIGHT: Yes
Body weight was recorded weekly
FOOD CONSUMPTION
Recorded Weekly
HAEMATOLOGY: Yes
Clinical determinations were made on 5 male and 5 female rats of each group prior to administration of the test materials and at 30, 60 and 90 days after initiation of the program. Haematology – total erythrocytes, haemoglobin, hematocrit, total and differential leukocyte counts
CLINICAL CHEMISTRY: Yes
Clinical determinations were made on 5 male and 5 female rats of each group prior to administration of the test materials and at 30, 60 and 90 days after initiation of the program. Biochemistry – blood urea nitrogen, blood glucose, serum alkaline phosphatase and serum glutamic pyruvic transaminase (SGPT).
URINALYSIS: Yes
Clinical determinations were made on 5 male and 5 female rats of each group prior to administration of the test materials and at 30, 60 and 90 days after initiation of the program. Urine – pH, specific gravity, qualitative tests for albumin, glucose, ketones, occult blood and microscopic examination of the centrifuged sediment.
OTHER: DETERMINATION OF PHTHALATES
Blood and urine samples were collected from representative rats in each group at 7, 30, 60 and 90 days after the initiation of test feeding. The urine samples were collected for 24 hours in a metabolism cage on the day prior to sacrifice and blood was obtained by cardiac puncture at autopsy. At the 7th and 90th day, 5 rats per sex per group were sacrificed. At the 30th and 60th day, 3 per sex per group were terminated.
Preparatory to analysis the blood samples were diluted with twice the volume of distilled water and the pH adjusted to 9.5 with NaOH. After complete haemolysis of the cells, the sample was dehydrated from the frozen state to provide a stable storage form until analysis could be completed. Urine samples were also adjusted to pH and freeze-dried.
Total phthalate content of the blood and urine samples were determined by a proprietary gas chromatographic method. Basically, the procedure depends on trans-esterification with trimethylphosphate in pyridine, extraction of the esters in chloroform and injection of an aliquot into a precalibrated gas chromatograph. A Model 7260 Hewlet-Packard Research chromatograph using the dual hydrogen flame detector and a 6 ft by 2 mm glass column packed with 3 % OV-101 on AWDMCS Chromosorb G. The column temperature was programmed at 15 °C rise per minute starting at 110 ° and ending at 265 °C with a 4 minute hold. The injection port temperature was 290 °C and the detector was maintained at 295 °C. The helium flow was 60 mL per minute. Under these conditions, the internal standard peak appeared at 2.9 minutes and the phthalate peaks at 7.8. Column calibration was done with the same test materials fed to the animals. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
After 30 and 60 days on test, 3 animals per sex per group were terminated and gross pathological examinations were performed. At 90 days of the study, all surviving animals were euthanized and submitted to detailed necropsies. The organs examined were liver, spleen, stomach, small and large intestine, pancreas, kidney, ureters, urinary bladder, adrenals, gonads, thyroid, pituitary, thymus, salivary gland, lymph nodes, heart, lungs, bone marrow, skin, skeletal muscle, brain and eye. The following organs were weighed: liver, spleen, kidneys, heart, brain, gonads, adrenals, thyroid and pituitary. Subsequently, the organ to body weight and organ to brain weight ratios were calculated.
HISTOPATHOLOGY: Yes
Microscopic examinations were performed on the liver, spleen, stomach, small intestine, large intestine, pancreas, kidneys, ureters, urinary bladder, adrenals, gonads, thyroids, pituitary, thymus, salivary, gland, lymph nodes, heart, lungs, bone marrow, skin, skeletal muscle and brain from 3 animals per sex per group at 1 and 2 months and from 5 animals per sex per group after the 3 month examination. For the 2 and 3 month examinations, thymus, salivary gland and lymph nodes were deleted from the histopathological studies. In addition, histopathological examinations were made of the bladders of all animals sacrificed terminally as well as any tissues which appeared to be grossly abnormal at time of autopsy. - Other examinations:
- No other examinations reported.
- Statistics:
- No information available.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- : reduced at the highest dose level
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- slightly reduced at the highest dose level
- 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
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- haematuria, crystalluria
- 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):
- : increased kidney weights
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- kidney, bladder
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortalities occurred during the study.
BODY WEIGHT AND WEIGHT GAIN
Examination of the weight gains of all rats at the end of the first week made it appear unlikely that the 5% level would allow growth, or even survival of the rats. The dose level was therefore dropped to 3%.
FOOD CONSUMPTION AND COMPOUND INTAKE
There was no effects on food intake. Food efficiencies were slightly reduced in the high dose groups.
HAEMATOLOGY
Results of haematological examinations performed in these animals revealed no adverse responses associated with the ingestion of IA on total or differential leukocyte counts, total erythrocyte counts, haemoglobin or hematocrit levels.
CLINICAL CHEMISTRY
The results from the Blood chemistry investigations showed no adverse effects associated with the ingestion of IA on blood urea nitrogen, fasting blood glucose, serum glutamic pyruvic transaminase or serum alkaline-phosphatase levels.
URINALYSIS
No major differences were seen between the control and various test groups with regard to pH or specific gravity in either male or female rats. Qualitative tests for albumin, glucose and ketones were essentially similar among all groups of animals. However, microscopic sediment showed evidence of red blood cells in the urine of animals given IA. The incidence appeared to be somewhat higher among males than females. In addition, crystals apparently similar to the test materials were found in all groups of animals given IA. On the basis of this data, it is evident that the only clinical observation which may be correlated with the occurrence of the reported pathology was that of hematuria or crystalluria. It is apparent that while there is not a one-to-one correspondence between these two semi-qualitative observations, the tendency toward increasing frequency with time is obvious. There is also a general correlation with dosage.
ORGAN WEIGHTS
There was no striking effect on organ weights in any group at any time. However, the weight for all organs except kidneys was lowered. This is probably due to decreased body weights. The increase in kidney weight, although statistically significant (p<0.01) is not physiologically impressive.
GROSS PATHOLOGY
There was no notable gross pathology in any of the rats which could be associated treatment. The organs examined were liver, spleen, stomach, small and large intestine, pancreas, kidney, ureters, urinary bladder, adrenals, gonads, thyroid, pituitary, thymus, salivary gland, lymph nodes, heart, lungs, bone marrow, skin, skeletal muscle, brain and eye. The most remarkable finding arising from this series of examination was the complete absence of significant pathology in all tissues examined except the kidney and bladder. The incidence of renal and urinary bladder calculi found at autopsy has been summarised as a list of animal numbers having positive findings. Grossly, the stones occurred almost exclusively in the bladder with three exceptions and then only after 90 days on the test diets. They ranged in colour from off-white to dark brown and in size from fine sand to stones several millimetres in diameter. The bladder contents of all rats having calculi at 90 days have been retained in the laboratory and are available for subsequent examination or analysis if desired. It should be noted that the data in Table 6 is skewed by the fact that only 3 rats per sex were examined at the 30 and 60 day intervals. Nevertheless, it seems apparent that calculus formation was a relatively slow process and that it increased in frequency as the dose level increased. Aside from the urinary tract findings, there was no notable gross pathology in any of the rats which could be associated treatment.
HISTOPATHOLOGY:
No evidence of neoplastic change.
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 0.5 other: % in diet
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Bladder and/or kidney stones were seen in all treated groups of males
- Dose descriptor:
- NOAEL
- Effect level:
- 1.6 other: % in diet
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Bladder stones bodyweight effects and increased kidney weights at the highest concentration of 3%
Target system / organ toxicity
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 0.5 other: % in the diet
- System:
- urinary
- Organ:
- bladder
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Examination of the weight gains of all rats at the end of the first week made it appear unlikely that the 5% level would permit growth or even survival of rats fed with IPA. The 5 % level was then reduced to 3%.
Weight gains (all rats) and food consumption for weeks 1 and 13
Test Group |
Dose Level |
Males |
Females |
||||||
Week 1 |
Week 13 |
Week 1 |
Week 13 |
||||||
Net Gain |
Food Intake |
Net Gain |
Food Intake* |
Net Gain |
Food Intake |
Net Gain |
Food Intake* |
||
Control |
0 |
34 |
72 |
307 |
156 |
24 |
69 |
169 |
112 |
IPA |
Low |
31 |
80 |
290 |
163 |
28 |
74 |
180 |
127 |
Mid |
30 |
76 |
310 |
170 |
26 |
76 |
175 |
126 |
|
High** |
17 |
57 |
278 |
156 |
18 |
60 |
167 |
128 |
|
Control |
0 |
31 |
82 |
294 |
164 |
24 |
74 |
170 |
117 |
* Food intake for 13th Week only
** Dietary levels were 5.0 % for the 1stWeek and 3.0 % thereafter
All weights in grams.
Kidney weights
|
Male |
Female |
|||||||
Control |
Low |
Mid |
High |
Control |
Low |
Mid |
High |
||
1 month |
Kidney (g) |
2.32, 2.24 |
2.20 |
2.40 |
2.45 |
1.60, 1.50 |
1.61 |
1.69 |
1.66 |
Kidney (%) |
0.89, 0.93 |
0.92 |
0.93 |
1.02 |
0.94, 0.88 |
0.92 |
0.95 |
0.98 |
|
Kidney (%brain) |
1.40, 1.33 |
1.30 |
1.50 |
1.36 |
1.01, 1.04 |
1.03 |
1.11 |
1.07 |
|
2 months |
Kidney (g) |
2.55, 2.81 |
2.31 |
2.67 |
2.13 |
1.66, 1.81 |
1.68 |
1.77 |
1.65 |
Kidney (%) |
0.82, 0.90 |
0.77 |
0.85 |
0.80 |
0.80, 0.83 |
0.83 |
0.89 |
1.01 |
|
Kidney (%brain) |
1.49, 1.57 |
1.53 |
1.60 |
1.25 |
1.02, 1.07 |
1.02 |
1.11 |
1.08 |
|
3 months |
Kidney (g) |
2.76. 2.79 |
2.60** |
2.91** |
2.73 |
1.89, 1.94 |
2.14 |
2.04 |
2.12 |
Kidney (%) |
0.75, 0.76 |
0.75 |
0.80 |
0.80 |
0.83, 0.85 |
0.90 |
0.88 |
0.95** |
|
Kidney (%brain) |
1.49, 1.51 |
1.44 |
1.61 |
1.48 |
1.13, 1.13 |
1.25 |
1.21 |
1.25 |
Identification of Animals Showing Urinary Occult Blood
Level |
30 Days |
60 Days |
90 Days |
Males |
|||
None |
- |
- |
- |
IPA, Low |
- |
- |
- |
IPA, Mid |
11135 |
11037 |
- |
IPA, High |
- |
11162 |
11169 |
None |
- |
- |
- |
|
Females |
||
None |
- |
- |
11233 |
IPA, Low |
- |
- |
- |
IPA, Mid |
- |
- |
- |
IPA, High |
- |
- |
11395 |
None |
- |
- |
- |
- = No animals displayed symptoms
Identification of Animals Showing Urinary RBCs in Centrifuged Sediment
Level |
30 Days |
60 Days |
90 Days |
Males |
|||
None |
- |
- |
- |
IPA, Low |
- |
- |
- |
IPA, Mid |
11129, 11135, 11137 |
11137 |
11146 |
IPA, High |
11160, 11162 |
11162 |
11169 |
None |
- |
- |
- |
|
Females |
||
None |
- |
- |
- |
IPA, Low |
- |
- |
- |
IPA, Mid |
- |
- |
- |
IPA, High |
- |
- |
11395 |
None |
- |
- |
11433 |
- = No animals displayed symptoms
Crystalluria does occur occasionally in normal urine. This became a constant finding by the 60thday, although it was not observed at the first urine collection period at 30 days. Microscopically, the crystals did not resemble any of the normal sedimentary components of rat urine but appeared grossly similar to the test materials. This finding did not correlate closely with the appearance of red blood cells or occult blood.
Blood levels of the test compounds were determined as total phthalate after trans-esterification and temperature programmed gas chromatography as described earlier. The average values obtained at each experimental period are summarised in the table below. The most striking feature of this data is the correlation with dose level with respect to both blood concentration and urinary output. At the low and middle dose levels, blood values of IA remained fairly constant or tended to decrease whereas the corresponding urinary outputs remained constant or tended to increase. At the high dosage level, IA tended to decrease in blood and increase in urine output concurrently. At the moderate levels of intake, the compounds achieve a steady state or equilibrium condition with respect to metabolism and/or excretion. However, faced with an overload, it appears that the rat may respond by utilizing an alternate pathway which may even involve enzyme induction or at least different intermediate steps in the degradation of the phthalate molecule. It should be noted that any reactions which would lead to partially decarboxylated metabolites would go undetected by the analytical methods employed for the blood and urine determinations.
Phthalate Blood Levels
Level |
7 day2 |
30 day3 |
60 day3 |
90 day2 |
||||
Males |
Females |
Males |
Females |
Males |
Females |
Males |
Females |
|
None |
- |
- |
ND |
ND |
ND |
ND |
ND |
ND |
IPA Low |
- |
- |
8.75 |
7.51 |
26.0 |
27.1 |
3.4 |
ND |
IPA Mid |
29.0 |
37.1 |
16.3 |
25.3 |
9.6 |
24.6 |
17.5 |
21.3 |
IPA High |
97.5 |
114.0 |
32.0 |
30.0 |
17.9 |
31.2 |
26.3 |
40.8 |
None |
- |
ND |
ND |
ND |
ND |
ND |
ND |
ND |
Rats were not fasted before blood drawing
2 – Average of five rats per sex per group
3 – Average of 3 rats per sex per group
ND = None detected at sensitivity of 5.0 mcg per ml.
Incidence of kidney (K) and urinary bladder (B) calculi at necropsy
Level |
30 Daya |
60 Daya |
90 Days |
|||
Kidney |
Bladder |
Kidney |
Bladder |
Kidney |
Bladder |
|
Males |
||||||
None |
- |
- |
- |
- |
- |
- |
IPA Low |
11087 |
- |
- |
- |
- |
11118 |
IPA Mid |
- |
- |
- |
- |
- |
11144 |
IPA High |
|
- |
- |
11175 |
- |
11153 11162 |
None |
- |
- |
- |
- |
- |
- |
Females |
||||||
None |
- |
- |
- |
- |
- |
- |
IPA Low |
- |
- |
- |
- |
- |
- |
IPA Mid |
- |
- |
- |
- |
- |
- |
IPA High |
- |
- |
- |
- |
11385 |
- |
None |
- |
- |
- |
- |
- |
- |
A= 3 rats per sex
Applicant's summary and conclusion
- Conclusions:
- Findings in this study were limited to reduced weight gain at the highest dose level, with haematuria, crystalluria and associated increases in kidney weights seen in treated groups.
- Executive summary:
Groups of rats (25/sex) were administered isophthalic acid in the diet at dose levels of 0.5, 1.6 and 3% for up to 90 days. The highest dose level was reduced from 5% to 3% after one week due to effects on bodyweight. Animals were observed for mortality and clinical signs; bodyweights were recorded at intervals. Blood samples were taken for the assessment of clinical chemistry and haematological parameters; urinalysis was also performed. Animals were investigated at necropsy (30, 60 and 90 days) for gross and microscopic findings; organ weights were also recorded. Blood levels of phthalates were also investigated.
No deaths occurred and there were no signs of toxicity. Bodyweights were markedly reduced at the highest dose level of 5/3%. No effects were seen on haematological and clinical chemistry parameters; urinalysis revealed the presence of red blood cells and crystals in the urine of treated animals. Findings were associated with increased kidney weights but did not have any gross or microscopic pathological correlates. A LOAEL of 0.5% (5000 ppm, equivalent to 500 mg/kg bw/d) can be determined for male rats in this study, based on the incidence of bladder/kidney stones in all treated groups. A LOAEL of 1.6% (16000 ppm, equivalent to 1600 mg/kg bw/d) can be determined for female rats in this study based on the incidence of bladder stones, bodyweight effects and kidney weight effects at the highest dose level.
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