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EC number: 209-506-8 | CAS number: 583-52-8
- Life Cycle description
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- Endpoint summary
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- 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
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- Toxicological Summary
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- Genetic toxicity
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- Specific investigations
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- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Study in Long-Evans rats, female and male, feeding study for 70 days, 0, 2.5, and 5% oxalic acid in feed corresponding to 1.98 g/kg bw in females and 1.78 g/kg bw in males and 5.3 g/kg bw in females and 5.2 g/kg bw in males, respectively. Parameters observed: Mortality, clinical signs, gross lesions at necropsy, organ weight. No NOAEL established. Dietary ingestion of 2.5% or 5.0% Oxalic acid over a 2 month interval resulted in marked depressions in growth rate, body weights, visceral, endocrine, and accessory reproductive tissue weights, particularly with the higher concentration. Inhibitory effects of Oxalic acid on gonadal, adrenal and thyroid activity may be indicated. 10% mortality in the 2% group and 25% mortality in the 5% group. read-across, WoE
Study in Long-Evans rats, female and male, feeding study for 70 days, 0, 2.5, and 5% oxalic acid in feed corresponding to 2.1 g/kg bw in females and 1.9 g/kg bw in males and 5.3 g/kg bw in both females and males, respectively. Observed effects: marked depression in rate of body weight gain, stunted appearance, devrease in thyroid weight,thyroidal uptake of 125I and the secretion of thyroidal hormones. NOEL is < 1.78 g/kg bw. read-across, WoE
NTP study in CD-1 mice, two generation study dose range-finding study for 14 days. Mice were administered 0, 0.25, 0.5, 1.0, 2.5, and 5.0% Oxalic acid in drinking water corresponding to 340 mg/kg(males) and 450 mg/kg (females), 590 mg/kg (males) and 690 mg/kg (females), 1060 mg/kg (males) and 1180 mg/kg (females), 1710 mg/kg (males) and 1570 mg/kg (females), and 3410 mg/kg (males) and 3680 mg/kg (females). Clinical signs of toxicity (rough hair coat and hunched back) were noted beginning day 6 of the dose range finding study in almost all animals in the 2.5 and 5.0% dose groups. Other than that, 1 animal in the 1.0% dose group also showed rough hair coat and hunched back from day 7 onwards.Except for 1 other male in the 0.25% dose group, there were no deaths in the, control or any of the remaining groups. Reduced water consumption from 0.25% upwards indicating dehydration at higher concentrations. Maximum dose applied in the main study (0.2%) 275 mg/kg bw. RL2, read-across, WoE
NTP study in CD-1 mice,Task 2 of the FACB protocol, i.e. continuous breeding phase, each 20 femal and male mice were exposed to 0, 0.05, 0.1, and 0.2% (0, 89, 162, and 275 mg/kg bw/day) oxalic acid in drinking water for at least 100 days. Up to 162 mg/kg bw/day no clinical signs of toxicity and no effects on fertility/reproduction and development were observed. The NOAEL was determined at 162 mg/kg bw/day. RL2, read-across, WoE
Supporting study: published data from treatment of pregnant Wistar rats with either 0.06, 0.05, or 0.03 g/rat/day Oxalic acid or (main study) to 0.035 and 0.045 g/rat/day to 5 and 10 animals, respectively. Animals were orally administered until parturition once daily. At the lowest dose no adverse effects were observed. Animals of the other treatment groups showed changes in the kidney caused by oxalate crystalls. Results from the preliminary study in foetuses could not be reproduced in the main study. Newborns and foetuses in the main study showed no alterations wihtin the kidney. No effectlevel was obtained, RL3, read-across, only supporting information.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- documentation insufficient for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: Pregnant rats were exposed to 0.035 g and 0.045 g oxalic acid per animal per day until parturition. All animals that died during the study were necropsied, furthermore selected tissues were fixed in formalin and stained either with hematoxylin-eosin or Roscher´s Ca-naphthalhydoxamate in order to detect calcium oxalate. During the study the effects on the respective litters were also observed.
- Short description of test conditions: Thirty adult female Wister rats bred seven days previously and weighing approximately 200 g were used. They were divided in three groups of ten animals with those in the first two groups receiving 0.5 ml solution of oxalic acid at 0.045 g and 0.035 g per head per day respectively. Each animal in the third group was dosed with 0.5 ml of normal saline. Dosing was done under ether anaesthesia once daily around 1.00 pm. Each animal was kept in a separate cage, fed commercial rat ration, with water available ad libitum throughout the course of the experiment. The weight of the animals was determined once daily at time of dosing. The physical condition of each animal was assessed each day.
All dams and their young were killed by inhalation of chloroform at the end of the experiment. These animals and those that died during the course of the experiment, any aborted foetus and all newborn were necropsied. Each foetus and newborn was carefully examined for gross anomalies. Selected tissues were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 6µ and stained with hematoxylin-eosin (H & E). Where indicated additional sections were treated with Pizzolato's Peroxide Silvers method (Pizzolato, 1964) and with Roscher's Ca-naphthalhydroxamate method (Roscher, 1971) for demonstration of calcium oxalate. All sections were examined under conventional and polarized light conditions.
- Parameters analysed / observed: Mortality, clinical signs of toxicity, histological changes - GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: n/a
- Weight at study initiation: 220g
- Fasting period before study: no
- Housing: Each animal was kept in a separate cage, fed commercial rat ration, with water available ad libitum throughout the course of the experiment.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not specified - Route of administration:
- oral: gavage
- Vehicle:
- physiological saline
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
two groups of ten animals each received Oxalic acid in normal saline at 0.045 and 0.035 g/head per day
VEHICLE
- Amount of vehicle (if gavage): 0.5 mL
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- Animals were exposed until parturition.
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0.045 other: mg/animal/day
- Dose / conc.:
- 0.035 other: mg/animal/day
- Dose / conc.:
- 0.03 other: mg/animal/day
- Remarks:
- pilot study
- Dose / conc.:
- 0.05 other: mg/animal/day
- Remarks:
- pilot study
- Dose / conc.:
- 0.06 other: mg/animal/day
- Remarks:
- pilot study
- No. of animals per sex per dose:
- pilot study: 5 animals per group
main study: 10 animals per group - Control animals:
- yes, concurrent vehicle
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes, daily
DETAILED CLINICAL OBSERVATIONS: Yes, daily
BODY WEIGHT: Yes, once daily at the time of dosing
OTHER: All dams and their young were killed by inhalation of chloroform at the end of the experiment. These animals and those that died during the course of the experiment, any aborted foetus and all newborn were necropsied. Each foetus and newborn was carefully examined for gross anomalies. Selected tissues were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 6µ and stained with hematoxylin-eosin (H & E). Where indicated additional sections were treated with Pizzolato's Peroxide Silvers method (Pizzolato, 1964) and with Roscher's Ca-naphthalhydroxamate method (Roscher, 1971) for demonstration of calcium oxalate. All sections were examined under conventional and polarized light conditions. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Pilot Study
Each animal developed anorexia, depression, rapid breathing and loss in body weight before death.
Principal Study
Two of the three that died were depressed, anorexic and breathing heavily before death. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Pilot Study
All ten animals in the two groups receiving the high and medium dose rates of oxalic acid (0.06 g and 0.05 g) died within seven days.
Principal Study
Three animals died during the study. The third animal died of an overdose of ether. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Pilot Study
The animals in the group receiving the lowest dose of oxalic acid (0.03 g) and in the control group, gained weight and did not show any signs of reluctance to eat.
Principal Study
With the exception of the two animals that died with gastritis and renal oxalosis and another in the low dose group, all animals gained weight. The mean weight gains for the high dose, low dose and control groups were 65.0 g, 51.5 g and 66.7 g, respectively. - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Pilot Study
At necropsy, the only remarkable gross findings in all animals were severe hemorrhagic gastritis and ballooned, mostly empty small intestine. A few animals had small amounts of blood in the small intestine.
Principal Study
From the treated groups, one each died with severe hemorrhagic gastritis and marked renal oxalosis on post-mortem examination.
At necropsy, four animals had hemorrhagic gastritis, three from the high dose group and one from the low dose group. Besides the presence of oxalate crystals in the gastric mucosa of the four animals with gastritis, oxalate crystals were demonstrated microscopically in the kidneys of 12 animals, seven in the high dose group and five in the low dose group. The amount of oxalate crystals in the kidney varied from very few to numerous. Animals in the the control group did not have any oxalate crystals in the kidney. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Pilot Study
No gross or histological lesions were noted in all animals in these two groups.
However, all the kidneys of the newborn in the treated group showed marked vacuolation of the cells of the proximal tubules and pyknotic as well as karyorrhectic nuclei. No oxalate crystals were demonstrated in these lesions, which were classified as tubulonephrosis. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Principal Study
Twelve animals were found to be not pregnant. Three belonged to the group receiving the high dose of oxalic acid, four to the low dose group and five to the control group. The mean birth weight of newborn in all groups was uniform but the mean litter size was higher in the control group, with 12.2 newborn per litter, than in treated groups at 7.1 and 8.8 respectively. Abortions did not occur, nor were any gross malformations observed in the foetuses and newborn. Neither tubulonephrosis nor oxalate crystals were observed histologically in the offspring. - Key result
- Dose descriptor:
- LOEL
- Effect level:
- 0.03 other: g/animal/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical signs
- gross pathology
- mortality
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 0.03 other: g/animal/day
- System:
- urinary
- Organ:
- intestine
- kidney
- stomach
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Conclusions:
- The study of Sheikh-Omar was conducted with female Wistar rats which were treated with either 0.06, 0.05, and 0.03 g Oxalic acid in aqueous solutions (Pilot study) or with 0.045 and 0.035 g Oxalic acid at the seventh day of breeding until parturition (Principle study) by stomach tube. Clinical signs and cage side observation were conducted daily and also the weight of the animals were recorded daily. All animals independent of spontaneous death or scheduled sacrifice were necropsied and check for gross abnormalties. selected tissues underwent histopathology. The response to oxalic acid in the rats in the principal study appeared to be dose dependent with renal oxalosis present in seven and five in the high and low dose groups respectively. A positive relationship is also apparent between the presence of hemorrhagjc gastritis and the severity of renal oxalosis. Further, a dose relationship may be postulated as an explanation of the difference in litter size. The high dose group had a mean litter size of 7.1, the low dose group a litter size of 8.8, as compared to the control group with 12.2. One can speculate that the oxalic acid interfered with nidation, causing early resorption of embryos, with no traces left at time of birth. The LOEL was determined at 0.03 g/animal/day based on the presented results.
- Executive summary:
This subacute toxicity study in Long Evans rats is acceptable as supporting information; although it does not satisfy the guideline requirement for a subacute oral study OECD 407 in rats due to the limited information reported.
The present study describes the effects of oxalic acid on growth, reproduction and the development of renal stomes/crystals. Female Wistar rats were exposed to 0.06, 0.05, and 0.03 g/animal/day (Pilot study) or 0.045 and 0.035 g/animal/day (Principal study) for approximately 20-22 days. The body weight and clinical signs were recorded in appropriate intervals. The litter size was determined. Histopathological examinations were made from kidney tissue (renal tubules) and gastric mucosa. Almost all animals gained weight during treatment. The litter size in the treatment groups was reduced. some animals showed oxalate crystals in the kidney which were absent in the offspring. These results indicate that Oxalic acid interferes with reproduction and causes renal stones in the rat.
acid. Based on these results the LOAEL of oxalic acid is considered to be 0.03 g/animal/day for female Wistar rats under the conditions of the test.
- 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
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- study conducted similar to 90-days repeated dose study, duration: 70-days, parameters observed: growth rate and body weight changes, Thyroid weight changes, Thyroid Radioiodine 125I uptake, and Plasma 125I Concentrations, Plasma TSH activity, 125I Distribution in Protein Hydrolysates of Thyroid Glands
- Deviations:
- yes
- Remarks:
- see Remarks
- Principles of method if other than guideline:
- - Principle of test:
subchronic oral repeated dose toxicity study, Feeding study in Long-Evans rats, duration 70 days
- Short description of test conditions:
Female Long-Evans rats (average 215 g) and male Long-Evans rats (average 225 g) of each sex were randomly divided into 3 groups which received, ad libitum, Purina laboratory chow supplemented respectively with 0, 2.5, and 5.0% oxalic acid mixed thoroughly into the ground diet, until necropsy.
- Parameters analysed / observed: Thyroid 125I uptake and distribution of 125I in protein hydrolysates from thyroid glands, Bioassay ofplasma TSH, Growth and body weight changes - GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Long-Evans
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: females average: 215 g, males average: 225 g
- Fasting period before study: no
- Housing: in three groups, number of animals per cage not reported
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Purina laboratory chow - Analytical verification of doses or concentrations:
- no
- Dose / conc.:
- 2.5 other: %
- Dose / conc.:
- 5 other: %
- No. of animals per sex per dose:
- females: Control: 12, 2.5% oxalic acid: 11, 5.0% oxalic acid: 10
males: Control: 12, 2.5% oxalic acid: 10, 5.0% oxalic acid: 10 - Control animals:
- yes, plain diet
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Not specified
BODY WEIGHT: Yes
- Time schedule for examinations: not reported
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: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Not specified
- Time schedule for collection of blood: at the end of the experimental time
- Anaesthetic used for blood collection: Not specified
- Animals fasted: No
CLINICAL CHEMISTRY: Not specified
URINALYSIS: Not specified
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Not specified
HISTOPATHOLOGY: Not specified - Statistics:
- The data were subjected to one-way analysis of variance, and the significance between means was determined by Duncan's multiple range. A p value < 0.01 was considered statistically significant.
- Clinical signs:
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The average weight gains in the groups receiving 2.5% oxalic acid, both male and female, were less than that observed in their respective control groups while a dramatic and steady reduction in body weight occurred in the groups of male and female rats ingesting 5.0% oxalic
acid. Moreover, the average cumulative weight gain for the control groups on the nonsupplemented Purina laboratory chow was approximately twice that observed in the groups on 2.5 % oxalic acid for both male and female rats; the groups receiving 5.0% oxalic acid showed a marked depression in rate of body weight gain. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- No significant difference in either water or food intake was observed in the control group and the groups receiving 2.5% dietary
oxalic acid either in male or female rats. However, both water and food intake were significantly increased in male and female rats ingesting 5.0% oxalic acid in the diet compared to male and female rats of the control group. - Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- Dietary ingestion of oxalic acid was determined from the food intake as 2.1 and 1.9 g/kg body weight/day, respectively, for female and male rats receiving 2.5 % oxalic acid in the diet and 5.3 g/kg/day for both female and male rats receiving 5.0 % oxlaic acid in the diet.
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- A significant decrease in thyroid weight (p< 0.01) was observed in both female and male Long-Evans rats that had ingested
5.0% oxalic acid . Although the absolute organ weights for the thyroid glands of male and female rats treated with 5.0% oxalic acid were reduced, the relative thyroid weights were significantly increased in all animals treated with 2.5 or 5.0% oxalic acid due to the severe depression
of body weight gain. - Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 1 900 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 900 mg/kg bw/day (nominal)
- System:
- endocrine system
- Organ:
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- no
- Relevant for humans:
- not specified
- Conclusions:
- This subchronic toxicity study in Long Evans rats is acceptable as supporting information; although it does not satisfy the guideline requirement for a subchronic oral study OECD 408 in rats due to the limited information reported and the limited and rather high applied doses.
The present study describes the effects of oxalic acid on growth rate and reproduction. Female and male Long Evans rats were exposed to 2.5% and 5.0% oxalic acid in normal laboratory chow (feeding study) for 70 days. The body weight, food and water consumption as well as clinical signs were recorded in appropriate intervals to determine the doses of oxalic acid that were ingested. Animals wre administered 125I and 24 h later the thyroid gland was removed and subsequently the uptake of 125I was determined as well as Plasma TSH level. Oxalic acid decreased the body weight remarkably in both groups. Thyroid weight was also significant decreased. 125I uptake was decreased and plasma TSH level increased. These result indicate that Oxalic acid interferes with thyroid function.
acid. Based on these results the LOAEL of oxalic acid is considered to be 1900 mg/kg bw for male and female Long Evans under the conditions of the test. - Executive summary:
In a study similar to a subchronic toxicity study (OECD guideline 408) Oxalic acid was applied to 10 Long Evans rats/sex/dose in diet at dose levels of 2.5 % and 5 % (2100 mg/kg bw/day for females and 1900 mg/kg bw/day for males of the 2.5 % group and 5300 mg/kg bw/day for females and males of the 5 % group).
The LOAEL is 2.5 % Oxalic acid, based on depression in body weight, growth rate, visceral weights, and endocrine weights, in rats on 2.5% oxalic acid.
The NOAEL could not be determined.
This subchronic toxicity study in Long Evans rats is acceptable as supporting information; although it does not satisfy the guideline requirement for a subchronic oral study OECD 408 in rats due to the limited information reported and the limited and rather high applied doses.
- 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Duration of the exposure was 70 days, feeding study with focus on growth and reproduction
- Principles of method if other than guideline:
- - Principle of test:
subchronic oral repeated dose toxicity study, Feeding study in Long-Evans rats, duration 70 days
- Short description of test conditions: Female Long-Evans rats (213 - 217 g) and male Long-Evans rats (250 - 259g) of each sex were randomly divided into 3 groups which received, ad libitum, Purina laboratory chow supplemented respectively with 0, 2.5, and 5.0% oxalic acid mixed thoroughly into the ground diet, until necropsy.
- Parameters analysed / observed: Daily intakes of food and water were noted, body weights were obtained and vaginal smears were examined daily. At necropsy, a number of visceral and endocrine tissues were removed, cleaned and weighed. Some ovaries and testes from each group were fixed and histological sections were made.. - GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Long-Evans
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
The source was not reported
- Weight at study initiation:
females (213-217 g), males (250-259 g)
- Fasting period before study:
No, the test item was mixed with Purina laboratory chow and provided until necropsy
- Housing:
not reported
- Diet (e.g. ad libitum):
ad libitum, Purina laboratroy chow
- Water (e.g. ad libitum):
ad libitum
ENVIRONMENTAL CONDITIONS
Not reported - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): not reported, the test item was provided via feed until necropsy
- Mixing appropriate amounts with (Type of food): Purina laboratory chow
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 70 days
- Frequency of treatment:
- daily ad libitum
- Dose / conc.:
- 2.5 other: %
- Dose / conc.:
- 5 other: %
- No. of animals per sex per dose:
- approximately 10: females: control-group: 12, 2.5% oxalic acid-group: 11, 5% oxalic acid-group: 10; males: control group: 12, 2.5% oxalic acid-group: 11, 5% oxalic acid-group: 9
- Control animals:
- yes, plain diet
- Details on study design:
- - Other: The present study was undertaken to determine the influence of chronic exposure to dietary ingestion of large quantities of oxalic acid in maintenance of growth and reproductive function in rats of both sexes.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
daily
DETAILED CLINICAL OBSERVATIONS: Not specified
BODY WEIGHT: Yes
- Time schedule for examinations:
in appropriate intevals
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
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 (if drinking water study): Yes
- Time schedule for examinations:
daily
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes, Some ovaries and testes from each group were fixed in Bouin's solution and histological sections were made at 6µ and stained with hematoxylin-eosin. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals in the groups receiving 5.0% oxalic acid appeared emaciated, stunted, gaunt with arched backs
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Dietary ingestion of 5.0% oxalic acid caused a mortality rate of 25% but less than 10% in the 2.5% oxalic acid groups.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- depression in body weight and growth rate (table 1) in both treatment groups but more pronounced in the 5.0% group
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Both food ingestion and water intake were markedly increased in the groups ingesting 5.0% oxalic acid (see table 1)
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- increased water intake in the 5.0% groups
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry 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):
- reduced weights of endocrine organs and visceral weights. Kodneys of the 5.0% group rats were discoloured
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Kidneys of the 5.0% group rats were discoloured, brownish with roughened crinulated surfaces, abnormal notching on the edges and
small stones. Absence of body fat in the 5.0% oxalic acid groups was conspicuous while the adipose tissue normally adherent to visa
ceral and endocrine tissues was minimal. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histologically, ovarian tissue from rats ingesting 5.0% oxalic appeared dense, compact with small cells, absence of adipose tissue, depressed follicular
development, and dense compact interstitial tissue. Luteal cells contained dark, condensed, and shrunken nuclei. Testes tissue appeared compact with seminiferous tubules of small diameter containing immature Sertoli cells and spermatogonia with absence of mitoses. Decreased interstitial tissue was also observed in rats on 5.0% oxalic acid. Ovarian and testes tissue from rats on 2.5% oxalic acid showed effects similar to but not as intense as that
observed in rats ingesting 5.0% oxalic acid. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Vaginal smears indicated the existence of prolonged diestrus in rats ingesting 5.0% oxalic acid with some diestrus and persistsnt vaginal cornification in rats on 2.5% oxalic acid.
- Key result
- Dose descriptor:
- LOEL
- Effect level:
- 1 980 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- mortality
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- LOEL
- Effect level:
- 1 780 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- mortality
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 780 mg/kg bw/day (nominal)
- System:
- endocrine system
- Organ:
- adrenal glands
- kidney
- spleen
- testes
- thyroid gland
- uterus
- Treatment related:
- yes
- Conclusions:
- The present study describes the effects of oxalic acid on growth rate and reproduction. Female and male Long Evans rats were exposed to 2.5% and 5.0% oxalic acid in normal laboratory chow (feeding study) for 70 days. The body weight, food and water consumption as well as clinical signs were recorded in appropriate intervals to determine the doses of oxalic acid that were ingested. Subsequent to sacrifice the weights of the thyroid, adrenal gland, spleen, kideney, ovary, uteri, testes, prostates and seminal vehicles were determined. Oxalic acid decreased the visceral and endocrine organ weight remarkably in the 5.0% group and to a lesser extent in the 2.5% group. During histopathological examination the kidney appeared discolored, brownish with roughened crinulated surfaces, abnormal notching on the edges and small stones. ovarian tissue from rats ingesting 5.0% oxalic appeared dense, compact development, and dense compact interstitial tissue. Luteal cells contained dark, condensed, and shrunken nuclei. Testes tissue
appeared compact with seminiferous tubules of small diameter containing immature Sertoli cells and spermatogonia with absence of mitoses. Decreased interstitial tissue was also observed in rats on 5.0% oxalic acid. Ovarian and testes tissue from rats on 2.5% oxalic acid showed effects similar to but not as intense as that observed in rats ingesting 5.0% oxalic acid. Based on these results the LOEL of oxalic acid is considered to be 1780 mg/kg bw for male Long Evans rats and 1980 mg/kg bw for female Long Evans rats under the conditions of the test. - Executive summary:
In a study similar to a subchronic toxicity study (OECD guideline 408) Oxalic acid was applied to 10 Long Evans rats/sex/dose in diet at dose levels of 2.5 % and 5 % (1980 mg/kg bw/day for females and 1780 mg/kg bw/day for males of the 2.5 % group and 5300 mg/kg bw/day for females and 5200 mg/kg bw/day for males of the 5 % group).
The LOEL is 2.5 % Oxalic acid, based on depression in body weight, growth rate, visceral weights, and endocrine weights, persistent vaginal cornification and effects on testisin rats on 2.5% oxalic acid
The NOAEL could not be determined.
This subchronic toxicity study in Long Evans rats is acceptable as supporting information; although it does not satisfy the guideline requirement for a subchronic oral study OECD 408 in rats due to the limited information reported and the limited and rather high applied doses.
Referenceopen allclose all
Growth and Body Weight Changes
No significant difference in either water or food intake was observed in the control group and the groups receiving 2.5% dietary oxalic acid either in male or female rats. Both water and food intake were significantly increased in male and female rats ingesting 5.0% oxalic acid in the diet compared to male and female rats of the control group. Dietary ingestion of oxalic acid was determined from the food intake as 2.1 and 1.9 g/kg body weight/day, respectively, for female and male rats receiving 2.5 % oxalic acid in the diet and 5.3 g/kg/day for both female and male rats receiving 5.0% oxlaic acid in the diet. Dietary ingestion of oxalic acid for 70 days resulted in depression in growth in male and female rats in both groups given the chemical in the diet. The average weight gains in the groups receiving 2.5% oxalic acid, both male and female, were less than that observed in their respective control groups while a dramatic and steady reduction in body weight occurred in the groups of male and female rats ingesting 5.0% oxalic acid. Moreover, the average cumulative weight gain for the control groups on the non-supplemented Purina laboratory chow was approximately twice that observed in the groups on 2.5 % oxalic acid for both male and female rats; the groups receiving 5.0% oxalic acid showed a marked depression in rate of body weight gain. The latter animals showed severe emaciation and were stunted in appearance.
Thyroid Weight Changes, Thyroid Radio-iodine125I Uptake, and Plasma125IConcentrations
A significant decrease in thyroid weight (p<0.01) was observed in both female and male Long-Evans rats that had ingested 5.0% oxalic acid. This was associated with a marked reduction in 24-hr radioiodine uptake (p<0.01) in male and female rats ingesting 5.0% oxalic acid.
Plasma radioactivity was significantly reduced (p<0.01) in both male and female rats ingesting 2.5% or 5.0% oxalic acid. Although the absolute organ weights for the thyroid glands of male and female rats treated with 5.0% oxalic acid were reduced, the relative thyroid weights were significantly increased in all animals treated with 2.5 or 5.0% oxalic acid due to the severe depression of body weight gain.
Plasma TSH Acitivity
Ingestion of 2.5% oxalic acid resulted in a slight but non-statistical increase in plasma TSH. A significant increase (p<0.01) in plasma TSH, which was a three-fold increase above that observed in the control group, occurred in those animals ingesting 5.0% oxalic acid in the diet.
A significant increase in extent of thyroidal labeling of the monoiodotyrosine (MIT) was observed in both male and female rats ingesting 5.0% oxalic acid (p<0.01). The increase in thyroidal labeling in MIT was associated with a reduction in labeling of diiodotyrosine (DIT), with concomitant elevation in MIT: DIT ratios above those observed in the control groups. While no alteration in extent of labeling of the tetra-iodothyronine (T4) was observed, a significant elevation in labeling occurred in the iodo-thyronine (T3) in both male and female rats maintained on 5.0% oxalic acid (p<0.01).
The significant increase in labeling of T3 resulted in an increase in the T3 : T4 ratio above that of their control groups.
Table 1:
Group |
No. of rats |
body weight (g) |
Mean intake mL or g/100g bw per day |
Liver weight |
Spleen weight |
Kidney weight |
|||||
initial |
terminal |
food |
water |
g |
g/100g bw |
g |
g/100g bw |
g |
g/100g bw |
||
females |
|||||||||||
controls |
12 |
217.2 ± 1.6 |
273.0 ± 3.3 |
8.0 ± 0.3 |
23.7 ± 1.1 |
10.1 ± 0.21 |
3.7 ± 0.05 |
511.1 ± 22.7 |
187.2 ± 4.1 |
2.3 ± 0.03 |
0.84 ± 0.02 |
2.5% Oxalic acid |
11 |
216.4 ± 1.6 |
236.7 ± 3.1# |
7.9 ± 0.3 |
19.2 ± 1.0 |
7.9 ± 0.19# |
3.4 ± 0.04 |
538.7 ± 7.1 |
227.6 ± 1.3# |
2.0 ± 0.03# |
0.86 ± 0.01 |
5.0% Oxalic acid |
10 |
213.4 ± 1.9 |
145.0 ± 3.7# |
10.6 ± 0.2# |
48.8 ± 1.3# |
5.7 ± 0.25# |
3.9 ± 0.14 |
314.1 ± 16.7# |
216.6 ± 1.1# |
1.8 ± 0.06 |
1.29 ± 0.05# |
males |
|||||||||||
controls |
12 |
259.2 ± 1.8 |
382.7 ± 6.5 |
8.6 ± 0.4 |
20.4 ± 1.0 |
13.7 ± 0.03 |
3.6 ± 0.03 |
575.6 ± 7.3 |
150.4 ± 1.5 |
3.2 ± 0.08 |
0.84 ± 0.01 |
2.5% Oxalic acid |
11 |
250.4 ± 1.7 |
314.7 ± 4.9# |
7.1 ± 0.3 |
19.9 ± 1.1 |
11.1 ± 0.20# |
3.5 ± 0.03 |
564.7 ± 13.4 |
179.4 ± 2.0# |
2.9 ± 0.07 |
0.91 ± 0.02* |
5.0% Oxalic acid |
9 |
254.6 ± 1.9 |
162.1 ± 1.9# |
10.3 ± 0.2* |
42.1 ± 1.2# |
6.8 ± 0.13# |
4.2 ± 0.07# |
349.6 ± 5.7# |
215.7 ± 2.6# |
2.4 ± 0.05# |
1.53 ± 0.03# |
mean values±SE
* = different from control group, p < 0.01 as determined by student´s t test.
# = different from control group, p < 0.001 as determined by student´s t test.
Table 2:
Group |
No. of rats |
Thyroid weight |
Adrenal weight |
Ovary weight |
Uterus weight |
||||
|
|
mg |
mg/100g bw |
mg |
mg/100g bw |
mg |
mg/100g bw |
mg |
mg/100g bw |
Control |
12 |
24.2±0.60 |
8.9±0.2 |
99.3±2.1 |
16.4±0.9 |
118.7±3.61 |
43.5±0.7 |
470.1±7.1 |
172.2±6.1 |
2.5% Oxalic acid |
11 |
23.7±0.39 |
10.1±0.1# |
71.2±3.6# |
30.1±0.8# |
115.5±3.4 |
48.8±1.4* |
359.8±8.2# |
152.0±3.5* |
5.0% Oxalic acid |
10 |
17.7±0.57# |
12.5±0.4# |
69.4±2.1# |
47.9±1.7# |
70.1±2.8# |
48.3±0.7# |
133.7±3.4# |
92.2±2.8# |
Table 3:
Group |
No. of rats |
Thyroid weight |
Adrenal weight |
Testes weight |
Prostate weight |
Seminal vehicles weight |
|||||
|
|
mg |
mg/100g bw |
mg |
mg/100g bw |
mg |
mg/100g bw |
mg |
mg/100g bw |
mg |
mg/100g bw |
Control |
12 |
31.8±0.6 |
8.3±0.1 |
65.0±2.1 |
17.0±0.5 |
3.1±0.03 |
0.81±0.01 |
595.9±11 |
155.7±5.3 |
1.43±0.04 |
0.37±0.02 |
2.5% Oxalic acid |
11 |
28.3±0.99 |
8.9±0.4 |
60.3±1.6 |
19.2±0.3* |
3.0±0.05 |
0.96±0.01# |
441.1±11.5# |
140.2±3.7 |
1.31±0.06 |
0.42±0.02 |
5.0% Oxalic acid |
9 |
16.7±0.45# |
10.3±0.3# |
60.8±1.0 |
37.5±0.6# |
2.1±0.11# |
1.30±0.05# |
181.4±12.1# |
111.9±5.6# |
0.36±0.03# |
0.22±0.01# |
mean values±SE
* = different from control group, p < 0.01 as determined by student´s t test.
# = different from control group, p < 0.001 as determined by student´s t test.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 162 mg/kg bw/day
- Study duration:
- subchronic
- Experimental exposure time per week (hours/week):
- 56
- Species:
- mouse
- Quality of whole database:
- dose range finding study from a two generation NTP Study performed accoding to FACB scheme. Although no GLP study the quality of the study is considered to be sufficient for assessment.
- System:
- other: water consumption/dehydration
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
No experimental data on repeated dose toxicity are available for dipotassium oxalate. However, a study similar to OECD guideline 416 conducted according to the FACB protocol and within the National Toxicology Program for Oxalic acid is available. A justification for read-across is attached to Iuclid section 13.
Caesarean originated Barrier-sustained (COBS) CD-l (ICR)BR outbred albino mice are used for the FACB study. It consists of four related tasks, not all of which are necessarily performed for a given compound. The present study consists of three Tasks. Task 1: dose range-finding study. This study was not statistically analysed. Task 2: the continuous breeding phase. In this part 40 males and 40 females were randomly paired for the vehicle control group. 19 pairs received the low dose of 0.05%, 19 pairs received the mid dose of 0.1% and 20 pairs were administered the high dose of 0.2% oxalic acid in drinking water. The pairs were housed together for 98 days and were then separated for 21 days to allow delivery. Under normal conditions, i.e. a positive response (affected fertility), Task 3 would be performed. However, the effect on fertility in the present study was only marginal at the highest dose, thus, the study was continued with Task 4: effects on offspring. Second generation animals (20 each group and sex) were mated each from the control and the highest dose group for seven days. Then the animals were separated and were allowed to deliver the litters.
At the end of all tasks (1, 2 and 4) the experimental animals were necropsied: the liver, kidneys, testes, epididymis, prostate, and seminal vesicles with coagulating glands are weighed and fixed for histopathologic evaluation. In addition, vaginal smears are prepared for 7 consecutive days prior to necropsy to check the effect on the estrous cycle. For male mice, sperm-are studied in detail to evaluate the effect on sperm density, sperm motility, and sperm head morphology.
Exposure to oxalic acid at any dose group produced no adverse effects on mating or fertility. In Task 2, treatment with 0.2% oxalic acid resulted in significant decreases in the average number of litters per fertile pair, unadjusted pup weight (males only) and adjusted pup weight. Adjusted prostate weight was significantly decreased (by 21%) in high dose males, and adjusted kidney weight was increased (by 9%) in high dose females. The frequency of estrus was prolonged in the 0.2% female mice in Task 2 and to a lesser extent in Task 4.
In Task 4, the only significant result found in the litter analysis was a decrease at the high dose level in the average number of live pups per litter. At necropsy, kidney weight was significantly increased in high dose males (by 11%) and females (by 9 %). The amount of abnormal sperm was increased in the 0.2% males and the prostate gland was significantly decreased.
In conclusion, oxalic acid administered in drinking water at up to the 0.1% dose level corresponding to 162 mg/kg bw, does not affect the fertility in adult or second generation CD-1 mice.
Justification for classification or non-classification
Based on the available data, Dipotassium oxalate does not need to be classified for repeated dose toxicity according to regulation (EC) 1272/2008. Thus, no labelling is required.
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