Dipotassium oxalate

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:

The Elfect of Dietary Ingestion of Oxalic Acid on Thyroid Function in Male and Female Long-Evans Rats

Author:

MAX GOLDMAN AND GREGORY J. DOERING

Year:

1978

Bibliographic source:

TOXICOLOGY AND APPLIED PHARMACOLOGY 48, 409-414 (1979)

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:

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

Test material

Test material information

Constituent 1

Reference substance name:

ethandioic acid

Cas Number:

144-62-7

Molecular formula:

C2H2O4

IUPAC Name:

ethandioic acid

Test material form:

not specified

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2.5 other: %

Doses / concentrations 2

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

Examinations

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.

Results and discussion

Results of examinations

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

Effect levels

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

Target system / organ toxicity

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

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.