7-(diethylamino)-4-methyl-2-benzopyrone

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1965

Report date:

1965

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 pre-dates OECD guidelines

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

7-(diethylamino)-4-methyl-2-benzopyrone

EC Number:

202-068-9

EC Name:

7-(diethylamino)-4-methyl-2-benzopyrone

Cas Number:

91-44-1

Molecular formula:

C14H17NO2

IUPAC Name:

7-(diethylamino)-4-methyl-2H-chromen-2-one

Test material form:

solid

Test animals

Species:

rat

Strain:

other: CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River- Housing: in cages of 5- Diet: Basal diet Spillers Laboratory Small Animal Diet, (autoclaved)

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

Group 1: Untreated control fed the basal diet Spillers Laboratory Small Animal Diet, (autoclaved).Group 2: Low or nil effect level fed a diet containing 0.1 ppm of the test substance which was equivalent to 0.005 mg/kg. The rate of administration was based upon "maximum likely exposure". Group 3: Intermediate level (100 x low level) fed diet containing 10.0 ppm of the test substance.Group 4: High or effect level to determine the effects arising from excessive intake of the test substance. Initially the rate of administration was10 ppm but this was gradually increased to 900ppm (=45 mg/kg day) at the end of week to cause a depression of the rate of body weight increase. 200 ppm in week 6, 300 ppm in week 7, 600 ppm in week 8, 900 ppm in week 9

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

Continuous

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.005 mg/kg diet

Remarks:

0.1 ppm

Doses / concentrations 2

Dose / conc.:

0.5 mg/kg diet

Remarks:

10.0 ppm

Doses / concentrations 3

Dose / conc.:

5 mg/kg diet

Remarks:

Initially the rate of administration was 100 ppm but this was gradually increased to 900ppm (45 mg/kg)

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: Based on maximun likely exposure (low level group 2) and possible excessive intake (high level group 2)

Positive control:

no

Examinations

Observations and examinations performed and frequency:

Interim observations: Throughout the fourteen week experimental period, all rats were observed daily for symptoms of toxicity. They were weighed individually at weekly intervals and group mean values calculated. Food consumption was recorded weekly on a group basis (males and females separately). After four weeks of treatment, urinalysis was performed on pooled samples from the high level and control groups. The determinations included: volume, pH, specific gravity, protein content, reducing substances, glucose, ketones, bile salts, bile pigments, urobilinogen, microscopic examination of any deposit, if present.Terminal observations: At termination, urinalysis was performed on pooled samples from all groups. At this time the urines were also examined under ultra-violet light to detect the presence of the test substance or its metabolites. The blood of high level and control rats was analysed for haemoglobin content (Hb), packed cell volume (PCV), erythrocyte count (RBC), white cell count (WBC), total and differential. The serum was examined under ultra-violet light to determine whether or not the test substance or its metabolites had been absorbed into the blood stream.

Sacrifice and pathology:

Immediately following ether euthanasia, all rats were subjected to gross pathological examination. The heart, lungs, liver, spleen, brain, kidneys, adrenals, gonads, pituitary and thyroid glands were weighed to allow calculation of organ/bodyweight ratios, (organ weight analysis). The above organs, together with sections of the stomach, small and large intestine and the pancreas were preserved in formol saline. In the first instance histological examination was confined to high level and control animals, 5 male and 5 female rats from each, with a view to extending the examination to other groups if effects were noted at the highest dosage.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No obvious symptoms of toxicity were noted.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Data showed that the bodyweight increase of female rats at the highest level of treatment was inhibited from the onset of treatment, becoming more marked after the 6th week when the concentration of the test substance in the diet was increased to 600ppm. Analysis of variance of the body weights at week 14 shows that the weight of high level females is significantly (P<0.01) reduced. The high level males, on the other hand show no marked inhibition of growth until after the 7th week, at the end of which the dietary concentration of thet test substance was increased to 900ppm, Analysis of variance carried out at the 14th week failed to show any significant difference between groups.

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

Description (incidence and severity):

No marked differences exist between groups and although the haemoglobin content of the test females is lower than that of the controls, the difference is by no means significant as judged as analysis of variance. Under ultra-violet light the serum of high level rats showed an increased blue fluorescence suggesting that the test substance and/or its metabolites were present.

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Description (incidence and severity):

There was no evidence of any effect upon urinary composition at either 4 or 14 weeks.The urines from Group 4 animals, fluoresced bright blue in ultra-violet light, indicating the presence of the test substance or its derivatives. A similar, but far less intense, fluorescence was recorded for Group 3 animals.

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):

The kidney/body weight ratio was Increased (P<0.01) for both sexes at the highest level of treatment due to both an increase in the true kidney weight and a decrease in body weight. Other organs were relatively unaffected in the male, but female rats showed Increased adrenal/bodyweight and ovary/body weight ratios at the two high levels of treatment (10ppm and 900ppm). The increased ratios are due to a true increase in organ weight.

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Respiratory tract: There was evidence of a minimal chronic inflammatory reaction, seen throughout most of the lungs examined, which extends up into the trachea in some animals. As its distribution was universal, it was not considered to be of any pathological significance from the point of view of this experiment.Various anomalies were seen which were considered to be unconnected with this experirment; they included hydronephrosis seen in the kidney and occasional chronic inflammatory cells in the pancreas.

Histopathological findings: neoplastic:

not examined

Effect levels

Remarks on result:

not determinable because of methodological limitations