Sodium 1-(3,4-dihydro-6-methyl-2,4-dioxo-2H-pyran-3-ylidene)ethanolate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Circa 1950

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

Dehydroacetic acid (DHA): 1. Acute and chronic toxicity

Author:

Spencer HC, Rowe VK & McCollister DD

Year:

1950

Bibliographic source:

J. Pharmacol. Exp. Therap., 99; 57-68

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Essentially an oral gavage four week sub-chronic toxicity study, conducted in the rat (a well-established experimental model), in which key toxicity endpoints were evaluated.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-acetyl-6-methyl-2H-pyran-2,4(3H)-dione

EC Number:

208-293-9

EC Name:

3-acetyl-6-methyl-2H-pyran-2,4(3H)-dione

Cas Number:

520-45-6

Molecular formula:

C8H8O4

IUPAC Name:

3-acetyl-6-methyl-2H-pyran-2,4(3H)-dione

Test animals

Species:

rat

Strain:

not specified

Details on species / strain selection:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

not specified

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

24 doses in 34 days

Frequency of treatment:

Daily - presumed not at weekends

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

10 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

30 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 5

Dose / conc.:

300 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5 or 6

Control animals:

yes, concurrent vehicle

Details on study design:

Male rats 10 weeks old at start of study

Positive control:

No

Examinations

Observations and examinations performed and frequency:

General condition, body weight

Sacrifice and pathology:

Pathology (lung, heart, liver, kidney, spleen, adrenal, pancreas, testis, and stomach), histopathology, blood urea-N

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 300 mg/kg bw/day - animals were emaciated, thin and unkempt

Mortality:

mortality observed, treatment-related

Description (incidence):

At 300 mg/kg bw/day - two deaths, one at 7 days the other at 11 days (7 doses). Remaining rats killed after 11 days. No adverse effects at 0, 10, 30, 100 mg/kg bw/day

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At 300 mg/kg bw/day - 20 to 30% of their body weight loss. No adverse effects at 0, 10, 30, 100 mg/kg bw/day

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At 300 mg/kg bw/day - contracted stomach with blood tinged contents, a congested mucosa, and a few haemorrhagic areas.
No adverse effects at t 0, 10, 30, 100 mg/kg bw/day

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Effect levels

1

Key result

Dose descriptor:

LOEL

Effect level:

ca. 300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

mortality

2

Key result

Dose descriptor:

NOAEL

Effect level:

> 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse toxicity at 100 mg/kg bw/day.

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

300 mg/kg bw/day (nominal)

System:

gastrointestinal tract

Organ:

stomach

Treatment related:

yes

Dose response relationship:

no

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

General condition and body weight at 0, 10, 30, 100 mg/kg bw/day was unaffected. Additionally, no adverse effects were noted for blood urea-N or after histopathological examination of selected tissues (lung, heart, liver, kidney, spleen, adrenal, pancreas, testis, and stomach). At 300 mg/kg bw/day loss, two deaths occurred (7 & 11 days). The remaining animals at 300 mg/kg bw/day were killed after 11 days (7 doses). These animals lost 20 to 30% of their body weight and were thin and unkempt. Examination of each of these animals revealed marked emaciation and contracted stomach with blood tinged contents, a congested mucosa, and a few haemorrhagic areas. The NOAEL was onsidered to be 100 mg/kg bw/day.

Executive summary:

In a repeat dose toxicity study (24 doses in 34 days) rats were dosed by oral gavage: 2 groups of 5 or 6 (10 weeks old at start), the dosages were: 0, 10, 30, 100 or 300 mg/kg bw/day (vehicle: olive oil).

There were no adverse effects at 10, 30, 100 mg/kg bw/day. At 300 mg/kg bw/day loss, two deaths occurred (7 & 11 days), there was 20 to 30% body weight loss, the animals appeared thin and unkempt and had a contracted stomach with blood tinged contents, a congested mucosa, and a few haemorrhagic areas. A NOAEL of 100 mg/kg bw/day was determined.