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Toxicological information

Repeated dose toxicity: oral

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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

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
not specified
Details on species / strain selection:
not specified
Sex:
male
Details on test animals 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 / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
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

open allclose all
Key result
Dose descriptor:
LOEL
Effect level:
ca. 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
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.