Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 d
Frequency of treatment:
The test item BHT-2NH3 5,5´-Bis-1H-tetrazole diammonium salt was administered daily by
oral gavage to 5 male and 5 female Wistar rats each at dose levels of 0, 63, 250 and 1000
mg/kg BW/day over a period of 28 days. Of these solutions, 4 ml/kg BW was administered
daily to each animal.
Test substance was administered to female rats weighing approximately 150 g at the start of
the in-life phase and 200 g at its end, whereas the male rats were weighing approximately
180 g at the start and about 340 g at the end of this study.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 63, 250 and 1000 mg/kg BW/day
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: softened stool, reduced body mass, increased water and food consumption, enlarged kidneys, altered maematological parameters

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Apart from the softened stool in both high dose groups, detailed clinical signs, motoric
activity, and reactivity to sensory stimuli showed no abnormalities.
Most prominent among the animal groups treated with the test item were the observed
effects on body mass, food and water consumption, where the high dose groups showed a
conspicuous reduction of body mass despite of an increased food and water uptake,
indication a negative influence of the test item on the nutritional metabolism. The
haematological changes, especially the ion reduction in combination with the tendency of
enlarged kidneys point towards a negative effect on the water-salt metabolism, which is not
unusual with the application of higher amounts of a salt. A large number of medicinal and
chemical agents with different chemical structures and/or therapeutic activities produce
kidney enlargement when given in high doses to species used in toxicity studies. GOT often
respond to kidney damage. Findings of this nature are in favour of an adaptive response
rather than a direct toxic effect of the test item.
These findings, not present in the control animals, are considered to be related to the
treatment with the test item. Although some additional significant changes were observed,
none of the average data points were overall extremely out of range for rats of this strain and
age.
The histomorphological examination of the selected rat organs did not reveal morphological
lesions considered to be related to the test item. The inflammatory lesions in different organs
were coincidental findings or spontaneous organ changes and are therefore not test item
related. No morphological differences were noted between the groups. The involution of the
thymus in some rats corresponded in type, incidence and severity to the age of the animals.
All the findings recorded in this study are commonly encountered in rats of this strain and age. Type, incidence, and severity of the lesions recorded were not increased in the treated animals as compared to the control animals.