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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
This 14 d study, intended to be a dose-ranging study to identify doses to be used in a subsequent 90 d study.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Principles of method if other than guideline:
duration: 14 d
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Remarks:
particle size: 0.5–10 μm
Details on test material:
manufactured by Epitech Group Srl, Milano Italy, supplied by Prismic

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Sprague-Dawley rats (Vivo Bio Tech Ltd), age: 6–7 weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: water with Tween 80 (0.5 % w/v) and carboxymethyl cellulose (1 % w/v)
Details on oral exposure:
Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5 % w/v) as a surfactant and carboxymethyl cellulose (1 % w/v) as a suspending agent.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses performed to verify the concentrations of the test substance in dosing formulations in the 90-day study showed that they were within an acceptable range compared to their respective nominal concentrations.
Duration of treatment / exposure:
14 d
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
five of each sex
Control animals:
yes
Details on study design:
The following observations and examinations were performed: mortality and clinical signs – daily, body weight and food consumption – weekly. Additionally samples for hematology and clinical chemistry analysis were taken just prior to sacrifice, and gross necropsy was performed, recording any gross pathological observations and organ weights.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the study conditions, the NOEL from this study was >1000 mg/kg bw/day.
Executive summary:

A study was conducted to determine repeated dose toxicity of the test substance according to a design based on OECD Guideline 407. This 14 d study intended to identify the dose-range to be used in a subsequent 90 d study. Preliminary tests found that the test substance was suitable for oral gavage by suspension in water with Tween 80 (0.5% w/v) as a surfactant and carboxymethyl cellulose (1% w/v) as a suspending agent. Ten Sprague-Dawley rats, five of each sex, were dosed with a vehicle control and with the test substance at 100, 300, and 1000 mg/kg bw/day daily through duration of the study. Observations for mortality and clinical signs were made daily and of body weight and food consumption weekly. Additionally samples for hematology and clinical chemistry analysis were taken just prior to sacrifice, and gross pathology was performed. Analyses performed to verify the concentrations of the test substance in dosing formulations in the 90-day study showed that they were within an acceptable range compared to their respective nominal concentrations. No incidence of clinical signs or death was found following 14 days of treatment with the test substance at 0, 100, 300, or 1000 mg/kg bw/day. Furthermore, no adverse effects were observed on body weight gain, food consumption, hematological parameters, clinical chemistry, gross pathology, or on absolute or relative organ weights. Under the study conditions, the NOEL from this study was >1000 mg/kg bw/day (Nestmann, 2017).