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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-05 to 2012-08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Test material form:
liquid
Specific details on test material used for the study:
- Test item: JEFFCAT ZF-10
- Chemical name: N,N,N'-Trimethyl-N'-hydroxyethyl-bis-aminoethyl ether
- Batch number: 1K703
- CAS number 83016-70-0
BIOAGRI code: AGR-1892/11
- Physical state: liquid
- Sample arrival date in BIOAGRI-DF: 28/Dec/2012
- Sample storage: in a specific room (Test Item Storage Room), at room temperature, protected from humidity and light

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
a) Species: rat (Rattus norvegicus)
b) Strain: Wistar Hannover
c) Source: BIOAGRI Laboratórios – DF/ Brazil
d) Sex: Males and females (nulliparous and non-pregnant)
e) Age (on the first day of dosing): 8 to 9 weeks old
f) Number of animals on study: 10 animals/sex/group.
- Weight : 286.0g +/- 14.2g for males and 184.4g +/- 8.2g for females after randomization
- Fasting period before study: yes
- Housing: polypropylene rodent cages (41x34x19 cm) with wire mesh tops and wood shavings as bedding material.
- Diet (e.g. ad libitum): Nuvilab CR-1 diet for rodents by Nuvital Nutrientes Ltda, Curitiba –PR, Brazil, available ad libitum
- Water (e.g. ad libitum): Filtered drinking water was supplied by CAESB (Companhia de Saneamento Ambiental do Distrito Federal) in water bottles and was available ad libitum.
- Acclimation period: minimum of 6 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.0 °C - 23.2 °C
- Humidity (%): 44.0% -70.0%
- Air changes (per hr): 10-20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: deionized water
Details on oral exposure:
Daily, by oral gavage, at approximately the same time of the day, on a 7-day-a-week-basis, for a period of 13 weeks, in a constant dosage volume of 10 mL/kg.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 mg/kg bw/day (nominal)
Remarks:
Basis: nominal in deionized water
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Basis: nominal in deionized water
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Basis: nominal in deionized water
No. of animals per sex per dose:
10 animals/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
All animals were randomized and observations were performed in a “blinded” study design.

Examinations

Observations and examinations performed and frequency:
Animals were checked twice daily for mortality or morbidity on working days and once daily on Saturdays, Sundays and public holidays.
They were subjected to a careful clinical examination before the initiation of the treatment and once a week during the dosing period.
Body weight and food consumption were recorded once a week during the study period.
An ophthalmoscopic examination was performed on all animals prior to the initiation of dosing and at the end of treatment period.
A neurotoxicological evaluation using a Functional Observation Battery was performed during study week 13.
At the end of the study, urine was collected after an overnight fasting period and urinalysis parameters were examined. Blood samples were collected for hematology, leukogram, clotting and clinical chemistry analyses.
Sacrifice and pathology:
A complete gross examination was performed on all animals after euthanasia by carbon dioxide inhalation.
At study termination, the animals were subjected to a gross examination and the appropriate organs/tissues were removed, weighed and processed for histopathological evaluation. Histopathological slides obtained from the control and high dose groups were evaluated microscopically, plus two males with macroscopic lesions (stomach and urinary bladder) at mid dose and two females at low (liver) and mid dose (ovary).
Statistics:
Quantitative variables such mean body weight and mean body weight change, food consumption, FOB, hematological assessment (hemogram, leukogram, clotting time and biochemistry) were analyzed by One-Way Analysis of Variance (ANOVA), followed by Dunnett’s test if significance is detected and mean body weight change, food consumption, FOB and hematological assessment (hemogram, leukogram, urinalysis and biochemistry), followed by Mann-Whitney U test if
significance is detected. For qualitative or non-parametric data such as urinalysis, macroscopic and microscopic findings comparison was carried out using the Chi-Square Test. The level of significance was set at 5% and the statistical program used was SAS Software (SAS Institute Inc., Cary, NC).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
The test item induced no clinical signs of toxicity.
Mortality:
no mortality observed
Description (incidence):
The test item induced no mortality.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Effects on body weight or body weight gain were not observed during this study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Effects on food consumption were not observed during this study.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
There were no significant findings in the hematological, leukogram and coagulation parameters.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no significant findings in the clinical chemistry parameters.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no significant findings in the urinalysis parameters.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no significant findings in the Functional Observation Battery.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Pathological changes of toxicological interest were not observed.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Pathological changes of toxicological interest were not observed.
Neuropathological findings:
no effects observed
Description (incidence and severity):
There were no significant findings in the Functional Observation Battery.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Pathological changes of toxicological interest were not observed.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
> 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results obtained in the repeated dose 13 week oral toxicity study, the NOAEL (No Observed Adverse Effect Level) of the test substance was considered to be greater than 100 mg/kg/day in males and female Wistar rats.
This test was requested by the National Competent Authority in accordance with Article 16(1) of Directive 67/548/EEC.