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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:
05-12-2012 to 10-09-2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
GLP and Quality Assured Study
Justification for type of information:
The study was designed to provide information for potential further repeat dose toxicity studies.

Data source

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

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Study was a repeat-dose dose range finding study.
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Colour: colourless
- Odour: odourless
- CAS-Number: 89-32-7
- Molecular formula: C10 H2 O6
- Molecular weight: 218.12
Specific details on test material used for the study:
PMDA, pyromellitic dianhydride 99.4%, batch NJC1207029

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Wistar Han™:RccHan™:WIST strain rat
Details on species / strain selection:
The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is recommended by regulatory authorities.
Sex:
male/female
Details on test animals and environmental conditions:
A sufficient number of male and female VVistar Han™:RccHan™:WIST strain rats were obtained from Harlan Laboratories U.K. Ltd., Oxon, UK. On receipt the animals were examined for signs of ill-health or injury. The animals were acclimatised for six days during which time their health status was assessed. A total of twenty-four animals (twelve males and twelve females) were allocated to the study. At the start of treatment, the males weighed 313 to 336g, the females weighed 206 to 221 g, and were approximately twelve weeks old.

The animals were housed in groups of three by sex in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding (Datesand Ltd., Cheshire, UK). The animals were allowed free access to food and water. A pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK) was used. A certificate of analysis of the batch of diet used is given in Addendum 1. Mains drinking water was supplied from polycarbonate bottles attached to the cage. The diet and drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study. Environmental enrichment was provided in the form of wooden chew blocks and cardboard fun tunnels (Datesand Ltd., Cheshire, UK).
The animals were housed in a single air-conditioned room within the Harlan Laboratories Ltd., Shardlow, UK, Barrier Maintained Rodent Facility. The rate of air exchange was at least fifteen air changes per hour and the low intensity fluorescent lighting was controlled to give twelve hours continuous light and twelve hours darkness. Environmental conditions were continuously monitored by a computerised system, and print-outs of hourly temperatures and humidities are included in the study records. The temperature and relative humidity controls were set to achieve target values of 22 ± 3°C and 50 - 60% respectively.

The animals were allocated to dose groups using a randomisation procedure based on stratified body weights and the group mean body weights were then determined to ensure similarity between the dose groups. The animals were uniquely identified within the study, by an ear punch system routinely used in these laboratories.

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item.
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% CMA with 0.1% Tween 80
Details on oral exposure:
Oral gavage for 14 consecutive days.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC Methodology.
Homogeneity assessed and proven at 3 mg/ml and 100 mg/ml
Stability at least 21 days at 4oC.
Verification of concentrations: 100 mg/ml: 100% - 139%; 25 mg/ml: 75%-114%
Duration of treatment / exposure:
14 consecutive days.
Frequency of treatment:
Daily.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
750 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
3 males/females per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
As a dose range finding study, the design had a defined number of endpoints to aid in the assessment of dosages for repeat oral toxicity studies.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
Daily clinical observations, before dosing, up to 30 minutes after dosing and one hour after dosing. Additionally 5 hours after dosing Monday to Friday.
Body weights recorded days 1, 4, 8, 11 and 15.
Food consumption recorded days 1-4, 4-8, 8-11 and 11-15.
Water consumption recorded daily.
Sacrifice and pathology:
Killed on completion of dosing by an iv overdose of a barbiturate followed by exsanguination. External and internal examinations performed.
Statistics:
Means and SD calculated. No tests of statistical significance were evident.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced body weight gains and body weight losses for the male rats were recorded at 750 and 1000 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
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

open allclose all
Key result
Dose descriptor:
LOAEL
Effect level:
>= 750 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effects.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the study evidence a NOAEL of 250 mg/kg bw/day for the males can be considered appropriate. And a NOAEL of greater than 1000 mg/kg bw/day would be appropriate for the females.
Executive summary:

The study was designed to provide information for further repeated dose toxicity studies.

The test item was administered by gavage to three groups, each of three male and three female Wistar Han™:RccHan™:WIST strain rats, for fourteen consecutive days, at dose levels of 250, 750 and 1000 mg/kg bw/day. A control group of three males and three females was dosed with vehicle alone (1% Carboxymethyl cellulose/0.1% Tween 80).

Clinical signs, body weight change, food consumption and water consumption were monitored during the study. All animals were subjected to gross necropsy examination.

There were no unscheduled deaths.

No clinically observable signs of toxicity were detected.

Reduced body weight gains and actual body weight losses were evident for males treated with 1000 and 750 mg/kg bw/day when compared to controls. Females were unaffected by treatment at any level tested.

 

No adverse effects on food consumption were detected.

No toxicologically significant differences in water intake were detected.

 

No macroscopic changes were detected at terminal kill.

 

A NOAEL of 250 mg/kg bw/day for males can be considered appropriate. A NOAEL of greater than 1000 mg/kg bw/day would be appropriate for the females.