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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:
21 Feb - 14 July, 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of International Trade and Industry Notification Nr.2
GLP compliance:
yes
Remarks:
21 CFR 58
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
414-490-2
EC Name:
-
Cas Number:
154212-59-6
Molecular formula:
C11H9ClN2O5S
IUPAC Name:
4-nitrophenyl 1,3-thiazol-5-ylmethylcarbonate hydrochloride

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation: 6 - 7 weeks
- Weight at study initiation: 150 - 250g
- Housing: ventilated, hanging stainless steel, wire bottomed cages.
- Diet: Certified Rodent Chow, ad libitum
- Water: ad libitum
- Acclimation period: 4 days followed by 8 days pretreatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71±6
- Humidity (%): ambient
- Photoperiod (hrs dark / hrs light):12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 5% ethanol, 95%propylene glycol
Details on oral exposure:
Method of administration:
Gavage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the dosing formulations were sent for assay analysis in weeks 1 and 4 of the test period. Formulations prepard on days 0 and 28 were 87.6 - 92.9% of nominal concentrations. Eight day stability analyses of high and low dose formulatons were ≥85.7% of nominal concentrations.
Duration of treatment / exposure:
Test duration: 30 - 31 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
15mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
150mg/kg
Basis:
other: gavage
Remarks:
Doses / Concentrations:
300mg/kg
Basis:
other: gavage
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 10 animals at 150 mg/kg bw/day
Male: 10 animals at 300 mg/kg bw/day

Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 10 animals at 150 mg/kg bw/day
Female: 10 animals at 300 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on acute oral toxicity testing results
- Rationale for animal assignment: random

Examinations

Observations and examinations performed and frequency:
All rats observed twice daily during pretrreatment, treatment and recovery for survival and general condition.
Physical condition and behavior recorded 1-2 hrs after thre daily dose at least 2 days per week during the treatment period and weekly during the recovery period.

BODY WEIGHT: Yes
- Time schedule for examinations: Twice during pretreatment and twice weekly during treatment and recovery. All surviving rats weighed on day of necropsy.
Sacrifice and pathology:
At the end of treatment and recovery period, up to 5 rats per sex per group were fasted overnight, euthanized and necropsied.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
at 150 and 300 mg/kg/day rough and discolored coat, respiratory distress, at 150 mg/kg/day : slight to moderate abdominal distention, at 300 mg/kg/day -emanciation , slight to severe abnormal distention
Mortality:
mortality observed, treatment-related
Description (incidence):
at 150 and 300 mg/kg/day rough and discolored coat, respiratory distress, at 150 mg/kg/day : slight to moderate abdominal distention, at 300 mg/kg/day -emanciation , slight to severe abnormal distention
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:
effects observed, treatment-related
Description (incidence and severity):
high dose: hemogloinuria, hematuria and aciduria
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
at 150 and 300 mg/kg/day- segmental gaseous gatrointestinal distention
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS:

MORTALITY: 3 males and 3 females at dosage of 300mg base/kg/day died. 1 of these females died toward the end of the 2-week recovery period. 1 female at 150mg base/kg/day also died.

Segmental gaseous distention of the gastrointestinal tract found post mortem at 150 and 300 mg base/kg/day was consistent with te obseervation of abdominal distention.

There were 3 male and two female mortalities at 300
mg/kg/day, animals were found dead or sacrificed due to
severe gastrointestinal distension. In addition, one female
at 150 mg/kg/day was found dead.

At 150 and 300 mg/kg/day clinical signs of toxicity included
respiratory distress, abdominal distension, emaciated
appearance and rough or discoloured coat.

There were no significant changes in bodyweight gain or food
consumption.

Laboratory findings:
At the end of the treatment period, very slight, but
statistically significant decreases in red cell parameters
were found in all treatment groups (reduced RBC,
haemoglobin, and haematocrit values [all <10% increase], and
increased reticulocyte counts [10-30% increase]). At 300
mg/kg/day, serum protein and globulin were slightly (<10% in
males, 22% in females) decreased. Urinalysis revealed
haemoglobinuria, haematuria and aciduria. At 150 and 15
mg/kg/day, no clear cut changes in haematology, clinical
chemistry or urinalysis parameters were found.

Effects in organs:
Mean liver weight was slightly increased in females at 300
mg/kg/day (7% increase). At 150 and 300 mg/kg/day, segmental
gaseous gastrointestinal distention was a consistent
macroscopic finding. There were no treatment-related effects
or microscopic findings.

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
THe no-toxic-effect level ws considered to be 15mg base/kg/day in this study.