Carbonic acid, 4-nitrophenyl 5-thiazolylmethyl ester, hydrochloride (1:1)

Repeated dose toxicity: oral

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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Test guideline 3

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

Test material information

Constituent 1

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-yl)methyl carbonate 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg
Basis:
other: gavage

Doses / concentrations 2

Remarks:

Doses / Concentrations:
15mg/kg
Basis:
other: gavage

Doses / concentrations 3

Remarks:

Doses / Concentrations:
150mg/kg
Basis:
other: gavage

Doses / concentrations 4

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

1

Dose descriptor:

NOEL

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

2

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.