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Description of key information

Acute Oral toxicity: Key study. Test method according to OECD 401, GLP study. The oral LD50 value for male rats was greater than 2000 mg/kg bw and between 1000 and 2000 mg/kg bw for females.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
07/01/1998 - 29/01/1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Remarks:
(Crj: CD, SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan Charles River Co. Atsugi rearing center
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 5-week old
- Weight at study initiation: on administration date, males average was 129.7 g (124.2-135.7 g) and females average was 108.3 g (100.9-113.7 g)
- Fasting period before study: yes, about 18h prior to administration. Feeding resumed at 4 hours after dosing.
- Housing: metal mesh floor cage (220WX270DX190H, (m))
- Diet: solid feed (CE-2, CLEA Japan), ad libitum.
- Water: tap water (Kanno City Waterworks Bureau water supply, ad libitum.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24.0 - 25.0°C
- Humidity (%): 54 - 64%
- Air changes (per hr): 15 times / hour
- Photoperiod (hrs dark / hrs light): 12 hours (7: 00-19: 00) light / 12 hours dark

IN-LIFE DATES: Arrival date of animals: January 7, 1998. Date of administration: January 15, 1998
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% w/v aqueous solution
Details on oral exposure:
VEHICLE
- Lot/batch no. (if required): Japanese Pharmacopoeia CMC sodium, lot number: 6Z09, Maruishi Pharmaceutical Co., Ltd., and water for injection of Japanese Pharmacopoeia, lot number: 9707SA, manufactured by HIKARI PHARMACEUTICAL CO., LTD.
- Purity: 0.5% w/v solution

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
700, 1000, 1400 and 2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: body weights 1, 2, 4, 8, 11 and 15 days after administration; clinical findings and mortality hourly until 6h after administration and daily afterwards.
- Necropsy of survivors performed: yes
Statistics:
Mean values and standard deviations were determined for body weight measurements. From the mortality rate of this study, it was not possible to calculate the LD50 value and the 95% confidence limit by the probit method.
Preliminary study:
In a preliminary study (A-97-028), 3 male and 3 female rats were administered the test item at 2000 mg/kg bw. Deaths were observed in both groups. Therefore, an additional preliminary study (A-97-039) was conducted by administering the test item at 1000 mg/kg bw. Symptoms such as hypothermia and respiratory depression were recognized, but no deaths were observed.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 000 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
In males, no deaths were observed in any of the treatment groups. In females, one animal died on the day of administration in the 1400 mg/kg dose group, and two died on the second day of observation, and in the 2000 mg/kg dose group two animals died on the day of administration.
Clinical signs:
Both males and females showed strong toxicity symptoms such as sedation, weakness, laterality, non-responsiveness to stimuli, respiratory distress, decreased respiratory rate, hypothermia, catalepsy, etc. immediately after administration.
Body weight:
In males in the 1400 and 2000 mg/kg dose groups, suppression of weight gain was observed, and also some in the 700 and 1000 mg/kg dose groups. However, in all treatment groups, body weight increased thereafter, and no difference was observed in all treatment groups at observation day 11. In females, mild suppression of weight gain was observed on the second day of observation in all treatment groups, but thereafter, body weight increased in all surviving cases.
Gross pathology:
The lungs of the females in the 1400 mg/kg dose group who died were colored red, and the gastric mucosa was cloudy. In addition, black spots were found in the glandular gastric mucosa in one case. In the 2000 mg / kg group, microscopic cysts were observed in the subcapsular cortex of the left and right kidneys, and the gastric mucosa was cloudy, and red spots were scattered in the glandular gastric mucosa. In one case, the lungs were partially reddish, cysts were scattered in the subcapsular cortex of the left and right kidneys, and white turbidity in the gastric mucosa and retention of samples in the stomach were observed. Therefore, it was presumed that the main cause of death was a strong central depressant action.
No abnormal findings were observed at necropsy of the surviving animals.

Table 2. Mortality of rats after single oral administration of o-toluenesulfonamide         

Sex

Dose

No. of animals

Mortality

Total

LD50 value (mg/kg)

(mg/kg)

0-1 h

1-2h

2-3h

3-4h

4-5h

5-6h

2d

3d

4d

5-9d

10-14d

Male

700

5

0

0

0

0

0

0

0

0

0

0

0

0

>2000

1000

5

0

0

0

0

0

0

0

0

0

0

0

0

1400

5

0

0

0

0

0

0

0

0

0

0

0

0

2000

5

0

0

0

0

0

0

0

0

0

0

0

0

Female

700

5

0

0

0

0

0

0

0

0

0

0

0

0

1000-2000

1000

5

0

0

0

0

0

0

0

0

0

0

0

0

1400

5

0

0

0

0

1

2

0

0

0

0

0

3

2000

5

0

0

0

1

1

0

0

0

0

0

0

2

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
EU criteria
Conclusions:
Based on the study results, the LD50 value of the test item was between 1000 and 2000 mg/kg for females and more than 2000 mg/kg for males.
Executive summary:

An Acute Oral Toxicity test was performed according to OECD 401, under GLP conditions. A total of 40 Sprague-Dawley (Crj: CD) male and female (20M/20F) rats were divided in 4 groups consisting of 5 animals per group and received a single oral administration of 700, 1000, 1400 and 2000 mg/kg of the test item. All animals were subject to daily observations and weekly determinations of body weight. Necropsy was performed on the day of their death or after sacrifice, at the end of the observation period. No deaths were observed in males at any dose tested, but 3 females in the 1400 mg/kg group and 2 females in the 2000 mg/kg group died. Both males and females showed severe toxic symptoms such as sedation, weakness, laterality, non-responsiveness to stimuli, respiratory distress, decreased respiratory rate, decreased body temperature, catalepsy, etc. immediately after administration. Some suppression of body weight gain was observed in most groups the second day after administration, but it normalized thereafter. In the necropsy findings of the death cases, it was presumed that the main cause of death was a strong central depressant action, because there were no organic changes caused by the test substance leading to the death. From these facts, it was estimated that the LD50 value of o-toluenesulfonamide under this test condition was between 1000 and 2000 mg/kg for females and more than 2000 mg/kg for males.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Based on the available data (1000 ≤ LD50 ≤ 2000 mg/kg bw in female rats), the test item is classified as Acute Oral Cat. 4 according to CLP, Regulation (EC) No. 1272/2008.