Trifluoromethanesulphonic anhydride

Endpoint summary

Description of key information

The LD50 value of trifluoromethanesulfonic anhydride when administered orally to male SD rats was 1012 mg/kg.

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:

From 23 July 1992 to 10 September 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc. (Hino, Gamo-gun, Shiga-ken)
- Age at study initiation: 5 weeks old
- Weight at study initiation: 141 - 165 g
- Fasting period before study: yes
- Housing: sterilized mesh hanger cages (depth 36 cm x width 25 cm x height 17 cm)
- Diet (e.g. ad libitum): ad libitum, solid feed (MM-6, Funabashi Farm Co., Ltd., Funabashi-shi, Chiba-ken) which had been radiation sterilized
- Water (e.g. ad libitum): ad libitum. tap water supplied by means of a drinking bottle
- Acclimation period: yes, 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 12 – 18 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily (7.00 - 19:00)

IN-LIFE DATES: From: 3 August To: 17 August 1992

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DOSAGE PREPARATION: No adjustments of the study substance were carried out, and after fasting for a night, rats were given a single forced oral administration of tri-FMS undiluted solution.

CLASS METHOD
- Rationale for the selection of the starting dose: In the preliminary study, deaths were found on the administration day or the following day in the 668 mg/kg or higher in administration groups, and at 1419.5 mg/kg or higher, all animals except for one in the 1670 mg/kg group died. In addition, there were no alterations in particular that could be considered abnormal in the weight changes up until the 10th day of observation of the surviving animals. The dosages for the main study were therefore set using a geometric progression of 1.3 at 450, 585, 760, 988, 1285 and 1670 mg/kg.

Doses:

450, 585, 760, 988, 1285 and 1670 mg/kg (corresponding to 0.35, 0.46, 0.59, 0.77, and 1.00 mL/kg respectively, calculated on the basis of the body weight on the administration day)

No. of animals per sex per dose:

5 males per group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: On the administration day, the animals were observed continuously for 3 hours following administration, and were observed several times after 3 hours. From the day after administration onward, the animals were observed once or more a day during the observation period.
Body weight was measured on the administration day (day 0) and observation days 1, 3, 5, 7, and 14.
- Necropsy of survivors performed: yes
- Other examinations performed:
* necropsy: In the autopsies, tissue from different organs was examined grossly for the presence of abnormality.

Statistics:

The LD50 value was calculated on the basis of the accumulated 14-day death rate by the probit method.

Preliminary study:

In the preliminary study, deaths were found on the administration day or the following day in the 668 mg/kg or higher in administration groups, and at 1419.5 mg/kg or higher, all animals except for one in the 1670 mg/kg group died. In addition, there were no alterations in particular that could be considered abnormal in the weight changes up until the 10th day of observation of the surviving animals.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1 012 mg/kg bw

Based on:

test mat.

95% CL:

> 823 - < 1 248

Mortality:

Death was found in the 760 mg/kg and higher groups from the administration day up to observation day 3 (see table 1 in Any other information on results incl. tables).

Clinical signs:

other: Symptoms of toxicity that were observed on the administration day were salivation at approx. 10 – 30 min after administration, with subsequent writhing, decrease in locomotor activity, prone position, bradypnea, cyanosis, and ataxic gait. In cases in the

Gross pathology:

In the autopsies of the animals that died, the external findings were peri-oral, peri-nasal, or lower abdominal staining, and the internal findings were retention of ascites fluid and pleural fluid, cloudy change on the surface of abdominal organs or tissues, and perforation of the pylorus. In addition, in 1 case in the 1285 mg/kg group (no. 23) in which emaciation was found, there was also adhesion between intraabdominal organs and tissues and thymus involution.
In the autopsies of the animals that survived (terminal kill), whitening and thickening of the forestomach-glandular stomach limiting ridge and thickening of the serosa in the same region were found, and in 1 case in the 760 mg/kg administration group (no. 15) this was accompanied by adhesion between intraabdominal organs and tissues and thickening of the splenic capsule. In addition, scarring of the glandular stomach mucosa and thickening of the serosa in the same region were observed in 1 case in the 760 mg/kg administration group (no. 14), and thickening of the forestomach mucosa was observed in 2 cases in the 585 mg/kg group. The same abnormalities were not found in the 450/mg group.

Table 1: Distribution of death in male rats after single oral administration of trifluoromethanesulfonic anhydride

Dose (mg/kg)	Distribution of death																					Mortality
	Hours							Days
	~1/2	~1	~2	~3	~4	~5	5~	1	2	3	4	5	6	7	8	9	10	11	12	13	14
450	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0/5
585	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0/5
760	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1/5
988	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0	2/5
1285	0	0	0	0	0	0	0	3	0	1	0	0	0	0	0	0	0	0	0	0	0	4/5
1670	0	0	0	0	0	0	1	4	-	-	-	-	-	-	-	-	-	-	-	-	-	5/5

DISCUSSION

In the observations of general condition, salivation was observed in all administration groups at approx. 10 – 20 min after administration, which wasprobably due to stimulation of the oral mucosa by trifluoromethanesulfonic anhydride (tri-FMS) or trifluoromethanesulfonic acid. This was followed by the appearance of writhing, decrease in locomotor activity, prone position, bradypnea, ataxic gait, and lacrimation. In the cases that died, this was probably a result of cyanosis, hypothermia, or wasting accompanying aggravation of the general symptoms.

In the autopsies of cases that died, perforation of the pylorus was found, and this was probably a result of the local stimulus property of orally administeredtri-FMSon the mucous membrane, or because super-strong acid trifluoromethanesulfonic acid that formed as a result of the reaction of tri-FMS with body fluids perforated the stomach or caused ulceration. Furthermore, it appeared that gastric content that had drained through the perforation into the abdominal cavity caused cloudy change on the surface of abdominal organs or tissues, becoming peritonitis, with retention of ascetic fluid and pleural fluid. In addition, in 1 case in the 1285 mg/kg group that showed worsening of general condition and died on observation day 3, no perforation of the pylorus was confirmed but as there was adhesion between intraabdominal organs and tissues and retention of ascetic fluid and pleural fluid, it is likely that there was perforation of the pylorus and drainage of gastric content.

In the surviving cases in the 585 mg/kg and higher groups, whitening, thickening, or scarring of the mucosa of the forestomach, the glandular stomach, or the limiting ridge, or else thickening of the membrane of the same region, were found, and these appeared to be signs of ulceration that had recovered. Also, adhesion between intra abdominal organs and tissues and thickening of the splenic capsule were found in 1 case in the 760 mg/kg group, suggesting that the animal had recovered from perforation of the pylorus without dying.

No gross abnormalities that might be attributable to the study substance were found in any other organs in any of the cases.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 value of trifluoromethanesulfonic anhydride (tri-FMS) when administered orally to male SD rats was 1012 mg/kg with a 95% confidence limit of 823 – 1284 mg/kg. The cause of death was considered to be perforation of the pylorus and peritonitis due to the stimulus property of tri-FMS and trifluoromethanesulfonic acid, which is formed when water is added to tri-FMS.

Executive summary:

Male SD rats were given a single dose of 450, 585, 760, 988, 1285, and 1670 mg/kg trifluoromethanesulfonic anhydride throughforced oral administrationin order to investigate the toxicity.

 

1. Death was found in the 760 mg/kg and higher groups from the administration day up to observation day 3, and the LD₅₀ value was 1012 mg/kg, with a 95% confidence limit of 823 – 1248 mg/g.

 

2. In the general condition, salivation, writhing, decrease in locomotor activity, prone position, bradypnea, ataxic gait, lacrimation, cyanosis, and hypothermia were observed.

 

3. In the changes in body weight among the surviving cases, decrease in mean body weight or else suppression of body weight increase were found until observation day 3, but body weight progressed normally from day 5 onward.

 

4.In the autopsies, perforation of the pylorus, retention of ascitic fluid or pleural fluid, cloudy change on the surface of abdominal organs or tissues, and emaciation or thymus involution were found among the animals that died. In the surviving cases of the 585 mg/kg and higher groups, whitening, thickening, or scarring of the mucosa of the forestomach, the glandular stomach, or the limiting ridge, and thickening of the membrane and thickening of the serosa of the same region were observed.

The LD50 value of trifluoromethanesulfonic anhydride (tri-FMS) was 1012 mg/kg with a 95% confidence limit of 823 – 1284 mg/kg. The cause of death was considered to be perforation of the pylorus and peritonitis due to the stimulus property of tri-FMS and trifluoromethanesulfonic acid, which is formed when water is added to tri-FMS.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 012 mg/kg bw

Quality of whole database:

Only available study, performed similarly to OECD 401 Guideline.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Considering the observed LD50 = 1012 mg/kg following oral administration, Trifluoromethansulfonate anhydride is classified for acute oral toxicity in category 4 according to regulation CE n° 1272/2008.