Registration Dossier

Administrative data

Description of key information

p-TSA is of low acute toxicity. Acute oral LD50 is 2330 mg/kgbw and dermal toxicity much lower.

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:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A 2 page study report is available. The study was performed pre-GLP. The study was performed according to a method similar to OECD401.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Very high dose volume. Animals were only observed for signs of intoxication and necropsy was performed on surviving animals.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Source: TNO
Body weight: males 242 to 380 g, females 120 to 180 g.
The rats were housed in groups of five in screem-bottomed stainless steel cages, in a well-ventilated room, maintained at 23-250 C.
Before dosing the rats were fasted overnight.
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Doses:
2075, 2500, 3000, 3600, 4325 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Dosing: By gavage as 25 % (w/v) suspension in propylene glycol to groups of five males and five females in single doses of 8.3, 10.0, 12.0, 14.4 or 17.3 ml per kg body weight.
They were observed for signs of intoxication during a 14-day period, after which autopsies were carried out on the survivors.
Statistics:
The LDso was calculated according to the method of Wei! (Biometrics 8, (1952) 249-263).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 330 mg/kg bw
95% CL:
2 080 - 2 600

Results:

Within a few hours after dosing the rats showed sluggishness, followed by loss of consciousness. Death occurred between 4 and 50 hours after dosing. Later on the survivors recovered gradually and looked quite healthy again at the end of the observation period. Macroscopic examination of the survivors at autopsy revealed dark discolouration of the liver in the rats of all dose groups. Some of the rats showed mottled kidneys. No other signs of treatment-related gross alterations were seen.

Dose

Mortality

Suspension ml/kg

Test substance g/kg

males

females

%

8.3

2.08

1/5

3/5

40

10.0

2.50

1/5

4/5

50

12.0

3.00

4/5

5/5

90

14.4

3.60

3/5

5/5

80

17.3

4.33

5/5

5/5

100

Interpretation of results:
Category 5 based on GHS criteria
Remarks:
Migrated information
Conclusions:
From the mortality-figures the LD50 of para-toluene sulphonamide was calculated to be 2.33 g per kg body weight, with 2.08 and 2.60 as the 95% confidence limits. Therefore, the test substance can be classified in Category V according to GHS.
Executive summary:

An acute oral toxicity study was performed according to a method similar to OECD401 and pre-GLP. 5 male and 5 female rats were dosed with 8.3, 10.0, 1.20, 14.4 or 17.3 ml/kg bw. The animals were observed for signs of intoxication during a 14-day period, after which autopsies were carried out on the survivors. Within a few hours after dosing the rats showed sluggishness, followed by loss of consciousness. Death occurred between 4 and 50 hours after dosing. Later on the survivors recovered gradually and looked quite healthy again at the end of the observation period. Macroscopic examination of the survivors at autopsy revealed dark discolouration of the liver in the rats of all dose groups. Some of the rats showed mottled kidneys. No other signs of treatment-related gross alterations were seen. From the mortality-figures the LD50 of para-toluene sulphonamide was calculated to be 2.33 g per kg body weight, with 2.08 and 2.60 as the 95% confidence limits. Therefore, the test substance can be classified in Category V according to GHS.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 330 mg/kg bw
Quality of whole database:
Although of low quality, the results are in-line with other available information.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1957
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Limited reporting, none GLP, only one rabbit was dosed per dose level.
Qualifier:
no guideline followed
Principles of method if other than guideline:
6 rabbits were dosed with increasing amounts of test substance applied on the skin and observed for evidence of toxicity
GLP compliance:
no
Test type:
other:
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
BW of rabbits between 1.6 and 2.3 kg
Type of coverage:
not specified
Vehicle:
corn oil
Details on dermal exposure:
A 25% suspension in corn oil was applied to the closely clipped, intact skin of New Zealand rabbits and observations made for evidence of toxicity. The treated areas were covered with plastic shields and a leather collar placed around the neck of each animal to prevent access to the sample.
Duration of exposure:
No data
Doses:
2.0, 3.5, 5.0, 6.0, 7.5 and 7.5 g/kg bw based on tests substance (Highest dose level of 7.5 g/kg was applied to both a male and a female animal)
No. of animals per sex per dose:
1. Only highes dose 2 (one male and one female)
Control animals:
not required
Details on study design:
Examinations included: observations on clinical signs and body weight changes during 5 days.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
7 500 mg/kg bw
Based on:
test mat.
Mortality:
No mortality obsrved
Clinical signs:
No signs of systemic toxicity developed. Appetite and activity remained about normal. There was no evidence of paralysis such as developed when rabbits were fed the product orally.
Body weight:
BW increased in 5 days between 0 and 6%, without relation to dose level.
Gross pathology:
Not performed

Animal

sex

BW in kg

Dose g/kg bw

BW change after 5 days

Results

1

Female

1.7

2.0

4.0%

survived

2

Male

2.1

3.5

6.0%

survived

3

Female

1.6

5.0

0.0%

survived

4

Female

1.9

6.0

5.0%

survived

5

Male

2.3

7.5

0.0%

survived

6

Female

2.0

7.5

3.0%

survived

The highest application of 7.5 g/kg bw was non lethal. No signs of systemic toxicity developed. Appetite and activity remained about normal. There was no evidence of paralysis such as developed when rabbits were fed the product orally.

The test article was not acutely toxic when applied to the skin of rabbits.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No mortality or systemic toxicity was observed following dermal application of 7500 mg/kg bw of o/p-TSA when applied as a 25% suspension in corn oil.
Executive summary:

The substance tested is a mixture of ortho-toluene sulfonamide (o-TSA: 30%) and para-toluenesulfonamide (p-TSA: 70%).

A 25% suspension in corn oil was applied to the closely clipped, intact skin of New Zealand rabbits and observations made for evidence of toxicity. The treated areas were covered with plastic shields and a leather collar placed around the neck of each animal to prevent access to the sample.

The following dose levels were applied on one animal each: 2.0, 3.5, 5.0, 6.0, 7.5 (male) and 7.5 (female) g/kg bw. Examinations included: observations on clinical signs and body weight changes during 5 days.

 

The highest application of 7.5 g/kg bw was non lethal. No signs of systemic toxicity developed. Appetite and activity remained about normal. There was no evidence of paralysis such as developed when rabbits were fed the product orally.

The test article was not acutely toxic when applied to the skin of rabbits.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
7 500 mg/kg bw
Quality of whole database:
Substance is of low acute oral toxicity, not requiring classification. Also no classification is required for skin or eye irritation. Information on absorption indicates that p-TSA is rapidly and completely absorbed by oral route, en only 20% by dermal route. Further acute testing by dermal route is therefore scientifically unjustified.

Additional information

Oral:

There are two studies available evaluating the acute oral toxicity:

An acute oral toxicity study was performed according to a method similar to OECD401 and pre-GLP. 5 male and 5 female rats were dosed with 8.3, 10.0, 1.20, 14.4 or 17.3 ml/kg bw. The animals were observed for signs of intoxication during a 14-day period, after which autopsies were carried out on the survivors. Within a few hours after dosing the rats showed sluggishness, followed by loss of consciousness. Death occurred between 4 and 50 hours after dosing. Later on the survivors recovered gradually and looked quite healthy again at the end of the observation period. Macroscopic examination of the survivors at autopsy revealed dark discolouration of the liver in the rats of all dose groups. Some of the rats showed mottled kidneys. No other signs of treatment-related gross alterations were seen. From the mortality-figures the LD50 of para-toluene sulphonamide was calculated to be 2.33 g per kg body weight, with 2.08 and 2.60 as the 95% confidence limits.

 

Similar results were obtained by a more recent Japanese study performed in 1994. Although the study was very extensive, reporting is only available from OECD SIDS dossier and a poor English translation of the Japanese report. The study evaluated the acute oral toxicity of p-TSA rats. Groups of 5 female animals received dose levels of 889, 1333, 2000 and 3000 mg/kg, and a group of 5 males 2000 mg/kg males. Observations included detailed clinical signs, body weights, and gross pathological examination. For the dead animals, all females of the 3000 mg/kg group and the 2000 mg/kg treated males the major organs and tissues were fixated for histopathological examination.

One animal from the 3000 mg group and two females of the 2000 mg group died on day 1 or 2. In the males treated at 2000 mg no mortality occurred. Directly following dosing there were clinical signs observed in all groups consisting of reduced activity, apathy, hunched posture and abnormal gait. Also haematuria was observed. Histopathology effects were seen in renal tubular epithelial cells and epithelial cells in urethra or bladder, and pulmonary oedema. In the surviving animals clinical signs were resolved from day 3. The LD50 was concluded to be > 2000 mg/kg bw for both males and females. Possibly there is a sex difference in toxicity.

All information, including from literature is presented in the below:

Route

Species (sex and strain)

LD50/LC50

Reference(s)

p. o.

Rat (male & female/ Wistar)

LD50 = 2330 mg/kg bw

TNO (1978)

Rat (male & female; Sprague Dawley Crj: CD(SD)

LD50 >2000 mg/kg

(MHW, cited by OECD, 1994)

Hatano (1991)

Mouse (sex and strain n. p.)

LD50 = 400 mg/kg

Sax and Lewis (undated, cited by OECD, 1994)

Rat and/or rabbit (sex and strain n. p.)

LD100 ~ 4.7 g/kg (in 15% suspension of 2% aqueous solution of methyl cellulose)

Monsanto Co. (1947)

Rat (sex and strain n. p.)

LD100 ~ 3.2 g/kg (in 15% olive oil)

Rat (sex and strain n. p.)

LD50 = 2400 mg/kg bw for mixture (41%o-TSA; 51%p-TSA)

EMEA (1999)

Wild bird species (sex and strain n. p.)

LD50 = 75 mg/kg

Schafer (1972; cited by OECD, 1994); RTECS (2000)

Rabbit (sex and strain n. p.)

LD100 ~ 1.4 g/kg (in 15% olive oil)

Monsanto Co. (1947)

The information from literature is generally of very low validity: very old, with no information available on test methods and product tested.

Additional information available from cross-reading (o-TSA and mixture of o/p-TSA) also support these findings generally low acute systemic toxicity.

 

Dermal:

Data is available from cross-reading with a product containing a mixture of ortho-toluene sulfonamide (o-TSA: 30%) and para-toluenesulfonamide (p-TSA: 70%) itself. The report is of low validity, but it indicates that levels of 7500 mg/kg bw do not result to any signs of toxicity when exposed to the skin as 25% suspension in corn oil. Besides the cross-reading to o-TSA, this also indicates no toxicity from at least 5000 mg p-TSA that is present at about 70% in the final product.

 

Further support is available from information on dermal absorption: p-TSA is of low acute oral toxicity, not requiring classification. Also no classification is required for skin or eye irritation. Information on absorption indicates that p-TSA is rapidly and completely absorbed by oral route, but only 20% by dermal route. Further acute testing by dermal route is therefore scientifically unjustified.

 

Inhalation:

vp is (less than) 2.86*10-7 kPa (= 0.0003 Pa) @ 20°C, and the respirable fraction (≤ 4 µm) of the crystalline solid is 0 %. Additionally, the likelihood of exposures by aerosols from the use of the substance is also low (water solubility is low with 3.1 g/L at 20°C).

Although no data is available via inhalation route, similar low toxicity can be expected.


Justification for selection of acute toxicity – oral endpoint
Key study.

Justification for selection of acute toxicity – inhalation endpoint
In accordance with column 2 of REACH Annex VIII, the test for acute inhalation toxicity (required in section 8.5) does not need to be conducted. Vp is low ( less than 2.86*10-7 kPa (= 0.0003 Pa) @ 20°C), and the crystalline solid is of low dustiness (the respirable fraction (≤ 4 µm) is 0%). In combination of low likelihood of exposures by aerosols from the use of the substance and the general low acute toxicity, testing of acute toxicity by inhalation is not necessary.

Justification for selection of acute toxicity – dermal endpoint
Data from cross-reading and limited validity. No other data available.

Justification for classification or non-classification

Available information indicates no toxicity by dermal route, and low oral toxicity with an LD50 of 2330 mg/kg resulting to a GHS classification for acute oral toxicity of Cat.5. In the EU however no classification is needed.

By inhalation route no data is available, but similar low toxicity can be expected.

Consequently no classification for acute toxicity is required for EU CLP.

The acute oral studies show effects of neurodepression at near lethal doses. Due to low dermal absorption, and unlikely exposures via inhalation (very low vp, solid with no respirable fraction) and general low exposures, no narcotic effects will occur in humans. Classification for STOT-SE Cat.3 for narcotic effects is therefore not indicated.