Registration Dossier

Administrative data

Description of key information

LD50 oral: 2065 mg/kg in rat.
LD50 dermal: >2000 mg/kg in rat

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:
weight of evidence
Study period:
January 1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Although the study is pre-dating OECD method and GLP, the description is solid justifying sufficient validity of results reported and follows scientific principles at the time of study (1969).
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
only females used, no negative control
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
12 hours prior to application rats were not fed. During observation period of 7 days rats received Standard Altromin R feed (supplied by Altromin GmbH, Lage/Lippe, Germany) and tab water.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
10% aqueous solution
Details on oral exposure:
single application by gavage of 10% aqueous solution.
Doses:
630, 1000, 1600, 2500 and 4000 mg/kg bw
No. of animals per sex per dose:
10 females per dose
Control animals:
no
Statistics:
LD50 was derived using the Kärber method.
Sex:
female
Dose descriptor:
LD50
Effect level:
2 065 mg/kg bw
Based on:
test mat.
Mortality:
at 630 mg/kg bw: no mortality (0/10)
at 1000 mg/kg bw.: 0/10
at 1600 mg/kg bw.: 3/10
at 2500 mg/kg bw.: 8/10
at 4000 mg/kg bw.: 10/10
Clinical signs:
all death occured within 30 minutes to 24 hours following application.
Clinical signs were imbalance, paralysis of rear extremities and death in lateral position. Ras dosed 2500 mg/kg bw showed slight shivering convulse.
Body weight:
Body weight at start of test: 84 - 108 g/rat (average 93 g). Body weight development not reported.
Gross pathology:
Upon autopsy clear signs of corrosivity to mucosa of gastro-intestinal tract were seen in animals that died during the study.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 (oral, rat, female) was determined being 2065 mg/kg bw.
Executive summary:

In this study 10 female Wistar rats per dose group were orally exposed (by gavage) to 630, 1000, 1600, 2500 and 4000 mg/kg bw. The substance was applied as 10% aqueous solution and the observation period was 7 days. Death occured within 24 hours in the dose groups 1600 (3/10), 2500 (8/10) and 4000 (10/10) mg/kg bw. and the LD50 was set to 2065 mg/kg bw. Although the study is pre-dating OECD method and GLP, the description is solid justifying sufficient validity of results reported and follows scientific principles at the time of study (1969).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 065 mg/kg bw

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:
experimental study
Adequacy of study:
key study
Study period:
2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:Charles River Deutschland GmbH, D-97633 Sulzfeld.
- Age at study initiation:Approximately 8 weeks (males) and 12 weeks (females) at the time of administration.
- Weight at study initiation: See Table 2.
- Health conditions: A health inspection was performed prior to the commencement of treatment to ensure, that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from any abnormality.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Mean of 22°C +/- 3 °C (continuous control and recording).
- Humidity (%): Mean of 30 – 70 % (continuous control and recording).
- Air changes (per hr): 12 per hour.
- Photoperiod (hrs dark / hrs light):Artificial light from 6 a.m. to 6 p.m.
- Cages:Single caging in Makrolon cages type III (37.5 cm x 21.5 cm bottom area, 18 cm height). Wire mesh lids. Sanitation of cages once a week.
- Bedding material:Aspen wood chips, Fa. ABEDD Dominik Mayr KEG, A-8580 Köflach, autoclaved. Random samples of the bedding material are analysed for contaminants by the supplier. Changes 1 / week.
- Environmental enrichment:Nibbling wood bricks (10 cm x 2 cm x 2 cm) and nesting material, both from the same material and source as the bedding material, were offered to the animals once a week.
- Feed: Ssniff R/M-H maintenance diet for rats and mice (item V1534-300) ad libitum, supplied by Ssniff Spezialdiäten GmbH, 59494 Soest, Germany. Analysis of the feed for ingredients and contaminants is performed randomly by Ssniff.
- Water:Tap water, from an automatic watering system, ad libitum.
Random samples of the water are analysed by the "AGES",
A-1226 Vienna, to check, if the water fulfils the requirements for drinking water for humans.
-Identification:Labelling with felt-tipped pen on the tail and on the cage.
-Acclimatisation: At least 7 days.
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
"SULPHAMIDIC ACID" was administered once topically on an area of approximately
6.5 cm x 8 cm on the dorsal thoracic region of 5 male and 5 female Sprague Dawley rats.
The dose was 2000 mg per kg body weight.
A cellulose patch with the calculated amount of the test substance on the surface and soaked with deionised water to get optimal contact with the skin, was applied to the test site and held in place by fixing marginally with non irritating tape.
The test site was covered by a semi-occlusive dressing.
The duration of the exposure was 24 hours.
Duration of exposure:
The duration of exposure was 24 hours.
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 per sex per dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: yes
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived until the scheduled termination of the study.
Clinical signs:
See Table 3.
General findings: All animals did not show any clinical signs during the entire observation period.
Observations of skin condition: Exposed skin was not found to be altered by the test substance.
Body weight:
Body weights were determined
• before administration.
• 7 days p.a.
• 14 days p.a.
Body weight gain was calculated for each week of the study, i.e. between
• 0 and 7 days p.a.
• 7 and 14 days p.a.
Gross pathology:
See Table 4.
No abnormal findings were made in the animals at terminal necropsy.
Other findings:
Sex differences:
No noteworthy sex difference in the response to the test substance was derived from clinical observations or post-mortem findings.

Table1: Synopsis of the results

Sex

Animal

Dose

Number of animals

 

Nos.

(mg / kg b.w.)

exposed

affected

deceased

m

321-325

2000

5

0

0

f

326-330

2000

5

0

0

Table2: Body weights and body weight gain.

Individual data, mean and standard deviation SD.

Dose

Animal

Body weight (g)

Body weight gain (g)

Sex

No.

before
administr.

7 days
p.a.

14 days
p.a.

death

0-7 days
p.a.

7-14 days
p.a.

 

321

293

340

388

-

47

48

2000 mg/kg

322

278

335

378

-

57

43

male

323

289

312

347

-

23

35

 

324

289

328

378

-

39

50

 

325

271

296

331

-

25

35

 

mean

284.0

322.2

364.4

-

38.2

42.2

 

SD

9.2

18.1

24.2

-

14.5

7.0

 

326

242

254

268

-

12

14

2000 mg/kg

327

253

253

261

-

0

8

female

328

229

230

234

-

1

4

 

329

234

241

252

-

7

11

 

330

233

235

246

-

2

11

 

mean

238.2

242.6

252.2

-

4.4

9.6

 

SD

9.5

10.7

13.2

-

5.0

3.8

Table3: Observations in life.

Findings

Dose
(mg / kg), sex

No. of the affected animals

Observation time
(p.a.)
   first      last

Maximum grade of severity

no clinical signs

2000 m

321, 322, 323, 324, 325

0 h / 14 d

-

 

2000 f

326, 327, 328, 329, 330

0 h / 14 d

-

Table4: Necropsy findings.

SYSTEM
Organ, finding

Dose
(mg / kg)
sex

No. of affected
animals

no abnormal findings

2000, m

321, 322, 323, 324, 325

 

2000, f

326, 327, 328, 329, 330

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No local or systemic test substance related effects were noted from clinical observations or post-mortem examination at a dose of 2000 mg test substance per kg body weight. Therefore, the LD50 (dermal, rat) is >2000 mg/kg bw.
Executive summary:

No local or systemic test substance related effects were noted in this limit test for acute dermal toxicity, applying 2000 mg/kg bw semiocclusively. Clinical observations and post-mortem examination did not reveal any test substance related effects. Therefore, the LD50 (dermal, rat) is >2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute toxicity by oral exposure

Sulphamidic acid has been assessed for acute oral toxicity by several studies.

Ambrose et al. investigated the acute toxicity in 1942 by applying up to 1.6 g/kg bw of sulphamidic acid to rats but also equimolar amounts of ammonium sulphamate. However, at the highest dose tested (1.6 g/kg bw sulphamidic acid) the LD50 value was not reached as only 2 out of 8 animals at the high dose group were found dead after 12 – 20 hours of exposure (by gavage). When equimolar amounts of ammonium sulphamate (approx. 1.88 g/kg bw) were applied in the same test design, no mortality was observed. Thus, mortality observed with sulphamidic acid at 1.6 g/kg bw may be mainly attributable to the very low pH of the test substance.

Marhold et al. published in a check Journal in 1972 results for acute oral toxicity to rats for sulphamidic acid to be 3160 mg/kg bw. As only an abstract of the publication is available in English, no further details are known and the reliability of this study was therefore considered not assignable (Klimisch 4). However, this result is widely used in the public domain for sulphamidic acid.

In a Russian publication from 1987 (no translation available but only secondary literature) an LD50 of 1450 mg/kg bw to rats is reported according to secondary sources. However, some secondary sources do indicate that in this publication rather behavioural changes such as altered sleep time (including change in righting reflex), excitement and rigidity (including catalepsy) of animals was observed and not necessarily mortality and thus this result maybe should be considered as an EC50 value rather than a LD50-value. Hence, due to lack of study details and clarity about the effects observed/reported this study is considered not assignable (Klimisch 4) and should not be given too much weight if any.

The most reliable study available on acute oral toxicity (considered reliable with restrictions, Klimisch 2) has been performed by Hoechst toxicology department in 1969. The study report is available and of good quality and although only female rats were used in this study and no negative control was used, the study design was in principle in line with OECD guidelines as developed some time later. Five dose groups (630, 1000, 1600, 2500, 4000 mg/kg bw) were tested and at 1600 mg/kg bw 3 out of 10 animals were found dead (at lower doses no mortality was observed). Whereas at 2500 mg/kg 8/10 animals were found dead at 4000 mg/kg all animals died. Mortality occurred within 24 hours after dosing (by gavage) in all cases. The LD50 in this study was set to 2065 mg/kg bw and observations made are well supported by the data published by Ambrose et al. (see above).

In summary, the LD50 value of 2065 mg/kg bw appears reliable and supported by the finding published by Ambrose et al. The other two publications (EC50 of 1450 mg/kg bw and LC50 of 3160 mg/kg bw) are of limited validity and cannot be assessed in detail.

Thus, in a weight of evidence approach the LD50 value for acute oral toxicity to rats taken forward for hazard and risk assessment is 2065 mg/kg bw.

Acute toxicity by inhalation exposure

No studies on acute toxicity of sulphamidic acid by inhalation were identified and considering the rather course particle size (the particle size was determined being 505.28 µm (median diameter) with a 10% percentile of 189.74 µm - No particles were found being below 5 µm and only 0.5 % of particles were smaller than 10 µm) and the very low vapour pressure of 0.8 Pa at 20 °C and 2.5 Pa at 100 °C, inhalation exposure to sulphamidic acid is not considered relevant.

Acute toxicity by dermal exposure

The acute dermal toxicity of sulphamidic acid was investigated by an OECD402 limit test according to GLP where a dose of 2000 mg/kg bw was applied to rat skin (males and females, semiocclusive). No mortality occurred in this study and also no treatment related effects to the animals were observed.

Acute toxicity by other routes of exposure

Ambrose et al. has investigated in 1942 also the toxicity of sulphamidic acid (pH of 0.82) and its ammonium salt (pH 4.82) by intraperitoneal exposure (compare to oral exposure above). Whereas the LD50 found for sulphamidic acid was lower than 100 mg/kg bw (at 100 mg/kg bw as lowest dose tested 4 out of 5 animals died) , the LD50 for ammonium sulphamate was found to be in the range of 400 – 940 mg/kg bw. These finding do support the assumption that the strong acidity of sulphamic acid is the dominant effect once the substance is absorbed and also show that the absorption rate of sulphamidic acid in the gastrointestinal tract in presumably lower than 10% when comparing these findings with those found by the same author by applying the substances through oral exposure.

The following information is taken into account for hazard and risk assessment:

LD50 oral: 2065 mg/kg bw in rat.

LD50 dermal: >2000 mg/kg bw in rat

Value used for CSA:

Acute oral toxicity: (LD50: 2065 mg/kg bw)

Acute dermal toxicity: No adverse effect observed (LD50: >2000 mg/kg bw)

Acute inhalation toxicity: No study available


Justification for selection of acute toxicity – oral endpoint
most reliable study in this weight of evidence approach

Justification for classification or non-classification

Based on the test results, no classification for acute toxicity is proposed for acute oral or dermal toxicity of this substance according to Regulation (EC) NO 1272/2008 of the European Parliament and of the Council of 16 December 2008. Data on acute inhalation toxicity is not required as the substance is a crystalline and course material with negligible vapour pressure. Also, classification for aspiration hazards according to CLP (Regulation EC No 1272/2008) is not required as the substance is solid and not a hydrocarbon. The available acute studies do not indicate any specific target organ toxicity effects and thus classification for STOT Single Exposure according to CLP is not required.