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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 13, 1994 - July 28, 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
(R)-α-phenylethylammonium (-)-(1R, 2S)-(1,2-epoxypropyl)phosphonate monohydrate
EC Number:
418-570-8
EC Name:
(R)-α-phenylethylammonium (-)-(1R, 2S)-(1,2-epoxypropyl)phosphonate monohydrate
Cas Number:
25383-07-7
Molecular formula:
C11H20NO5P
IUPAC Name:
(R)-α-phenylethylammonium (-)-(1R, 2S)-(1,2-epoxypropyl)phosphonate monohydrate
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Fosfomycin PEA salt
- Physical state: white crystalline powder
- Lot/batch No.: 4177
- Expiration date of the lot/batch: At least 3 years from the manufacturing date
- Stability under test conditions: at least 3 years
- Storage condition of test material: plastic bag in a catboard box, at room temperature protected from the light.
- Other: manufacturing date: June 10, 1994.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Italia S.p.A.
- Age at study initiation: 7/9 weeks
- Weight at study initiation: Males: 225-250 g. Females: 200-225 g
- Housing: Individual caging in air-conditioned rooms. Grill cages 40.5x38.5x18h cm with stainless steel feeder.
- Diet (e.g. ad libitum): Ad libitum (GLP 4 RF21 top certificate pelleted diet).
- Water (e.g. ad libitum): Ad libitum (from the municipal water main system, filtered).
- Acclimation period: 5 days before the start of the test.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ºC
- Humidity (%): 55 ± 10 %
- Air changes (per hr): 20 per hour (filtered on HEPA 99.97 %)
- Photoperiod (hrs dark / hrs light): 12 h dark/12 h light (7 a.m. - 7 p.m.)

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 6x5 cm of the body dorsal surface.
- % coverage: 10 %
- Type of wrap if used: the treated area was covered with a porous gauze dressing fixed to the skin with hypoallergenic non-irritation tape. The test side was further covered in a suitable manner in order to ensure that the animals could not ingest the test substance.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the exposure period the residual test substance was wiped off.
- Time after start of exposure: about 24 h.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000mg/kg bw. Individual dosages were based on body weight taken just before treatment.
- For solids, paste formed: No, the test article was administrated by uniform application onto the cleared area.
Duration of exposure:
About 24 hours.
Doses:
2000 mg/kg bw.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical signs and mortality: at 30 minutes, 2, 4 and 6 hours on the first day after the administration on exposure day and then twice a day up to termination of the observation period.
Weighing: twice pre-trial (at randomization and on day 1 just before treatment), on days 8 and 15.
- Necropsy of survivors performed: Yes, animals (fasted overnight) were killed by excision of the femoral arteries, after i.p. overdosage anesthesia with 5 % sodium pentobarbital, at the end of the observation period.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: clinical signs and behaviour, body weight and gross pathology.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animals died during the study.
Clinical signs:
No clinical signs nor behavioural alterations were observed in any treated rat. Slight erythema was observed at the application site during the first days of the study in two male and one female rats.
Body weight:
Body weight gain of all treated animals was considered within normal limits.
Gross pathology:
No changes were observed in the animals killed at the end of the study.

Any other information on results incl. tables

Table 1. Clinical signs frequency (cumulative)

Clinical signs

No. of rats affected

Signs observed (time)

From*

Toº

Treatment site: erythema

3

2d

3d

Recovery

3

3d

4d

*) First observation in one or more animals

º) Last observation in one or more animals

d) Days

Table 2. Body weight (g). Dose: 2000 mg/kg.

Day

1 M

2 M

3 M

4 M

5 M

6F

7F

8F

9F

10F

Pre-trial

270

273

271

268

255

237

229

220

233

214

1*

280

285

282

288

279

241

243

235

250

225

8

333

342

341

324

323

253

248

250

256

227

15

379

400

388

366

378

277

264

284

278

238

*pre-dosing.

Table 3. Gross pathology examination.

Dose

(mg/kg)

Animals

Macroscopic findings

2000

Males No. 1-5

No appreciable macroscopic findings

 

Females No. 6-10

No appreciable macroscopic findings

 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
EU criteria.
Conclusions:
LD50 value of test article in rats by dermal route at 24 h exposure period is higher than 2000 mg/kg bw.
Executive summary:

A toxicity study in Sprague Dawley Crl:CD (SD) rats (5 males and 5 females) with a single dermal administration of the test article Fosfomycin PEA salt at the dosage of 2000 mg/kg bw (24 hours exposure) was performed in accordance with EU Method B.3 and OECD Guideline 402. The test article was administered by uniform application on the cleared area and covered for the exposure period of 24 hours. The day of treatment was considered day 1 of the study. The animals were weighed twice before treatment (at randomization and on day 1 just before treatment) and on days 8 and 15. They were clinically observed for 24 days after patch removal. On day 15 all treated rats were killed by excision of the femoral arteries, after i.p. overdosage anesthesia with 5% sodium pentobarbital and they were submitted to a thorough autopsy.

No deaths occurred as a result of treatment.

No clinical signs or behaviour alterations were observed during the study.

Slight transient erythema was occasionally observed at the application site in some animals during the first day of the study.

The body weight gain appeared normal.

No changes were found at the gross pathology examination performed at the end of the observation period.

In conclusion, the test article Fosfomycin PEA salt, when administrated by dermal route to rat, under the conditions adopted in this experiment, did not cause mortality nor show systemic toxic effects at the limit dose of 2000 mg/kg bw. The LD50 by dermal route is higher than 2000 mg/kg bw.