Amoxicillin

Endpoint summary

Description of key information

Acute oral toxicity: Key study. Test method OECD 423. GLP study. The oral LD50 in rats was determined to be > 2000 mg/kg bw.
Acute dermal toxicity: Key study: Test method OECD 402. GLP study. The dermal LD50 in rats was determined to be > 2000 mg/kg bw.

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:

December 2015 to February 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Test method according to OECD 423. GLP study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Husbandry of laboratory animals of the Experimental Medicine Centre at the Medical University in Białystok.
- Age at study initiation: 3 females at the first step were 8 weeks-old and the other 3 females were 10 week-old
- Weight at study initiation: 197.3 g (3 females first step) and 193.7 g (3 females second step)
- Fasting period before study: 19 hours
- Housing: Plastic cages (58x37x21 cm) covered with wire bar lids. Three animals per cage. UV-sterilized wood shavings were used as bedding.The environment of the animals was enriched by placing wooden blocks and nesting materials for laboratory animals in the cages.
- Diet (e.g. ad libitum): Murigran standard laboratory food ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24 ºC
- Humidity (%): 25 - 50 %
- Air changes (per hr): 16 times per hour.
- Photoperiod: 12 hours light/ 12 hours dark

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

CMC sodium salt

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 400 mg test subtance/mL
- Amount of vehicle (if gavage): 0.5 mL/100 g b.w.
- Justification for choice of vehicle: Low water solubility, an attempt to disolve/suspend the test item in oil was conducted, solubility was weak. Carboxymthylcellulose sodium salt was used because his negligible toxicity.

DOSAGE PREPARATION
Shortly before the administration.

CLASS METHOD
- Rationale for the selection of the starting dose: Based on the bibliographic toxicity data of the test subtance.

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

6 in total, 3 female rats at the first step, 3 female rats at the second step

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The general observation at least once a day, detailed clinical observations on the administration day, 10, 30 and 60 minutes after the administration and then at hourly intervals up to 5 hours, then once a day up to 14 days. Animals were weighed directly before the administration of the test item, on day 7 and 14 before euthanasia.
- Necropsy of survivors performed: yes, after the day 14th observation period, all surviving animals were euthanized and subjected to gross examination.
- Other examinations performed: clinical signs, body weight, gross examinations.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities were recorded.

Clinical signs:

other: No signs of toxicity were stated.

Gross pathology:

The gross examination did not reveal any pathological changes.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral-LD50 for amoxicillin trihydrate in female rats is above 2000 mg/kg bw.

Executive summary:

An acute oral toxicity study was conducted according to the acute toxic class method (OECD 423) under GLP conditions. In a first step amoxicillin trihydrate was administered at a single dose of 2000 mg/kg bw to 3 Wistar female rats suspended in 0.5 carboxymethylcellullose sodium salt in a volume of 0.5 mL/100 g b.w. by gavage, at the second step the test item was adminstered to 3 additional female rats under the same conditions. After the administration the test animals were observed for 14 days, general and detailed clinical observations were performed on a daily basis, body weights were determined on day 0, 7 and 14. After the 14 -day observation period the animals were euthanized and subjected to detailed gross examination. All the tested animals survived the entire experiment, the examinations did not reveal any pathological change in the animals. The oral LD-50 for amoxicillin trihydrate is above 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study is GLP compliant and has Klimisch score of 1.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: According to OECD 402 and EU method B3 with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Wistar male and female rats (Cmdb: WI; outbred).
- Source:obtained from the husbandry of laboratory animals of the Experimental Medicine Centre at the Medical University in Białystok.
- Age at study initiation: males 8 week old, females 10 week old.
- Weight at study initiation: average body weight males 249.8 and females 203.6 g.
- No fasting period before study.
- Housing: plastic cages covered with wire bar lids, dimensions 58 x 37 x 21 cm. UV-sterilized wood shavings were used as bedding, and the environment was enriched with wooden blocks and nesting materials for laboratory animals.
- After application of the test item, each animal was housed individually.
- After removal of the test item, group housing (5 animals of the same sex per cage).
- Diet: ad libitum access to "Murigran" standard granulated fodder (batch number: 7/15, 8/15 and 1/15) produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz
- Water: ad libitum access to tap water.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24.
- Humidity (%): 25-50.
- Air changes (per hr): 16.
- Photoperiod (hrs dark / hrs light): 12h light / 12h dark.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- One day before the test, fur from the dorsal area of the trunks of the animals was shaved with an electric shaver.
- Area of exposure: 30-45cm2
- % coverage: 10% of the body surface area.
- Type of wrap if used: gauze patches.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the residual test item was removed using water.
- Time after start of exposure: 24h.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000mg/kg bw.
- The test item, in form of powder, was applied to gauze patches, and moistened of a few drops of water.

Duration of exposure:

24h

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: the observation of all animals for mortality and morbidity was conducted twice a day or once a day (on days off). The detailed clinical observations were made on the application day (day 0) at hourly intervals up to 5 hours. From the 1st to the 14th day of the experiment, the detailed clinical observations were performed once a day.
- Body weights of the animals were determined on days 0 (directly before the application of the test item), 7, and 14 (before euthanasia).
- After the 14-day observation period, all animals were euthanized by intraperitoneal administration of morbital at a dose of 200 mg/kg b.w. and transferred to a detailed gross examination: observation of the external body surface, all natural apertures, and the cranial, thoracic, and abdominal cavities with their contents.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities were recorded.

Clinical signs:

other: No clinical signs were noticed.

Gross pathology:

The gross examination did not reveal any pathological changes in the examined animals.

During the experiment, the air temperature dropped below 19ºC a few times, and the relative air humidity dropped below 30% a few times. These changes were temporary and did not influence the study course and results.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Dermal-LD50 > 2000 mg/kg bw.

Executive summary:

An study of acute dermal toxicity on rats was performed for the test substance amoxicillin trihydrate according to OECD No.402 and EU method B3 under GLP conditions. Amoxicillin trihydrate at a single dose of 2000 mg/kg body weight was applied to the shaved dorsal area of the trunks of 5 males and 5 females. After the application of the test item, the animals were observed for 14 days. General and detailed clinical observations of all animals were performed daily during the entire experiment. Body weights of the animals were determined on days 0, 7, and 14. After the 14-day observation period, the animals were euthanized, dissected, and subjected to detailed gross examinations.Based on the results of the study, the dermal-LD50 is greater than 2000mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The study is GLP compliant and has Klimisch score of 1.

Additional information

Acute oral toxicity: Key study: An acute oral toxicity study was conducted according to the acute toxic class method (OECD 423) under GLP conditions in rats up to 2000 mg/kg bw/day. After the administration the test animals were observed for 14 days The oral LD-50 for amoxicillin trihydrate is above 2000 mg/kg bw.

Acute dermal toxicity: Key study: An study of acute dermal toxicity on rats was performed for the test substance amoxicillin trihydrate according to OECD No.402 and EU method B3 under GLP conditions in rats up to 2000 mg/kg bw. After the application of the test item, the animals were observed for 14 days. Based on the results of the study, the dermal-LD50 was greater than 2000mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
Only one test available

Justification for selection of acute toxicity – inhalation endpoint
According to REACH Annex VIII, column 2: In addition to the oral route, for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route need be provided. The information is provided for dermal route.

Justification for selection of acute toxicity – dermal endpoint
Only one study available.

Justification for classification or non-classification

Based on the available data (oral and dermal LD50 > 2000 mg/kg bw), the substance is not classified for acute toxicity according to CLP Regulation (EC) no. 1272/2008.