Ampicillin

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Equivalent or similar to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents), with deviations (no data on haematology, clinical biochemistry and organ weight measurements)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1980

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

(No data on haematology, clinical biochemistry and organ weight measurements)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(2S,5R,6R)-6-{[(2R)-2-amino-2-phenylacetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate

Cas Number:

7177-48-2

Molecular formula:

C16H25N3O7S

IUPAC Name:

(2S,5R,6R)-6-{[(2R)-2-amino-2-phenylacetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate

Details on test material:

- Name of test material (as cited in study report): Ampicillin trihydrate
- Lot/batch No.: 61849K
- Other:
Supplier: E.R. Squibb & Sons, Inc. (Princeton, NJ), manufactured by Ersana, Inc. (Humacao, Puerto Rico)

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles Rive:r Breeding Laboratories (Portage, MI)
- Age at study initiation: 7 weeks of age
- Housing: All animals were housed five per cage; Polycarbonate (Lab Products, Int ., Rochelle Park, NJ)
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration (Zeigler Bros , Gardners, PA]; available ad libitum
- Water (e.g. ad libitum): Half deionized/half tap water; automatic watering system (Edstrom Industries, Waterford, VII); available ad libitum.
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.44 ± 0.84 ºC
- Humidity (%): 53 ± 7.4%
- Air changes (per hr): 12 room air changes/h
- Photoperiod (hrs dark / hrs light): fluorescent light 12 h/d

IN-LIFE DATES: From 20/12/1979 to 19/3/1980

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

- Justification for use and choice of vehicle (if other than water): Ampicillin trihydrate is only slightly soluble in water; therefore, corn oil was selected to improve suspendability in the gavage vehicle.
- Preparation: Weighed ampicillin trihydrate was mixed with corn oil in Waring blender, transferred to volumetric flask and brought to volume with corn oil, mixed in flask, then transferred to a beaker and mixed with a stirring bar and magna-stirrer.
- Amount of vehicle (if gavage): 5 mL/kg bw

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 180, 370, 750, 1500 or 3000 mg/kg ampicillin trihydrate in corn oil by gavage; 3000 mg/kg group given 1500 mg/kg 2 X d at least 5 h apart.
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
The highest dose of 3000 mg/kg was selected because no dose-related deaths were seen at 2400 mg/kg in a 14-day study. This dose is the maximum one that was practical to administer to rats (administered as two 1500 mg/kg doses with a dose volume of 5 mL/kg body weight).

Examinations

Observations and examinations performed and frequency:

Observation: 2/day
Body weight: 1/week

Sacrifice and pathology:

Necropsy performed on all animals.

Histologic exams performed on vehicle control and 3000 mg/kg group and on all animals dying during the study.

Tissues examined: regional lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary glands, thigh muscle, sciatic nerve, bone marrow, costo-chondral junction (rib), thymus, larynx, trachea, lungs and bronchi, heart, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph nodes, liver, pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal vesicles/prostate/testis or ovaries/uterus, nasal cavity, brain, pituitary gland, eyes, external and middle ear, and spinal cord.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
The 12 deaths observed in dosed and vehicle control rats were considered to be due to gavage error.
Male and female rats that received 3000 mg/kg ampicillin trihydrate had diarrhea.

BODY WEIGHT AND WEIGHT GAIN
The final mean body weights of the female rats were not related to the dose levels. The final mean body weight of the males that received 3000 mg/kg was 9% lower than that of the vehicle controls.

GROSS PATHOLOGY
No compound-related gross pathology effects were observed.

HISTOPATHOLOGY
No compound-related histopathologic effects were observed.

No dose-related effects were seen in the 13-week studies at 1500 or 3000 mg/kg.

Effect levels

Dose descriptor:

NOEL

Effect level:

3 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No dose-related effects were seen in the 13-week study at 1500 or 3000 mg/kg.

Executive summary:

A thirteen-week study was conducted to evaluate the cumulative toxic effects of repeated administration of ampicillin trihydrate.

Groups of 10 rats of each sex were administered 0,180, 370, 750, 1500, or 3000 mg ampicillin trihydrate/kg in corn oil by gavage, 5 days per week for 13 weeks (dose volume: 5 mL/kg body weight)

Necropsy was performed on all animals. Histologic exams were performed on vehicle control and 3000 mg/kg group and on all animals dying during the study. Tissues examined were: regional lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary glands, thigh muscle, sciatic nerve, bone marrow, costo-chondral junction (rib), thymus, larynx, trachea, lungs and bronchi, heart, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph nodes, liver, pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal vesicles/prostate/testis or ovaries/uterus, nasal cavity, brain, pituitary gland, eyes, external and middle ear, and spinal cord.

The final mean body weights of the female rats were not related to the dose levels. The final mean body weight of the males that received 3000 mg/kg was 9% lower than that of the vehicle controls. Male and female rats that received 3000 mg/kg ampicillin trihydrate had diarrhea. No compound-related gross or histopathologic effects were observed.

No dose-related effects were seen in the 13-week study at 1500 or 3000 mg/kg.