Phenoxymethylpenicillin potassium

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1987

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Two-years study design. Groups of 50 rats and 50 mice of each sex received penicillin VK in corn oil by gavage 5 days for 103-104 weeks. Rats received 0, 500, or 1000 mg/kg penicillin VK. Mice 0, 500, or 1000 mg/kg penicillin VK. The control groups received corn oil alone. At the conclusion of the 2-year dosing period, animals were kept for 1 to 2 weeks of observation without dosing and killed by carbon dioxide inhalation. Necropsy was performed on all animals. ods (Cox, 1972). Differences in survival were analyzed by life-table methods (Cox, 1972).

GLP compliance:

not specified

Test material

Test material information

1

Reference substance name:

Phenoxymethylpenicillin potassium

EC Number:

205-086-5

EC Name:

Phenoxymethylpenicillin potassium

Cas Number:

132-98-9

Molecular formula:

C16H17KN2O5S

IUPAC Name:

potassium (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate

Test material form:

solid

Specific details on test material used for the study:

USP grade lots C9014 and H1688

Test animals

Species:

other: Rodents : Male and female F344/N rats and B6CF3 mice obtained from Charles River Breeding Laboratories (portage, MI)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rodents were placed on study at 7-8 weeks of age. Animals were assigned to groups using a table of random numbers and were housed by sex, five
per cage, in polycarbonate cagescovered with fiber filters and were provided with heat-treated hardwood chips as bedding (Ancare Corp., L.I., NY). Tap water and NIH 07 feed (Zeigler Bros, Gardners, PA) were provided ad libitum. The animals were maintained in a room that was kept at 66-81°F [19 - 27 °C] with 10- 12 air changes per hour, and a 12-hr fluorescent light cycle. All animals were checked daily for clinical signs and moribund animals were necropsied. Animal body weights were taken once a week during the first 13 weeks of study and thereafter every 4 weeks.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Details on oral exposure:

Rodents were placed on study at 7-8 weeks of age. Animals were assigned to groups using a table of random numbers and were housed by sex, five
per cage, in polycarbonate cagescovered with fiber filters and were provided with heat-treated hardwood chips as bedding (Ancare Corp., L.I., NY). Tap water and NIH 07 feed (Zeigler Bros, Gardners, PA) were provided ad libitum. The animals were maintained in a room that was kept at 66-81°F [19 - 27 °C] with 10- 12 air changes per hour, and a 12-hr fluorescent light cycle. All animals were checked daily for clinical signs and moribund animals were necropsied. Animal body weights were taken once a week during the first 13 weeks of study and thereafter every 4 weeks.

Analytical verification of doses or concentrations:

yes

Remarks:

Dose solutions were checked throughout the course of the study and were within ± 10% of the targeted concentrations (Dunnick, 1987, 1988).

Duration of treatment / exposure:

103-104 weeks

Frequency of treatment:

Daily once. 5 days weekly

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Groups of 50 rats and 50 mice of each sex received Penicillin VK in corn oil.

Control animals:

yes, concurrent no treatment

Positive control:

NO

Examinations

Observations and examinations performed and frequency:

All animals were checked daily for clinical signs and moribund animals were necropsied. Animal body weights were taken once a week during the first 13 weeks of study and thereafter every 4 weeks.

Sacrifice and pathology:

Necropsy was performed on all animals. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. The following tissues were examined microscopically: grossly observed tissue masses,mandibular, or mesenteric lymph nodes; salivary glands;
bone including marrow;
thyroid gland, parathyroids;
small intestine;
large intestine;
liver;
prostate/testes/epididymis or ovaries/uterus;
lungs with mainstem bronchi;
skin;
heart;
esophagus;
stomach;
brain;
thymus;
trachea;
pancreas;
spleen;
kidneys;
adrenal glands;
urinary bladder;
pituitary gland;
eyes (if gross lesions were evident);
and mammary glands.

Statistics:

Differences in survival were analyzed by life-table methods (Cox, 1972). For the analysis of tumor incidence data, survival-adjusted procedures were used to assessdose-response trends and to make pairwise comparisons between dosed groups and controls (Haseman, 1984). Fisher exact tests and Cochran rmitage trend tests were also utilized to assesstumor incidence data. Results are considered as significant where the p value is ~0.05.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical signs were observed sporadically and included diarrhea in rats and male
mice dosed with penicillin.

Mortality:

no mortality observed

Description (incidence):

Survival in all groups of rats was 50% or greater until Week 92. Survival of
mice dosed with penicillin VK was comparable to vehicle controls.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of male and female rats receiving penicillin VK were similar to the corresponding vehicle control groups. Mean body weights of male mice receiving penicillin VK were comparable to controls, but mean body weights of dosed female mice were 4- 16% lower than those of the vehicle controls from Week 28 to the end of the study.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Nonneoplastic lesions of the glandular stomach were seen in dosed male
and female mice, and lesions of the gallbladder were seen in male mice. The incidence of hepatocellular adenomas was decreased in high-dose male mice (14/50, 15/49,4/49).

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No compound-related increases in neoplasms were seen in male or female rats or mice.

Effect levels

Key result

Dose descriptor:

LOAEL

Effect level:

> 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day (actual dose received)

System:

gastrointestinal tract

Organ:

stomach

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Applicant's summary and conclusion

Conclusions:

There is no evidence of carcinogenicity in rats or mice after penicillin VK dosing. Short-term genetic toxicity test results with ampicillin trihydrate and penicillin V and VK indicate that these drugs are not genotoxic (Dunnick, 1987, 1988). The most common side effects reported in humans after penicillin tratment are hypersensitivity (anaphylactoid reactions). Gastrointestinal toxicity was seen in mice after penicillin V Potassium amministration and this target organ toxicity is similar to what has been observed in humans.

Executive summary:

Toxicology and carcinogenesis studies of ampicillin trihydrate and penicillin VK, two widely used β-lactam antibiotics, were performed in F344/N rats and B6C3F, mice. In these studies ampicillin trihydrate was administered for 2 years to rats at doses of 0, 750, or 1500 mg/kg and to mice at doses of 0, 1500, or 3000 mg/kg, and penicillin VK was administered to rats and mice at doses of 0, 500, or 1000 mg/kg. Both drugs were administered
by oral gavage in corn oil. Toxic lesions of the stomach were seen in rats and mice after ampicillin trihydrate administration and in mice after penicillin VK administration. There was no evidence for
carcinogenic activity in female rats or male and female mice after ampicillin trihydrate administration or in rats and mice after penicillin VK administration.