Phenoxymethylpenicillin potassium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: Compilation and interpretation of available data.

Adequacy of study:

key study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Compilation and interpretation of available data.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

The most common reactions to oral penicillin in both animals and humans are gastrointestinal effects and hypersensitivity reactions. Gastrointestinal reactions are mild diarrhea, nausea or vomiting. The hypersensitivity reactions reported are skin eruptions (maculopapular to exfoliative dermatitis), urticaria and other serum-sicknesslike reactions, laryngeal edema, and anaphylaxis.

Under the condition of the 28-days Reapeated dose toxcicty study, Pen V Potassium did not cause adverse systemic effects – clinical signs, changes in body weight, food consumption, hematologyand blood coagulation, clinical chemistry organ pathology or organ weights – in male or female Han:WIST rats after the consecutive 28-day oral (by gavage) administration of 100, 300 or 1000 mg/kg bw/day. Based on these observations, the No Observed Adverse Effect Level (NOAEL) was determined as 1000 mg/kg bw/day in male and female Han:WIST rats.

Furthermore given the long history of safe use of penicillin in humans, the Repeated Dose 90-Day Oral Toxicity Study in Rodents (OECD TG 408)” are unlikely to add to the already known hazard profile of penicillin, and will result in the unnecessary use of animals.

Chronic Toxicity: Two-year toxicology and carcinogenesis studies of penicillin VK were performed in F344/N rats and B6C3F1 mice. In these studies penicillin VK was administered for 2 years to rats and mice at doses of 0, 500, or 1000 mg/kg by oral gavage in corn oil. Toxic lesions of the stomach were seen in mice after penicillin VK administration. There was no evidence for carcinogenic activity in rats and mice after penicillin VK administration (Dunnick JK et al., 1987).

Sub-chronic toxicity: Additionally, in a 13-week penicillin VK study, lesions of the forestomach were seen at levels of 1500 mg/kg in the rats and mice (Dunnick JK et al., 1989).

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Side/Adverse Effects- Incidence less frequent: Allergic reactions, specifically anaphylaxis (fast or irregular breathing; puffiness or swelling around face; shortness of breath; sudden, severe decrease in blood pressure), exfoliative dermatitis (red, scaly skin), serum sickness-like reactions (skin rash; joint pain, fever), skin rash, hives, or itching.

Side/Adverse Effects -Incidence rare: Hepatotoxicity (fever, nausea and vomiting, yellow eyes or skin); interstitial nephritis (fever, possibly decreased urine output, skin rash); leukopenia or neutropenia (sore throat and fever); mental disturbances (anxiety, confusion, agitation or combativeness, depression, seizures, hallucinations, or expressed fear of impending death) pain at site of injection; platelet dysfunction or thrombocytopenia (unusual bleeding or bruising); Clostridium difficile colitis (severe abdominal or stomach cramps and pain; abdominal tenderness; watery and severe diarrhea, which may also be bloody; fever); seizures.

Side/Adverse Effects- Incidence more frequent: Gastrointestinal reactions (mild diarrhea, nausea or vomiting); headache; oral candidiasis (sore mouth or tongue, white patches in mouth and/or on tongue); vaginal candidiasis (vaginal itching and discharge).

 

Toxic effect type:

dose-dependent

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

mouse

System:

gastrointestinal tract

Organ:

stomach

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Human data: Penicillin V has been used since many decades in patients. Penicillin antibiotics are in general substances with low toxicity. The most often described effects in humans are gastrointestinal, demonstrated in mouse and rat. Penicillin V is generally well-tolerated in humans but may occasionally cause transient nausea, diarrhoea and allergic reactions. It is well-known that changes in the intestinal flora occur in all individuals treated orally with penicillin. The degree of alteration is related directly to the quantity administered. This effect is usually of no clinical significance and the normal microflora is re-established shortly after therapy is stopped.

The hazard characterisation of penicillin and derivatives in humans can be deduced from the available long-term studies in the literature. A review of the safety profile of long-term penicillin therapy revealed some cases of adverse effects such as transient nausea, diarrhea, and allergic reactions - albeit these adverse effects are consistent with the known adverse event profile of penicillin. There was no report of an increase in adverse drug reactions involving long-term administration of penicillin in these studies. Therefore, given that Penicillin has an extensive history of safe use, and the lack of any serious adverse events in these studies supports its status as a safe drug. Additionally, the European Medicines Agency (EMA) Committee for veterinary medicinal products (CVMP) has assessed Phenoxymethylpenicillin, and the CVMP concluded that phenoxymethylpenicillin is rapidly metabolised and excreted, and has minimal direct toxicity to humans or animals. They noted that the therapeutic index of penicillin is more than 100 and that any toxic effects of non-allergic nature have only been reported after extremely high doses.

The data from some large published clinical trials assessing the effectiveness of long-term administration of penicillin and derivatives are outlined below. There appeared to be no reports of uncharacteristic adverse events including serious adverse events or adverse events requiring treatment in these studies.

Basil et al (2000) was a cross-sectional study conducted to establish the profile of secondary prophylaxis among children (n=150) with rheumatic heart disease in Egypt. Prophylactic failure occurred in one-third of the patients, raising doubts about the efficacy of the brands of penicillin prescribed. Recurrence of rheumatic fever was recorded in 37.3% of the patients with semiurban or rural residence, with non-compliance with secondary prophylaxis the significant risk factors (Basil et al., 2000).

Lue et al (1994) investigated the long-term outcome of patients with rheumatic fever receiving benzathine penicillin G. The study compared the efficacy of injections of 1.2 million units of benzathine penicillin G given every 3 weeks versus every 4 weeks for secondary prevention of rheumatic fever, based on the long-term outcome of patients receiving such prophylaxis. 249 patients with rheumatic fever, randomly assigned to either a 3-week or a 4-week regimen, were examined every 3 to 6 months, and followed for 794 and 775 patient-years, respectively. There were no reports of adverse effects (Lue et al., 1994). 

In Massell et al (1979) study, orally administered clindamycin and penicillin were compared for effectiveness in preventing streptococcal infections in 202 randomly assigned patients with previous rheumatic fever (RF). Among 143 patients aged 21 years or younger observed for 537 patient-years, the number of streptococcal infections (and number per patient-year) was 23 (0.084) in the penicillin group, and 12 (0.045) in the clindamycin group (Massell et al., 1979).

Angelin et al (1984) investigated the effect of penicillin on nasopharyngeal colonization with Streptococcus pneumonia in children with sickle cell disease. They studied nasopharyngeal colonization with pneumococci in 34 patients with sickle cell anemia (aged 6 months to 5 years) receiving penicillin prophylaxis and in 63 age- and race-matched comparison patients. Their data suggested a mechanism of action for penicillin prophylaxis and provided evidence for its relative safety (Angelin et al., 1984).

Buchanan et al (1986) reviewed seven-year experience with a regimen of twice-daily oral penicillin V potassium prophylaxis in 88 affected children. The median age at the start of prophylaxis was 10 months, and the median duration of prophylaxis was 29 months (range, three months to seven years). The total period of observation of patients who were prescribed penicillin was 248 person-years. Most patients also received one or two doses of polyvalent pneumococcal vaccine (Buchanan et al., 1986).

Gatson et al (1986) conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the daily administration of oral penicillin would reduce the incidence of septicemia due to S. pneumonia in children with sickle cell anemia who were under the age of three years. The children were randomly assigned to receive either 125 mg of penicillin V potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up. 84% reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients vs. 2 of 105; P = 0.0025), with no deaths from pneumococcal septicemia occurring in the penicillin group but three deaths from the infection occurring in the placebo group. (Gatson et al., 1986).

John et al (1984) investigated the efficacy of prophylactic penicillin in preventing pneumococcal infection in homozygous sickle cell (SS) disease in 242 children aged 6 months to 3 years at entry. Penicillin was well tolerated, and no confirmed allergic reactions occurred in the study (John et al., 1984).

No significant adverse effects were observed below the relevant guidance value, as adjusted for  set out in 1272/2008/EC; therefore classificaiton is not warranted.

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 June 2019 - 14 November 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted 07 September 2009

Deviations:

yes

Remarks:

Relative humidity during the inhalation exposure

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

Official Journal L 142, 31/05/2008

Deviations:

yes

Remarks:

Relative humidity during the inhalation exposure

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

yes

Remarks:

Relative humidity during the inhalation exposure

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

Test item: Pen V Potassium
Lot No.: B519322
Appearance:White solid powder
Manufacturing date:April 2019
Expiry date: 30 April 2024
Storage:Room temperature (15-25°C), protected from light
Safety precautions: Routine safety precautions were applied (lab coat, mask, gloves, safety glasses)

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats are the preferred species of choice as historically they have been used for safety evaluation studies and they are specified by the appropriate regulatory authorities. The Wistar rat was selected due to a wide range of experience with this strain of rat in toxicity studies.
Hygienic level at arrival: SPF
Hygienic level during the test: Good conventional
Justification of strain: Same strain was used in the preliminary and in the main tests
Number of animals: 2 animals in the sighting exposure (1 male and 1 female) 10 animals in the main study (5 males and 5 females)
Sex:Male and female. Females were nulliparous, non-pregnant
Age of animals: Young adult rats, 8-12 weeks old (at start of the study) Bodyweight range at starting: The weight variation did not exceed ± 20% of the mean weight for either sex
Acclimatization time: 19 days (sighting exposure), 34 days (main study)

Husbandry
Animal health: Only healthy animals were used. The breeder certified the healthy status.
Hygienic level during the test: Good conventional Animal room number: 401/7
Housing: Group caging (up to 3 animals, by sex, per cage)
Cage type:Polypropylene/polycarbonate (type III) with stainless steel mesh lids.
Bedding: Laboratory bedding
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature:22 ± 3 °C
Relative humidity: *30 - 70 %
Ventilation: Above 10 air exchanges/hour by central air-conditioning system.
Housing/Enrichment: Rats were group-housed to allow social interaction, and with deep wood sawdust bedding, to allow digging and other normal rodent activities.
The temperature and relative humidity were checked and recorded daily during the study. Before housing the animals, the microbiological status of the room was checked.

Food and Water supply
Animals received ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany, ad libitum. Food was changed at weekly intervals. The food is periodically analysed and is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. Copy of the relevant Certificate of Analysis of the diet is attached to the Report as Appendix 6. Copies of the relevant Certificates of Analysis are maintained in TOXI-COOP ZRT.’s archive. Animals received tap water from municipal supply, as for human consumption, from watering bottles ad libitum. Fresh drinking water was given daily. The drinking water is periodically analysed and is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. Copies of the relevant Certificates of Analysis are maintained in TOXI-COOP ZRT.’s archive.

Bedding
SAFE 3/ 4-S-FASERN, Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH+Co.KG (Holzmühle 1, D-73494 Rosenberg, Germany) was used in the study. The quality of the bedding material is guaranteed by the supplier. Cages and bedding material were changed twice a week. A copy of the relevant certificate is retained in the archives of TOXI-COOP ZRT.The bedding is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

ca. 2.4 µm

Geometric standard deviation (GSD):

ca. 2.29

Remark on MMAD/GSD:

The MMADs and GSDs were within the respective target ranges. In conclusion, the particle size distributions obtained was considered to be appropriate for this type of study.

Details on inhalation exposure:

The test item was aerosolised using a Wright Dust Feeder II. (CH Technologies (USA), Inc., 263 Center Ave, Westwood, NJ 07675, USA; Serial Number: 052) located at the top of the exposure chamber. Compressed air was supplied by means of an oil-free compressor and passed through a suitable filter system prior to introduction to the dust generator.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The actual concentration of generated atmosphere was measured gravimetrically at regular intervals during exposures by pulling a suitable, known volume of test atmosphere from the exposure chamber, through GF10 glass fibre filters .

Duration of exposure:

ca. 4 h

Remarks on duration:

The animals were exposed to an atmosphere of the test item for a single, continuous four-hour period, generated according to the system and flow rates determined during the technical trials. The four-hour exposure period

Concentrations:

5 mg/L

No. of animals per sex per dose:

A group of ten animals (five males and five females) was exposed for a four-hour period to the target concentration of 5 mg/L.

Control animals:

no

Details on study design:

The animals were held in polycarbonate restraining tubes and exposed “nose-only” under dynamic air flow conditions, using an anodised aluminium Flow Past Exposure Chamber (TSE Systems GmbH, Bad Homburg, Germany). Validation of this type of system was published by J. Pauluhn. (1994). The exposure unit was placed in closed hood in order to avoid cross-contamination and contamination of the laboratory environment. Fresh aerosol from the generation system was constantly supplied to the inner plenum (distribution chamber) of the exposure system from where, under positive pressure, it was distributed to the individual exposure ports. The animals were held in polycarbonate restraint tubes located around the chamber which allowed only the animal’s nares to enter the exposure port. After passing through the animal’s breathing zone, used aerosol entered the outer cylinder from where it was exhausted through a suitable filter system. Atmosphere generation was therefore dynamic. A schematic diagram of the exposure system is presented in Figure 1. Airflows and relative pressures within the system were constantly monitored and controlled by the computer system thus ensuring a uniform distribution and constant flow of fresh aerosol to each exposure port (breathing zone). The flow of air through each port was at least 0.7 L/min. This flow rate was considered adequate to minimise re-breathing of the test atmosphere as it is about twice the respiratory minute volume of a rat.Homogeneity of the test atmosphere within the test chamber and amongst the exposure ports was not specifically determined during this study. However, chambers of this design have been fully validated and have shown to produce evenly distributed atmospheres in the animals’ breathing zones (J. Pauluhn, 1994).

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.07 mg/L air

Based on:

test mat. (dissolved fraction)

Exp. duration:

4 h

Mortality:

No mortality was observed

Clinical signs:

other: In Group 1 (5.07 mg/L), red staining on snout (2/5♂, 1/5♀) and dyspnoea (5/5♂, 5/5♀) were observed in animals during and/or after the exposure. All clinical signs ceased from the day following exposure until the end of the observation period.

Body weight:

Slight bodyweight loss was noted in two male exposed animals on the day following exposure and in four males during period Day 1-3 of the observation period. In further animals normal bodyweight gain was noted during whole observation period.

Gross pathology:

A single four hours nose-only exposure of test item Pen V Potassium to Han: WIST of Wistar origin rats followed by a 14-day observation period at the mean achievedtest concentration of 5.07 mg/L was not associated with any test item-related macroscopic findings on the exposed animals, except one case where right side pyelectasis was observed in one male.

Other findings:

Under the experimental conditions of this study, no death occurred in a group of 10 rats exposed to the mean achieved test concentration of 5.07 mg/L of Pen V Potassiumfor 4 hours. The acute inhalation median lethal concentration of Pen V Potassium, in Han: WIST of Wistar origin rats is therefore considered to be greater than 5.07 mg/L.

Interpretation of results:

GHS criteria not met

Remarks:

Based on the results of the current study Pen V Potassium is non-toxic after acute inhalative administration.The study result triggers the following classification/labelling: - Regulation (EC) No 1272/2008 (CLP): none

Conclusions:

The acute inhalation LC50 of the test substance in Wistar rats is >5.07 mg/L.

Executive summary:

This study was performed to assess the acute inhalation toxicity of Pen V Potassium following a 4 hour exposure at the mean achieved concentration of 5.07 mg/L to 5 male and 5 female rats. A single sighting exposure was performed prior to the main study with 1 maleand 1 female at the target concentration of 5 mg/L.The main study group, consisting of 10 Han: Wistar rats (5 males and 5 females), was exposed to the target concentration of Pen V Potassium of 5 mg/L. The animals were exposed for 4 hours using a nose-only exposure system, followed by a 14-day observation period. The day of exposure was designated Day 0. Aerosol concentration was measured gravimetrically. The particle size distribution of the test aerosol was determined regularly during the exposure period. Clinical observations and bodyweights were recorded throughout the study and at the end of the scheduled period the surviving animals were euthanised and subjected to a gross examination post mortem. The quality of the test atmosphere fully complied with criteria documented in the respective guidelines: OECD No. 403, EPA OPPTS 870.1300 and Council Regulation (EC) No 440/2008. Under the experimental conditions of this study, no death occurred in a group of 10 rats exposed to the mean achieved test concentration of 5.07 mg/L of Pen V Potassiumfor 4 hours. The acute inhalation median lethal concentration of Pen V Potassium, in Han: WIST of Wistar origin rats is therefore considered to be greater than 5.07 mg/L.

Cross-reference 3

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting 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

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

Specific details on test material used for the study:

USP grade lots C9014 and H1688

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.

Route of administration:

oral: feed

Vehicle:

corn oil

Details on 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

Dose / conc.:

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

Dose / conc.:

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

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

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.

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.

Dermal irritation (if dermal study):

not specified

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.

Key result

Dose descriptor:

dose level:

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

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). he 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.

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: Section R.7.12.2.1 of the 'Guidance on information requirements and chemical safety assessment'

Version / remarks:

2017

Deviations:

not specified

Principles of method if other than guideline:

Compilation and interpretation of available data.

GLP compliance:

no

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

Radiolabelling:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No relevant systemic toxic effects were noted in the acute oral and the acute inhalation toxicity studies.

Absorption: Approximately 25–73% of an oral dose of penicillin V absorbed from the GI tract in healthy, fasting adults. Peak serum concentrations attained within 30–60 minutes.
Variable results obtained in studies evaluating effect of food on GI absorption of penicillin V potassium. Food may result in lower and delayed peak serum concentrations, although the total amount of drug absorbed is unaffected.

In the acute inhalation toxicity study in rats with a MMAD of 3.65 µm did not show systemic toxic effects at the limit concentration of 5.24 mg/L, therefore no indication of an absorption was obtained. The relevant parameters for absorption at inhalation exposure are not very different to those for oral absorption, as described in the Section R.7.12.2.1 of the 'Guidance on information requirements and chemical safety assessment'.

Water Solubility: The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis

Details on distribution in tissues:

Distribution: Widely distributed into body tissues. Highest concentrations in kidneys; lower concentrations in liver, skin, intestines, bile, tonsils, maxillary sinus secretions, saliva, and ascitic, synovial, pleural, and pericardial fluids. Only minimal amounts in CSF.
Crosses the human placenta and is distributed into human milk.

Bioaccumulation:
No relevant accumulation is expected, based on the low log Pow as wella as on the short half-life.

Transfer into organs

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Remarks:

Plasma Protein Binding: Approximately 75–89%.

Details on excretion:

Elimination Route: Penicillin V and metabolites principally excreted in urine by tubular secretion. Approximately 26–65% of an oral dose excreted in urine as unchanged drug and metabolites within 6–8 hours; approximately 32% of the dose excreted in feces.
Serum half-life is 0.5 hours in adults with normal renal function..

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolized in the liver. Approximately 35–70% of an oral dose is metabolized to penicilloic acid which is microbiologically inactive.

Applicant's summary and conclusion

Conclusions:

Penicillin V (Penicillin V potassium, Phenoxymethyl penicillin, Phenoxymethylpenicillin Benzathine) oral and parenteral formulations indicated in the treatment of mild to moderately severe infections due to penicillin sensitive microorganisms. Penicillin V acts through the inhibition of biosynthesis of bacterial cell-wall mucopeptide. The doses and duration of treatment depends on microorganism and product formulation.
The most common reactions to oral penicillin are gastrointestinal effects and hypersensitivity reactions. Gastrointestinal reactions are mild diarrhea, nausea or vomiting. The hypersensitivity reactions reported are skin eruptions (maculopapular to exfoliative dermatitis), urticaria and other serum-sicknesslike reactions, laryngeal edema, and anaphylaxis.

Executive summary:

Absorption: Approximately 25–73% of an oral dose of penicillin V absorbed from the GI tract in healthy, fasting adults. Peak serum concentrations attained within 30–60 minutes.
Variable results obtained in studies evaluating effect of food on GI absorption of penicillin V potassium. Food may result in lower and delayed peak serum concentrations, although the total amount of drug absorbed is unaffected.
Distribution: Widely distributed into body tissues. Highest concentrations in kidneys; lower concentrations in liver, skin, intestines, bile, tonsils, maxillary sinus secretions, saliva, and ascitic, synovial, pleural, and pericardial fluids. Only minimal amounts in CSF.
Crosses the human placenta and is distributed into human milk.
Plasma Protein Binding: Approximately 75–89%.
Metabolized in the liver. Approximately 35–70% of an oral dose is metabolized to penicilloic acid which is microbiologically inactive.
Elimination Route: Penicillin V and metabolites principally excreted in urine by tubular secretion. Approximately 26–65% of an oral dose excreted in urine as unchanged drug and metabolites within 6–8 hours; approximately 32% of the dose excreted in feces.
Serum half-life is 0.5 hours in adults with normal renal function.
Special Populations: Renal clearance delayed in neonates, young infants, and individuals with renal impairment (FDA prescribing information, Penicillin V potassium tablets, oral solution)