Phenoxymethylpenicillin potassium

Endpoint summary

Description of key information

Penicillin V oral (Penicillin V potassium, Phenoxymethyl penicillin) and parenteral (Phenoxymethylpenicillin Benzathine) formulations are indicated in the treatment of mild to moderately severe infections due to penicillin sensitive microorganisms and have been widely used in human medicine for several decades having a well defined safety profile. 

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

Penicillin V has low acute toxicity with oral LD50 > 4000 mg/kg in mouse and LD50 > 1040mg/kg in rat. Due to the long term use it is well established that penicillins have a minimal direct toxicity to animals and man, and toxic effects of non-allergic nature have only been observed after extremely high doses. At oral administration the target organ is gastrointestinal tract. Penicillin Vis 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.

Safety after single administration
A large oral overdose of phenoxymethylpenicillin may cause nausea, vomiting, stomach pain, diarrhoea, and rarely, major motor seizures. If other symptoms are present, consider the possibility of an allergic reaction. Hyperkalaemia may result from overdose, particularly in patients with renal insufficiency (Sandoz, 2015).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Species:

rat

Key result

Dose descriptor:

LD50

Effect level:

> 2 220 mg/kg bw

Remarks on result:

other: LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)

Clinical signs:

other: other:

Interpretation of results:

GHS criteria not met

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Data on Penicillin V free base

Adequacy of study:

supporting study

Study period:

1958

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Species:

mouse

Route of administration:

oral: unspecified

Key result

Effect level:

ca. 6 578 mg/kg bw

Remarks on result:

other:

Clinical signs:

other: other:

Interpretation of results:

GHS criteria not met

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

not specified

Adequacy of study:

supporting study

Study period:

1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

GLP compliance:

not specified

Species:

rat

Route of administration:

oral: unspecified

Key result

Dose descriptor:

LD50

Effect level:

> 1 040 mg/kg bw

Remarks on result:

other: low acute oral toxicity

Clinical signs:

other: other:

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on published data

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 040 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

50.7