Paracetamol

Endpoint summary

Description of key information

The substance Paracetamol exhibits acute toxicity effect by the oral route in category IV,whereas it is non toxic by the inhalative route.

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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data from publication

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

The acute oral toxicity and analgesic potency, in mice, of Paracetamol have been determined.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:No data
- Expiration date of the lot/batch:No data
- Purity test date:No data

RADIOLABELLING INFORMATION (Not applicable)
- Radiochemical purity: N/A
- Specific activity:N/A
- Locations of the label:N/A
- Expiration date of radiochemical substance:N/A

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:No data
- Stability under test conditions:No data
- Solubility and stability of the test substance in the solvent/vehicle:No data
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:No data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:The compounds were reduced to fine powder, suspended in 1% methylcellulose mucilage, and the mixture was homogenized.
- Preliminary purification step (if any):No data
- Final dilution of a dissolved solid, stock liquid or gel:No data
- Final preparation of a solid:No data

Species:

mouse

Strain:

other: QS strain

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation:18-22 g

Route of administration:

oral: gavage

Vehicle:

other: 1% methylcellulose mucilage, and the mixture was homogenized

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: volume of 0.5 ml/20 g

No. of animals per sex per dose:

20 female mice

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: Deaths were counted after 48 hr.
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: No data
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: No data

Statistics:

LD50 and confidence limits were calculated by the method of Litchfield and Wilcoxon.

Sex:

female

Dose descriptor:

LD50

Effect level:

338 mg/kg bw

Based on:

test mat.

95% CL:

306 - 373

Mortality:

Not reported

Clinical signs:

other: Not reported

Gross pathology:

Not reported

Other findings:

- Other observations: Analgesic Activity : 4-Hydroxyacetanilide (paracetamol) was only weakly active as an analgesic, which was somewhat surprising in view of its widespread clinical use.The analgestic toxicity was found to be 22% observed with the help of hotplate test.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of Paracetamol,when administered to mouse was found to be 338 mg/kg body weight. Thus by considering the CLP criteria for acute toxicity rating for the chemicals, it infers that Paracetamol exhibits acute toxicity by the oral route in “Category 4”.

Executive summary:

The acute oral median lethal dose (LD50) of Paracetamol,when administered to mouse was found to be 338 mg/kg body weight. Thus by considering the CLP criteria for acute toxicity rating for the chemicals, it infers that Paracetamol exhibits acute toxicity by the oral route in “Category 4”.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

338 mg/kg bw

Quality of whole database:

The data is K2 level as the data has been obtained from the experimental study from the 'Journal of Toxicology and Applied Pharmacology.’.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

 

Acute toxicity: oral No. of studies were reviewed for acute oral toxicity from reliable sources having Klimisch rating 2 .

Based on the study conducted by G.A. Starmera et.al (Toxicology and Applied Pharmacology. Vol. 19, Pg. 20, 1971.) And other reliable sources, The acute oral median lethal dose (LD50) of Paracetamol in mouse was found to be 338 mg/kg of body weight.

Similarly in the study conducted on mice byAnthony et.al (Biorganic & Medicinal Chemistry 15,2206,2007) reported the LD 50 to be 559mg/kgbw.

Another publication by Michael Helliwel et.al ( Hum Exp Toxicol January 1981 vol. 1 no. 1 25-30) found the LD 50 to be714mg/kg.data fromAmerican Journal of Emergency Medicine and SAX handbook predicted the LDL0 and LD50 to be 650mg/kg and 367mg/kg ,Clearly indicating the toxicity of substance classifying it under oral acute category IV.

Acute toxicity: inhalation

No. of studies were reviewed for acute inhalation toxicity from reliable sources having Klimisch rating 2.

The summary of the results are presented below

Sr.No	Endpoint	Effect values	Species	Exposure Duration	CAS No.	Sources
1	LC50	49.8 mg/L	Rat	4 h	103-90-2	Predicted data from QSAR
2	LC50	33900 mg/m³ air	Mouse	-	Read Across 62-44-2	Experimental data from Gigiena i Sanitariya.

 

By applying weight of evidence approach to the target substance Paracetamol and the read across substance phenacetin,the endpoint value was found to vary between LC50 = 49.8 mg/L to 33900 mg/m³ air.Thus it is concluded that Paracetamol does not exhibits acute toxicity by the inhalative route within the mentioned dose level.

 

Acute toxicity: dermal

Acute toxicity testing by the dermal route was considered for waiver due to the following exposure considerations; the physicochemical and toxicological properties of paracetamol do not suggest potential for a significant rate of absorption through the skin. In addition, for paracetamol, the most likely route of exposure is oral considering its use. Considering that paracetamol is a solid, the other potential route of exposure could be inhalation, given the exposure to the fine particles. Thus having satisfied all the conditions as mentioned in column 2 of Annex VIII, this end point was considered for waiver. 

Justification for selection of acute toxicity – oral endpoint

The acute oral median lethal dose (LD50) of Paracetamol in mouse was found to be 338 mg/kg of body weight. Acute toxicity of Paracetamol to mouse by oral route indicates that Paracetamol exhibits acute toxicity by the oral route in the category IV.

Justification for selection of acute toxicity – inhalation endpoint

For paracetamol, acute toxicity testing by the inhalation route was considered for waiver given that the substance particle size distribution indicates that the majority particle size is 500 micro meter. Thus, exposure by inhalation route is also unlikely for paracetamol given the comparatively larger size of the particulates.

Justification for selection of acute toxicity – dermal endpoint

Acute toxicity testing by the dermal route was considered for waiver due to the following exposure considerations; the physicochemical and toxicological properties of paracetamol do not suggest potential for a significant rate of absorption through the skin. In addition, for paracetamol, the most likely route of exposure is oral considering its use. Considering that paracetamol is a solid, the other potential route of exposure could be inhalation, given the exposure to the fine particles. Thus having satisfied all the conditions as mentioned in column 2 of Annex VIII, this end point was considered for waiver.

Justification for classification or non-classification

Based upon the study results and available information, the substance Paracetamol exhibits acute toxicity effect by the oral route in category IV,whereas it is non toxic by the inhalative route.