Paracetamol

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other:

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Toxicology Study Of Acetaminophen In F344/N Rats (Feed Studies)

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:Acetaminophen was obtained from S.B. Penick & Company in two lots.Lot number 7042-LAR-5 was used.
- Purity :greater than 99%

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:Throughout the studies, the bulk chemical was stored in sealed containers protected from light at 25 degC.
- Stability under test conditions:Stability studies performed with HPLC found that acetaminophen was stable as a bulk chemical when stored protected from light for 2 weeks at tempera- tures up to 60degC. Stability of the bulk chemical was monitored by the study laboratory using infrared and ultraviolet spectroscopies. No changein the study material was detected.

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Age at study initiation:Rats: 7-8 weeks old
- Housing:The rats were housed five per cage
- Diet (e.g. ad libitum):NIH-07 Rat and Mouse Ration, powdere (Zeigler Bros., Inc., Gardners, PA); available ad libitum
- Water (e.g. ad libitum):Tap water (City of Worcester Public Water Supply) via outside-the-cage automatic watering system (Edstrom Industries, Waterford, WI) available ad libitum
- Acclimation period: 19days
- Method ofAnimal Distribution: Animals distributed to weight classes and then assigned to test and control groupsso that all cage weights were equal for each sexand species.
- Animals per Cage: 5
- Method of Animal Identification: Ear punch
Bedding: AspenBed heat-treated hardwood chips (American ExcelsiorCo., Baltimore, MD); changed twice weekly
Cage Filters: Nonwoven fiber filters (Snow Filtration, Cincinnati, OH)

ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.6°-27.2° C
- Humidity (%):34%-73%
- Air changes (per hr): 12-15/hour
- Photoperiod (hrs dark / hrs light):12hours/day

IN-LIFE DATES: From:23 February 1981 To:8 March 1981

Route of administration:

oral: feed

Vehicle:

other: diet

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):once
- Mixing appropriate amounts with (Type of food):The dose formulations were prepared by mixing appropriate quantities of acetaminophen with feed in a blender. Dose formulations were prepared once for the 14-day studies.
- Storage temperature of food: 25 degC.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Studies were conducted by the analytical chemistry laboratory to determine homogeneity and stability of the dosed feed preparations. For homogeneity analyses, the formulations were extracted with methanol and the concentrations determined by an ultraviolet method at 247 nm. For the stability studies, the formulations were extracted using a methanol/acetic acid (95/5) solution and then injected into a HPLC system equipped with a µBondapak C18 column and a 254 nm detector. The mobile phase was methanol:water (24:76) with a flow rate of 1mL/minute.
Acetaminophen at the 20,000 ppm dose level mixed in rodent feed (NIH-07 Rat and Mouse Ration) produced a homogeneous blend and was found to be stable when stored protected from light in sealed containers at temperatures up to 25 degC. There was a 4% loss of chemical in feed stored 2 weeks at 45 degC.
Periodic analyses of the dose formulations of acetaminophen were conducted at the study laboratory and at the analytical chemistry laboratory using ultraviolet spectroscopy. For the 14day studies, dose formulations were analyzed prior to study initiation.

Duration of treatment / exposure:

14 Days

Frequency of treatment:

Daily

Dose / conc.:

0 ppm

Remarks:

0 mg/kgbw/day

Dose / conc.:

800 ppm

Remarks:

80 mg/kgbw/day

Dose / conc.:

1 600 ppm

Remarks:

160 mg/kgbw/day

Dose / conc.:

3 100 ppm

Remarks:

310 mg/kgbw/day

Dose / conc.:

6 200 ppm

Remarks:

620 mg/kgbw/day

Dose / conc.:

12 500 ppm

Remarks:

1250 mg/kgbw/day

No. of animals per sex per dose:

Control: 5 males and 5 females
80mg/kg: 5 males and 5 females
160mg/kg: 5 males and 5 females
310mg/kg: 5 males and 5 females
620mg/kg: 5 males and 5 females
1250mg/kg: 5 males and 5 females

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:clinical findings noted during the daily checks were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations:The animals were weighed at study initiation and on days 7 and 14.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Feed consumption was measured weekly.

FOOD EFFICIENCY:No data
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Necropsy were performed on all animals.

HISTOPATHOLOGY: No

Statistics:

Survival Analyses:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958) and is presented in the form of graphS. Animals were censored from the survival analyses at the time they were found dead from other than natural causes. Animals dying from natural causes were not censored.Statistical analysis for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) life table
test to identify dose-related trends. All reported P values for the survival analysis are two sided.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Description (incidence):

All rats survived to the end of the studies.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The final mean body weight of male rats receiving 1250 mg/kg bw/day acetaminophen was 20% lower than the mean final body weight of controls.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The average feed consumption by male and female rats receiving 1250 mg/kg bw/day was lower than that of controls.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

No compound-related lesions were found at necropsy and no histopathology was performed.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Dose descriptor:

LOEL

Effect level:

12 500 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: effects on food consumption,body weight

Critical effects observed:

not specified

Concentration in ppm              Mean body weights b Final weight relative to control Food consumption Male Survival Initial Final Change  (%) in Week 1  Week 2 0 5/5 115 ± 2.7 203 ± 5.0  88 ±4.6   12 21 80 5/5 115 ± 3.5 191 76± 5.8 94  12  19 160 5/5 115 ± 3.7 201 ±5.4 86 ± 2.9 99  15 17 310 5/5 115 ±3.7 206 ± 3.9 91 ± 2.4 101  15 20 620 5/5 115 ± 4.4 201 ±7.7 86 ± 3.4 99  15  20 1250 5/5 116 ± 3.8 163 ± 5.9** 47 ± 3.0** 80  10  14 Concen. In Females               0 5/5 98 ± 2.1  138 ±1.9 40 ± 2.5 - 12 13 80 5/5 98 ± 1.9 146 ± 3.6 48± 1.9 106  14  13 160 5/5 99 ± 2.0 141 ±1.4 41 ±2.3 102  13  13 310 5/5 98 ± 2.3 146 ±2.4 47 ± 3.4 106 13 14 620 5/5 99 ±1.8 142 ±2.6  43 ± 1.9 103 12 13 1250 5/5 99 ±2.5 133 ± 2.0 34 ±2.7 96 10 10

** Significantly different (PSO.01) from the control group by Dunn's or Shirley's test

a Number suMng/number initially in group

Conclusions:

The Lowest Observed Effect Level (LOEL) of Acetaminophen (Paracetamol) on rats by the oral route was observed at a dose concentration of 12500 ppm (1250 mg/kg bw) in a 14 days study period.

Executive summary:

The toxic effects of acetaminophen (paracetamol) were examined in a 14-day feed study in F344rats. Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen.Different parameters like clinical effects,mortality,body weights,feed consumption and gross pathology were analyezed. All rats survived to the end of the studies . The final mean body weight of male rats receiving 1250 mg/kg acetaminophen was 20% lower than the mean final body weight of controls. The average feed consumption by male and female rats receiving 1250 mg/kg was lower than that of controls. No compound-related lesions were found at necropsy and no histopathology was performed.Thus from above findings we can conclude that the Lowest Observed Effect Level (LOEL) of Acetaminophen (Paracetamol) on rats by the oral route  was observed at a dose concentration of 12500 ppm (1250 mg/kg bw) in a 14 days study period.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEL

1 250 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The data is K2 level

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.1

GLP compliance:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

not specified

Duration of treatment / exposure:

28 days

No. of animals per sex per dose:

5

Control animals:

not specified

Dose descriptor:

NOAEC

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects was observed.

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEC
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(("a" or "b" or "c" or "d" or "e" or "f" )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl AND Carboxamide AND Phenol AND Precursors quinoid compounds by Organic functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Carboxamide AND Overlapping groups AND Precursors quinoid compounds by Organic functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] AND Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amide, aliphatic attach [-C(=O)N] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Hydroxy, aromatic attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid amide AND Carboxylic acid derivative AND Carboxylic acid sec. amide AND Hydroxy compound AND Phenol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.36

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.68

Conclusions:

The subchronic repeated dose toxicity NOAEC ( No observed adverse effect concentration) of Paracetamol to Wistar rats by inhalation route was observed at a dose concentration of 66.208 mg/m³ air in a 28 days study period.Thus it is concluded that the test substance Paracetamol is non toxic by repeated dose exposure within the concentration level mentioned.

Executive summary:

The subchronic repeated dose toxicity NOAEC ( No observed adverse effect concentration) of Paracetamol to Wistar rats by inhalation route was observed at a dose concentration of 66.208 mg/m³ air in a 28 days study period.Thus it is concluded that the test substance Paracetamol is non toxic by repeated dose exposure within the concentration level mentioned.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

66.208 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is K2 level as the data has been obtained from the QSAR model considered by OECD.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity (Oral)

For Repeated dose toxicity

 

Based on the various studies available with Klimish rating 2 for the target as well as read across substances for CAS: 103-90-2. The results are summarized as follows

As describe by A. A. Oyagbemi, et.al (Toxicologist.216,2009) test was conducted on wister rats for the duration of 10days and Toxicologist.216,2009 repeated dose toxicity LOEL value of Paracetamol to rats by the oral route was observed at a dose concentration of 3000mg/kg bw .

In summary, the results obtained in this study show that lower dosages (100mg/kg and 500mg/kg) of Cnidoscolus aconitifolius may potentiate the toxicity associated with Paracetamol overdose while high dosage (1000mg/kg body weight) of the extract showed promising hepato-protective effect against hepatic damage induced by Paracetamol poisoning.

Another study reported by National Toxicology Program Technical Report Series No. 394 reported the LOEL (low observed effect level ) of Acetaminophen (Paracetamol) at a dose concentration of 1250g/kg bw/day calculated as :1250mg/kg diet) in a 14 days study period. Similar study report the The LOEL (low observed effect level) of Acetaminophen to mouse by the oral route was observed at a dose concentration of 25000 ppm-4166.6mg/kg bw(calculated as : 4166.6 mg/kg bw/day) in a 13 weeks study period.

According the study presented by Mohamed H. et.al (Journal of Pharmacology and Experimental Therapeutics. 305,123,2003) the subchronic repeated dose toxicity TDLo (Lowest published toxic dose) of Paracetamol to rats by the oral route was observed at a dose concentration of 500 mg/kg bw/day in a 30 days study period where the dosage of paracetamol was given continuously. This indicates that paracetamol does not exhibit any toxic effects to rat by the oral route below the above mentioned dose level.

Based on the studies summarized in the above table with repeated dose oral routes it can be observed that LOEL values varies from 1250 - 3000 mg/Kg bw/ d. Also the published lowest toxic dose value (TDLo value) is 500 mg/kg bw/d. The effects observed on the these doses was listed as follows

·        Liver - hepatitis (hepatocellular necrosis),significant reduction in ALP, TP, ALB, TC and HDL

·        Change in hematology, body weights, microscopic (hepatocellular hypertrophy) liver changes associated.

·        effect on food consumption, body weight, organ weight were observed

·        Kidney/Ureter/Bladder - renal function tests depressed

. BIOCHEMICAL: Metabolism (intermediary) changes were observed Thus based on above discussion it can be concluded that substance CAS: 103-90-2 has low effect dose value (LOAEL) as >1250 mg/Kg bw/d. Thus based on this value it can be concluded that substance CAS: 103-90-2 is considered to be not toxic to repeated dose via oral route for the above mentioned dose. Also there are no known evidence of adverse effect to Human of CAS: 103-90-2 and also mechanistic trigger does not indicate the toxicity of paracetamol.

Repeated dose toxcity :Inhalation

The subchronic repeated dose toxicity NOAEC ( No observed adverse effect concentration) of Paracetamol to Wistar rats by inhalation route was observed at a dose concentration of 66.208 mg/kg air in a 28 days study period.Thus it is concluded that the test substance Paracetamol is non toxic by repeated dose exposure within the concentration level mentioned.

Repeated dose toxicity: dermal

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 considering the exposure scenario of paracetamol; this end point was considered for waiver.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The LOEL (low observed effect level ) of Acetaminophen (Paracetamol) to rat by the oral route was observed at a dose concentration of 12500 ppm(calculated as :1250mg/kg diet) in a 14 days study period.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

The subchronic repeated dose toxicity NOAEC ( No observed adverse effect concentration) of Paracetamol to Wistar rats by inhalation route was observed at a dose concentration of 66.208 mg/m³ air in a 28 days study period.Thus it is concluded that the test substance  Paracetamol is non toxic by repeated dose exposure within the concentration level mentioned.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

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 considering the exposure scenario of paracetamol; this end point was considered for waiver.

Justification for classification or non-classification

The substance Paracetamol do not show repeated dose toxicity effect for oral and inhalation route and thus will not be considered for further classification.