Paracetamol

Repeated dose toxicity: oral

Administrative data

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:

Data source

Reference

Reference 1

Reference Type:

other: report

Title:

Toxicology And Carcinogenesis Studies Of Acetaminophen In F344/N Rats And B6c3f1 Mice (Feed Studies)

Author:

NTP Database

Year:

1993

Bibliographic source:

National Toxicology Program Technical Report Series No. 394

Reference 2

Reference Type:

review article or handbook

Title:

RTECS Number : AE4200000

Author:

RTECS database

Year:

2012

Bibliographic source:

RTECS (Registry of Toxic Effects of Chemical Substances):National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific & Technical Information. Volume(issue)/page/year: #PB85204667/AS

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Paracetamol

EC Number:

203-157-5

EC Name:

Paracetamol

Cas Number:

103-90-2

Molecular formula:

C8H9NO2

IUPAC Name:

.

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): Paracetamol
- Substance type: Organic
- Physical state: Solid

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.

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm

Remarks:

0 mg/kgbw/day

Doses / concentrations 2

Dose / conc.:

800 ppm

Remarks:

80 mg/kgbw/day

Doses / concentrations 3

Dose / conc.:

1 600 ppm

Remarks:

160 mg/kgbw/day

Doses / concentrations 4

Dose / conc.:

3 100 ppm

Remarks:

310 mg/kgbw/day

Doses / concentrations 5

Dose / conc.:

6 200 ppm

Remarks:

620 mg/kgbw/day

Doses / concentrations 6

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

Examinations

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.

Results and discussion

Results of examinations

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

Effect levels

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.