Paracetamol

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

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 Type:

publication

Title:

Effects of Acetaminophen on Preimplantation Embryo Glutathione Concentration and Development in Vivo and in Vitro

Author:

Delia N. Laub, Nawal O. Elmagbari, Nura M Elmagbari, Melissa A. Hausburg, and Catherine S. Gardinerl

Year:

2000

Bibliographic source:

TOXICOICAL SCIENCES 56, 150-155 (2000)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Effects of Acetaminophen on Preimplantation Embryo

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

Test animals

Species:

mouse

Strain:

not specified

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Harlan (Indianapolis, IN).
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Use of restrainers for preventing ingestion (if dermal): yes/no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:

other: Intragastrically

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: 0.5% tragacanth solution

Details on exposure:

APAP was given daily from 8 days prior to ovulation until day 3 of gestation.

Details on mating procedure:

Females were bred with proven breeder males and were checked the next day for a copulation plug (designated as day 0 of gestation).

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

8 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0 or 1430 mg/kg of body weight
Basis:

No. of animals per sex per dose:

Control:
36 females
1430 mg/kg:
36 females

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data
- Time schedule:
- Cage side observations checked in table were included.

BODY WEIGHT: Yes
- Upon evaluation of the females on d17 of gestation, maternal body weight did not differ significantly.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake 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:

Statistics:

Morphological development was analyzed using Kruskal-Wallis analysis of variance. Analysis of variance and least-significant- difference procedures were used to determine differences in GSH and GSSG content of embryos, liver, and ovaries. A t-test was used to analyze the number of fetuses per dam, number of resorptions per dam,individual fetal weight, total fetal weight, uterine weight, liver weight, and weight of dam on d17. Chi-square analysis was used to analyze the number of mice with copulation plugs and the number of deceased mice. Statistica software was used for statistical analysis. All experiments were repeated at least twice with a `minimum of 3 replications for each treatment each time.

Offspring viability indices:

Liver and ovary collection and evaluation: Portions of the liver and both ovaries were dissected from euthanized female mice and weighed. The overall morphology of the tissues was assessed, and the samples were prepared for quantification of GSH.

Fetus coHection and evaluation. :Female pubertal mice were bred with proven breeder males on day -1. On d17 of gestation, dams were euthanized and fetuses were removed via cesarean section. Maternal and fetal evaluation consisted of recording the number of resorptions in the uterus, weighing the intact uterus with the fetuses, weighing the pregnant dam, examining each fetus for gross malformations, weighing individual fetuses, and noting the number of pups per liner

ElTects of one dose of APAP on GSH concentration and embryo develop- ment in vivo:. Mice found to have copulation plugs on do were treated on d2 with 0, 800, or 1430 mg APAP/kg. Mice were euthanized, and samples were collected 12 h after dosing.

Enects of preimplantation exposure with APAP on development to term. :Female mice were treated with 0 or 1430 mg|kg APAP daily starting 8 days prior to ovulation and continuing until 3 days after copulation plugs were detected. Fetuses were removed by cesarean section on d17 of gestation

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

9 mice treated with APAP died during the course of the study.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

9 mice treated with APAP died during the course of the study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Upon evaluation of the females on d17 of gestation, maternal body weight did not differ significantly .

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 specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

effects observed, treatment-related

Description (incidence and severity):

significantly fewer female mice were found with copulation plugs each day of breeding in the 1430 mg/kg APAP group .

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

Administration of one dose of APAP intragastrically to pregnant female mice on d2 of gestation significantly decreased liver GSH concentrations.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 430 other: mg/kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Copulation plugs each day of breeding, decreased liver GSH concentrations

Target system / organ toxicity (P0)

Critical effects observed:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

chnges in number of live fetuses was observed.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

changes were observed at higher dose.

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

changes in uterine weights.

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 430 other: mg/kg

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: live fetuses, body weights,uterine weights

Target system / organ toxicity (F1)

Critical effects observed:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL (no observed adversed effect level ) of Acetaminophen in female mice and offsprings were observed at a dose level of 1430 mg/kg.

Executive summary:

Effects of Acetaminophen on Preimplantation Embryos were studied in pregnant mice. APAP (Acetaminophen) was given daily at a dosge of 0 or 1430 mg/kg from 8 days prior to ovulation until day 3 of gestation.Different parameters like GSH concentration and embryo development in vivo, body weight,organ weight, resorptions and live fetuses were analyzed.Upon evaluation of the females on d 17 of gestation, maternal body weight did not differ significantly, nor did liver or uterine weight, and significantly fewer female mice were found with copulation plugs each day of breeding in the 1430 mg/kg APAP group. While no mice died in the control group, 9 mice treated with APAP died during the course of the study. No gross malformations were found, but individual fetuses from females treated with APAP weighed significantly more than fetuses from the control dams. Thus we can conclude that the NOAELs (no observed adverse effect levels) of Acetaminophen in female mice and offspring were observed atadose level of 1430 mg/kg.