Paracetamol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No teratogenic effetcs observed .

Link to relevant study records

Reference

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:

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

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

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

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

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

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: 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.

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

Critical effects observed:

not specified

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

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

Critical effects observed:

not specified

Reproductive effects observed:

not specified

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 430 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The data is K2 level as the data has been obtained from the experimental study from the 'TOXICOICAL SCIENCES .’

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

WoE Summary of 103-90-2 for toxicity to reproduction

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 is summarized as follows

Reproductive toxicity-Richard Wiger et.al (Reproductive Toxicology, Vol. 9, No. I, pp. 21-33, 1995) conducted a study on 6 -8 week old mice to test the effects of acetaminophen on spermatogenesis and Sperm chromatin structure were studied in maleB6C3F1Laboratory Mice at a dose level of 0 or 400 mg/kg. Different parameters like testicular germ cells,Body weight,organ weight and Sperm measures were analyzed. Considering the results at high doses (400mg/kg) of acetaminophen inhibited DNA synthesis in the testis is observed. Thus we can conclude that the LOAEL value for general and reproductive toxicity of acetaminophen in male mouse was observed at a dose level of 400 mg/kg. Delia N. Laub Et.al (TOXICOICAL SCIENCES 56, 150-155 (2000) presented a study elucidating Effects of Acetaminophen on Preimplantation Embryos were studied in pregnant mice. APAP (Acetaminophen) was given daily at a dose 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. The NOAEL (no observed adversed effect level ) of Acetaminophen in female mice and offsprings were observed at a dose level of 1430 mg/kg.

In another NTP report, Acetaminophen (ACET), a common over-the-counter analgesic agent, was tested for its effects on reproduction and fertility in CD-1 mice, following the RACB protocol.The dose concentrations used were 0, 370, 770, or 1400 mg/kg/d .Based on the reduced body weights the LOEL (low observed effect level)was predicted to be 1400mg/kg/day 

Based on the studies summarized with various routes in the above table it can be observed that LOEL values is found to be in the range of 400 - 1400 mg/Kg bw/ d and no observed adverse effect level is found to be 1430 mg/kg bw. The effects observed on the higher doses was listed as follows

·        Inhibition of DNA replication  reduction in early pachytene spermatocytes,reduced relative testicular weight.

·        Copulation plugs each day of breeding, decreased liver GSH concentrations

·        Sperm abnormalities increased,organ weights ,body weight

Thus based on above discussion it can be concluded that substance CAS: 103-90-2 has lowest observed effect value (LOEL) as 400 mg/kg bw/d via intraperitoneal route whereas LOEL via oral route is found to be much higher range 1400 mg/ kg bw/d and thus based on these value it is considered that CAS: 103-90-2 does not have any reproductive toxic effect below the mentioned dose levels. It is the most commonly used as medicine and also there are no known evidence of adverse effect on reproduction to Human of CAS: 103-90-2

which was further supported by the negative results estimated for teratogenicity using the Danish EPA prediction model

 

Short description of key information:

From the various data available and adopting the weight of evidence approach, it has been concluded that Paracetamol is not likely to have reprotoxic effects within the dose levels mentioned in the respective end points.

Justification for selection of Effect on fertility via oral route:

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

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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:

The toxicity of paracetamol on Neonatal children during a study period of 29 weeks

GLP compliance:

not specified

Limit test:

no

Species:

other: Human-woman

Route of administration:

oral: unspecified

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

29 week(s) after conception

Remarks:

Doses / Concentrations:
500 mg/kg
Basis:

No. of animals per sex per dose:

22 year old Caucasian mother

Control animals:

not specified

Maternal examinations:

The mother had a toxic blood concentration of paracetamol.4 She had no clinical signs of liver damage after delivery, but 50 hours after the ingestion of paracetamol her aspartate transaminase activity rose to a maximum of 4300 IU/l, bilirubin to 30 [±mol/l (1 .75 mg/100 ml) and prothrombin time to 22 seconds .

Fetal examinations:

- There were no malformations.The Apgar scores were 4 at 1 minute and 7 at 5 minutes
- She subsequently developed hyaline membrane disease
- Clinical jaundice was apparent on day 5 with a bilirubin value of 180 .tmol/l
- Urinary reducing substances were negative.The aspartate transaminase was 86 IU/l, bilirubin 37 ,umol/l (2.2 mg/100 ml), and prothrombin time 28 seconds (control 13). She underwent exchange transfusionswith whole donor blood at 4, 23, 28, and 41 hours after delivery
- Examination of th cerebrospinal fluid and examination of the blood culture did not show infection
- She died unexpectedly at the age of 106 days.

Historical control data:

The post mortem examination showed no definite cause of death, the only positive findings being many petechiae on the surface of the thymus, heart, and lungs.

Details on maternal toxic effects:

The mother had a toxic blood concentration of paracetamol.4 She had no clinical signs of liver damage after delivery, but 50 hours after the ingestion of paracetamol her aspartate transaminase activity rose to a maximum of 4300 IU/l, bilirubin to 30 [±mol/l (1 .75 mg/100 ml) and prothrombin time to 22 seconds .

- There were no malformations.The Apgar scores were 4 at 1 minute and 7 at 5 minutes
- She subsequently developed hyaline membrane disease
- Clinical jaundice was apparent on day 5 with a bilirubin value of 180 .tmol/l
- Urinary reducing substances were negative.The aspartate transaminase was 86 IU/l, bilirubin 37 ,umol/l (2.2 mg/100 ml), and prothrombin time 28 seconds (control 13). She underwent exchange transfusionswith whole donor blood at 4, 23, 28, and 41 hours after delivery
- Examination of th cerebrospinal fluid and examination of the blood culture did not show infection
- She died unexpectedly at the age of 106 days.

Dose descriptor:

LOAEL

Effect level:

500 other: mg/kg

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
hyaline membrane disease and decreased in bilirubin value was observed.

Remarks on result:

not measured/tested

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

In a chronic study of 29 weeks, LOAEL (Lowest observed effect level) for developmental toxicity of Paracetamol in human by the oral route was observed to be 500 mg/kg.

Executive summary:

In this study report a case of paracetamol poisoning in an infant of 29 weeks' gestation whose mother ingested paracetamol before delivery.The baby girl, birthweight 1.22 kg (25th centile), was born by spontaneous vertex delivery,There were no malformations .She subsequently developed hyaline membrane disease,The bilirubin value fell to 90 Fmol/l (5.2 mg/100 ml) by day 8 and the jaundice was attributed to her prematurity,Examination of the cerebrospinal fluid and examination of the blood culture did not show infection.Plasma paracetamol concentrations did not decrease continuously in the infant but showed a rebound effect after each of the first 3 exchange transfusions.Thus we can conclude that the developmental toxicity study LOAEL (Lowest observed toxic dose) of Paracetamol in human by the oral route was observed to be 500 mg/kg in a chronic study of 29 weeks.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

other: human

Quality of whole database:

The data is K2 level as the data has been obtained from the experimental study from the 'Archives of Disease in Childhood'.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental study-The first study presented in the journal of Archives of Disease in Childhood. 58,631,1983 by S Lederman et.al reported a case of paracetamol poisoning in an infant of 29 weeks' gestation whose mother ingested paracetamol before delivery.The baby girl, birthweight 1.22 kg (25th centile), was born by spontaneous vertex delivery,There were no malformations .She subsequently developed hyaline membrane disease,The bilirubin value fell to 90 Fmol/l (5.2 mg/100 ml) by day 8 and the jaundice was attributed to her prematurity, Examination of the cerebrospinal fluid and examination of the blood culture did not show infection.Plasma paracetamol concentrations did not decrease continuously in the infant but showed a rebound effect after each of the first 3 exchange transfusions.Thus we can conclude that the developmental toxicity study LOAEL (Lowest observed toxic dose) of Paracetamol in human by the oral route was observed to be 500 mg/kg in a chronic study of 29 weeks.

 

K.  Hess et.al (Toxicologist. 4,166,1984) The fetotoxicity LOEL value (Lowest observed effect level ) of Paracetamol in mouse by the oral route was observed to be 140 mg/kg in a subacute study of 15 days.

Developmental study was conducted By another NATIONAL TOXICOLOGY PROGRAM on CD-1 mice as a range finding study and Since ACET had no effect on fertility and only relatively minor effects on reproductive performance in F0 breeding pairs , it was decided to evaluate the reproductive effects of ACET in the Fl generation. The Fl litters randomly selected at day 28 for rearing were housed by sex in groups of two or three animals and maintained on the same dietary level of ACET as their Task 2 parents (F0 generation). At 7410 days of age a male and female from different litters within dose group were cohabited for 7 days. The pairs then were separated and the females allowed to deliver their litters (F 2 generation). Exposure to the respective dietary levels of ACET continued during cohabitation andpregnancy.Based on the effects following results are found-F0-NOEL Effect level-1666.6mg/kg bwBasis of effect-no effectsF1-NOAEL Effetc level-416.6mg/kgBasis of effect-Body weight and abnormal spermsF2-NOAEL Effetc level-416.6mg/kgBasis of effect- Decrease Body weight

 

 

Based upon the Danish EPA database, the teratogenicity of paracetamol to humans was found to be negative.

.

Justification for selection of Effect on developmental toxicity: via oral route:

The developmental toxicity study LOEL (Lowest observed toxic dose) of Paracetamol in human by the oral route was observed to be 500 mg/kg in a chronic study of 29 weeks

Justification for classification or non-classification

The chemical Paracetamol does not exhibit toxicity to the reproductive system as well as developmental toxicity within the doses mentioned in the various study end points.