Paracetamol

Developmental toxicity / teratogenicity

Administrative data

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:

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Neonatal paracetamol poisoning: treatment by exchange transfusion

Author:

S Lederman, W J Fysh, M Tredger, And H R Gamsu

Year:

1983

Bibliographic source:

Archives of Disease in Childhood. 58,631,1983

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):ADCHAK Archives of Disease in Childhood. (British Medical Journal, POB 560B, Kennebunkport, ME 04046) V.1- 1926- Volume(issue)/page/year: 58,631,1983

Materials and methods

Test guideline

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

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:

.

Details on test material:

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

Test animals

Species:

other: Human-woman

Administration / exposure

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

Doses / concentrations

Remarks:

Doses / Concentrations:
500 mg/kg
Basis:

No. of animals per sex per dose:

22 year old Caucasian mother

Control animals:

not specified

Examinations

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.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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.

Effect levels (maternal animals)

Dose descriptor:

LOAEL

Effect level:

500 other: mg/kg

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Maternal abnormalities

Abnormalities:

not specified

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

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

Effect levels (fetuses)

Remarks on result:

not measured/tested

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

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.