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EC number: 203-157-5 | CAS number: 103-90-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
No teratogenic effetcs observed .
Link to relevant study records
- 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.
Reference
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
- 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.
Reference
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.
Additional information
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