4-Acetamidophenol

103-90-2

Analgesic and antipyretic. 
In manufacture of azodyestuffs and 
photographic chemicals.

Soluble in organic solvents: methanol, ethanol, acetone and
ethyl acetate (Richardson et al. 1993).

Acetaminophen is metabolised in the liver via two routes, one
pathway leads to the formation of N-acetyl-p-benzoquinone imine
(NAPQI) mediated by cytochrome P-450, the other detoxification
pathway leads to the formation of glucuronide, sulfate and
glutathione conjugates which are excreted in the urine, t1/2
1-4 hr.

The toxic pathway metabolites predominate in the bile, whrereas
non-toxic metabolites are excreted in the urine.

Acetaminophen passes rapidly into the breast milk of mursing
mothers. 
Acetaminophen and its glucuronide, sulfate, cysteine
and mercapturate conjugates were found in the urine neonates
(Richardson et al. 1993).

LDLo (unspecified exposure) oral human 150-800 mg/kg central
nervous system gastrointestinal tract and liver effects
(Richardson et al. 1993).

A single oral dose was administered to fasted adult male mice,
which were subsequently sacrified 30 min to 48 hr after
treatment. 
Damage to liver, kidney, necrosis of bronchiolar
epithelium, lymphoid necrosis and testicular changes were
observed. 
Spermatid degeneration with early development of
spermatid multinucleated gaint cells was a characteristic
feature (Plake et al. 1987).

Single or multiple intraperitoneal doses of 300-1000 mg/kg with
pretreatment (P-448 inducer) in C57BL/6 and DBA/2 mice and
500-1500 mg/kgwith pretreatment (P-450 inducer) in New Zaeland
white and chinchilla rabbits showed that susceptibility to
acetaminophen cataractogenesis can be genetically 
predeterminated and may involve enzymic bioactivation possibly
independent of hepatic biotransformation and toxicity 
(Lubek et al.1988).

Skin rashes have been reported (Richardson et al. 1993).

No adequate evidence for carcinogenicity to humans, IARC
classification group 3.

Acetaminophen promoted kidney tumour development in rats.

Acetaminophen, 1000 or 5000 ppm for 40 wk, produced transient
chronic hepatic hyperplasia without evidence of carcinogenicity
in B6C3F1 (6 wk old) mice.

Acetaminophen did not reveal tumour initiating potential in
rats with preexisting fatty liver induced by a
choline-deficient diet.

Administration of 1.1% or 1.25% acetaminophen respectively to
B6C3F1 and NIH mice for 41 wk caused severe liver injury
characterised by centrilobular necrosis. 
The results are
discussed in terms of their importance to the interpretation of
carcinogenicity studies (Richardson et al. 1993).

In vitro testing, acetaminophen was cytotoxic to Chinese
hamster ovary V79 cells, inhibited DNA synthesis and increased
sister chromatid exchanges (Richardson et al. 1993).

Effects on hydroxyurea-resistant mouse mammary tumour cell line
(TA3H2) showed that acetaminophen reduced DNA synthesis by
inhibiting ribonucleotide reductase activity. 
In wild-type
cells acetaminophen produced a concentration-dependent
induction of chromosomal aberrations and sister chromatid
exchanges (Hongslo et al. 1990).

In vivo testing in the mouse micronucleus test, an increased
occurence of micronuclei in polychromatic bone marrow
erythrocytes was seen (Richardson et al. 1993).

In human volunteers, following the oral administration of acet-
aminophen (1000 mg x 3 doses during 8 hr), blood and buccal
mucosal cell samples were taken at time 0, 24, 72 and 168 hr
after first dose. 
Treatment reduced the level of unscheduled
DNA synthesis in 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)
treated lymphosytes, and increased the frequency of micro-
nucleated cells in the buccal mucosa at 72 hr (Topinka et al.
1989).

In ouabain-resistant mouse embryo cells (3H10T1/2clone 8),
acetaminophen produced negative mutation, positive induction of
non-neoplastic cells and morphological transformation 
(Patiemo et al. 1989).

Low birth rate, foetal hepatoxicity and neonatal death occurred
when male mice (16-19 days pregnant) were administered 42-84
mg/kg acetaminophen simultaneously with a fatty diet.

Acetaminophen administered orally at 14 mg/kg to near term rats
resulted in constriction of foetal ductum.

Addition of acetaminophen to rat embryos in culture produced an
increased incidence of morphologically abnormal anterior
neuropores. 
The data suggest that the visceral yolk sac plays a
vital role in the metabolic transformation of acetaminophen to
catechol and quinone-imine reactive metabolites.

Acetaminophen inhibited Na+, K+ and Mg2+-ATPase activities in
vitro in human foetal cerebrum and cerebellum in a
dose-dependent manner (Richardson et al. 1993).