Absorption, Distribution and Excretion
Tissue concentrations of 4-tert-octylphenol were determined in male and female Sprague-Dawley rats (n=5) 4 and 24 hours after administration of a single oral dose of 125 or 250 mg/kg, and after repeated doses of 25, 50 or 125 mg/kg bw/day for 60 day (males) or 35 d (females). The tissue concentrations appeared to be within a single-digit ug/g tissue range. After single oral administration the highest concentration was found in liver, followed by fat, kidneys and ovaries. Lowest concentrations were found in muscle tissue. 4- tert-octylphenol tissue concentrations appeared to be higher in female animals compared to the males. After repeated oral administration a dose-dependent increase of tissue 4-tertoctylphenol concentrations were observed. The highest concentrations were found in fat and liver. The tissue concentrations of animals treated with repeated doses of 125 mg/kg bw/day were compared to those of animals which received a single oral dose of 125 mg/kg bw. No significant differences occurred between the tissue concentrations from single and repeated treatment indicating no bioaccumulation of 4-tert-octylphenol.
Groups of male or female Sprague-Dawley rats (n=5, each) received daily doses of 25, 50 or 125 mg/kg bw/d 4-tert-octylphenol for 57 (male) or 33 (female) consecutive days. Blood samples were collected on day 1, 1 hour after administration and on the respective last day of treatment, 1 and 4 hr after administration. After repeated exposure, blood 4-tert-octylphenol concentrations were higher at the end of the exposure period in both female (mean 2.26-fold, not significant compared to controls) and male (mean 3.47-fold, significant) rats. Blood 4-tert-octylphenol concentrations were higher in male than in female rats 1 hr after the end of exposure on the first day of exposure (mean 1.69-fold, not significant).
Groups of 5 male or female Sprague-Dawley rats (n=5, each) received single oral doses of 4- tert-octylphenol (purity 97%) of 50, 125 or 250 mg/kg bw in propylene glycol. Blood was sampled up to 24 hr after administration. The maximum blood concentrations were measured after 2 hr in the 50 mg/kg group and after 1 hr in groups receiving 125 or 250 mg/kg bw. In male and female rats Cmax of 133, 238 or 386 ng/mL and 106, 290 or 272 ng/mL, respectively were determined. In male and female rats AUC of 1235, 2300, or 4264 and 1503, 4501, or 7838 (ng/mL/hr) were determined, respectively. Bioavailability ranged from 26-38% in male animals and 46-55% in females. 4-tertoctylphenol half life ranged from 5-16.6 hr in male animals and 8.3-37.9 in females. The authors concluded that there may remain uncertainties regarding the half-life determined after oral application due to relatively high 4-tert-octylphenol blood concentrations at the last sampling time point.
Two male Sprague-Dawley rats received a single dose of 100 mg/kg bw 4-tert-octylphenol in propylene glycol by gavage. Blood samples were collected for up to 5 hr after administration. Untreated animals served as controls. After 1 hr 4-tert-octylphenol blood concentration was determined to be 730 ng/mL (Cmax), which was decreased to about 400 ng/mL after 5 hr.
For more Absorption, Distribution and Excretion (Complete) data for 4-(1,1,3,3-Tetramethylbutyl)phenol (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metabolism of 4-tert-octylphenol was investigated using liver perfusion in male Sprague Dawley (SD)rats and Eisai hyperbilirubinemic rats (EHBR) with a solution containing 0.05 mM 4-tert-octylphenol. Metabolites were detected using HPLC and LC/MS. In this study 4-tert-octylphenol was shown to be metabolized by hydroxylation and subsequent glucuronidation or glucuronidation alone. The metabolites were identified as hydroxyl-tert-4-tert-octylphenol glucuronide, hydroxyl-tert-4-tert-octylphenol, tertoctylcatechol-glucuronide, 4-tert-4-tert-octylphenol-glucuronide, 4-tert-octylcatechol unchanged 4-tert-4-tert-octylphenol. Glucuronides were shown to be excreted into the bile (38% of the perfused substrate) and were detected in liver tissue in SD rats. In EHBR rats only 32 % of perfused 4-tert-octylphenol were recovered almost all of which (approximately 68 %) was found in the hepatic vein (and not in the bile or the livers). In a second part or the study an UDP-glucuronosyltransferase assay was performed. Yeast cells expressing several isoforms of UDP-glucuronosyltransferase (UGT1A1, UGT1A6, UGT1A7, and UGT2B1) were incubated with 4-tert-octylphenol. In this test only the UGT2B1 isoform metabolized 4-tert-octylphenol with a Vmax of 11 nmol/min/mg and Km of 94 uM. Conversion of 4-tert-octylphenol was also measured in vitro in microsomes of liver, kidney, intestine and testis of rats as well as in human liver microsomes. Liver, rat and human, as well as rat intestine showed the highest conversion rate. Vmax and km were determined to be 7.7, 3.8 and 2.75 nmol/min/mg or 57, 24 and 125 uM, respectively.
4-tert-Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in mammals. In the present study, the glucuronidation of 4-tOP in humans, monkeys, rats, and mice was examined in an in vitro system using microsomal fractions. The kinetics of 4-tOP glucuronidation by liver microsomes followed the Michaelis-Menten model for humans and monkeys, and the biphasic model for rats and mice. The K m, V max, and CL int values of human liver microsomes were 0.343 uM, 11.6 nmol/min/mg protein, and 33.8 mL/min/mg protein, respectively. The kinetics of intestine microsomes followed the Michaelis-Menten model for humans, monkeys, and rats, and the biphasic model for mice. The K m, V max, and CL int values of human intestine microsomes were 0.743 uM, 0.571 nmol/min/mg protein, and 0.770 mL/min/mg protein, respectively. The CL int values estimated by Eadie-Hofstee plots were in the order of mice (high-affinity phase) (3.0) > humans (1.0) = monkeys (0.9) > rats (high-affinity phase) (0.4) for liver microsomes, and monkeys (10) > mice (high-affinity phase) (5.6) > rats (1.4) > humans (1.0) for intestine microsomes. The percentages of the CL int values of intestine microsomes to liver microsomes were in the order of monkeys (27 %) > rats (high-affinity phase in liver microsomes) (7.9 %) > mice (high-affinity phase in liver and intestine microsomes) (4.2 %) > humans (2.3 %). These results suggest that the metabolic abilities of UGT enzymes expressed in the liver and intestine toward 4-tOP markedly differ among species and imply that species differences are strongly associated with the toxicities of alkylphenols.
4-tert-Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in humans. The purpose of this study was to assess inter-individual variability in and the possible roles of UGT isoforms in hepatic 4-tOP glucuronidation in the humans. 4-tOP glucuronidation activities in the liver microsomes and recombinant UGTs of humans were assessed at broad substrate concentrations, and kinetics were analyzed. Correlation analyses between 4-tOP and diclofenac or 4-hydroxybiphenyl activities in pooled and individual human liver microsomes were also performed. Typical CLint values were 17.8 mL/min/mg protein for the low type, 25.2 mL/min/mg protein for the medium type, and 47.7 mL/min/mg protein for the high type. Among the recombinant UGTs (13 isoforms) examined, UGT2B7 and UGT2B15 were the most active of catalyzing 4-tOP glucuronidation. Although the K m values of UGT2B7 and UGT2B15 were similar (0.36 and 0.42 uM, respectively), the CLint value of UGT2B7 (6.83 mL/min/mg protein) >UGT2B15 (2.35 mL/min/mg protein). Strong correlations were observed between the glucuronidation activities of 4-tOP and diclofenac (a probe for UGT2B7) or 4-hydroxybiphenyl (a probe for UGT2B15) with 0.79-0.88 of Spearman correlation coefficient (r s) values. These findings demonstrate that 4-tOP glucuronidation in humans is mainly catalyzed by hepatic UGT2B7 and UGT2B15, and suggest that these UGT isoforms play important and characteristic roles in the detoxification of 4-tOP.

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Biological Half-Life
Groups of 5 male or female Sprague-Dawley rats were treated with 125 mg/kg 4-tertoctylphenol (purity 97%) in DMSO by subcutaneous injection. ... 4-tert-octylphenol half life was 9.8 hr in male and 39.6 in female animals. ...
A Group of 12 female DA/Han rats was treated with a single i.v. dose of 5 mg/kg bw 4-tertoctylphenol (purity 98%) in 1,2-popanediol. ... A half-life of 36.1 hr was calculated from this study.
Groups of 5 male or female Sprague-Dawley rats (n=5, each) received single oral doses of 4- tert-octylphenol (purity 97%) of 50, 125 or 250 mg/kg bw in propylene glycol. ... 4-tertoctylphenol half life ranged from 5-16.6 hr in male animals and 8.3-37.9 in females. The authors concluded that there may remain uncertainties regarding the half-life determined after oral application due to relatively high 4-tert-octylphenol blood concentrations at the last sampling time point.
A group of 6 male Wistar rats received a single i.v. dose of 5 mg 4-tert-octylphenol (purity 98%) in polypropylene into the tail vein. A group of animals receiving vehicle alone served as negative control. In the 4-tert-octylphenol treated group the maximum blood concentration of 1970 ng/mL blood was reached immediately after injection, decreased within 30 min and was not detectable after 6-8 hr. An AUC of 0.433 (ug/mLhr) and a half-life of about 310 min were calculated. ...

Toxicity Summary
IDENTIFICATION AND USE: 4-(1,1,3,3-Tetramethylbutyl)phenol (tOP) is a white solid. It is used in the synthesis of chemical surfactants. HUMAN STUDIES: tOP is a skin and eye irritant. An epidemiological study suggested significant negative associations between maternal urinary tOP concentrations and neonatal sizes at birth. ANIMAL STUDIES: tOP produced eye and skin irritation in rabbits. tOP was evaluated for subchronic dietary toxicity through administration to rats for 3 months. For all concentrations, food intake and death rates were not influenced by treatment. Toxic signs included decreased weight gain. Females had reduced hematocrit and thyroxin values. Neonatal exposure to a high-dose tOP enhanced uterine carcinogenesis in rats, and the type of uterine tumors was changed by the periods of neonatal exposure to tOP, suggesting that the mechanism of uterine tumor development is dependent upon neonatal exposure periods. A reproduction/developmental screening test was conducted in the rat. tOP was administered at dosages of 125, 250 or 500 mg/kg/day, once daily by gavage for two weeks prior to mating, throughout the two weeks mating period, and until litters reached day 4 post partum. Slight impairment of the mating performance and development of the conceptus, observed as a reduced conception and implantation rate, a prolonged duration of pregnancy and a developmental delay, only occured at 500 mg/kg/day. tOP interfered with uterine contractility in immature rats. tOP exposure caused dose-dependent maturation of oviducts in both male and female frogs. tOP has been shown to exert estrogenic effects on mammalian cells in culture. ECOTOXICITY STUDIES: tOP is a prevalent environmental pollutant that has been shown to exert both toxic and estrogenic effects on mammalian cells. In male bank voles, treatment for 60 days adversely influenced weights and histological structure of the testes and seminal vesicles. In these tissues, expression of 3beta-hydroxysteroid dehydrogenase and androgen receptor and testosterone levels were reduced, whereas expression of aromatase and estrogen receptor a and estradiol levels were increased. Short-term exposure to the tOP and the natural estrogen 17beta-estradiol changed important sexual characteristics in the adult male guppy. Both compounds increased the number of sperm cells in the ejaculates, reduced the area and color intensity of the sexually attractive orange spots, and inhibited testis growth. The effect of various concentrations of tOP (0, 0.5, 1, 1.5, 2 and 3 mg/L) was studied in an aquatic plant, the submersed macrophyte Ceratophyllum demersum. The toxic effect caused by tOP inhibited the plant's growth rate, reduced total chlorophyll content and increased levels of the reactive oxygen species. tOP treatment significantly increased the activities of antioxidant enzymes including superoxide dismutase, guaiacol peroxidase, glutathione reductase and ascorbate peroxidase.

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Toxicity Data
LC50 (rat) < 29,000 mg/m3/4h

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Interactions
The current study was carried out to elucidate the modulating effect of chicory (Cichorium intybus L.) fruit extract (CFR) against 4-tert-OP induced oxidative stress and hepatotoxicity in male rats. Rats were divided into four groups and treated for 8 weeks as follow: group 1: normal control-treated (saline); group 2: chicory fruit extract-treated (100 mg/kg); group 3: 4-tert-OP treated; group 4: 4-tert-OP plus chicory fruit extract. The obtained results revealed that rats which received 4-tert-OP showed a significant increase in liver TBARS and bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGTP) activities. While a significant decrease in the levels of GSH, SOD, catalase recorded. On the other hand, CFR extract succeeded to modulate these observed abnormalities resulting from 4-tert-OP as indicated by the reduction of TBARS and the pronounced improvement of the investigated biochemical and antioxidant parameters. Histopathological evidence, together with observed PCNA and DNA fragmentation, supported the detrimental effect of 4-tert-OP and the ameliorating effect of CFR extract on liver toxicity. So, it could be concluded that chicory has a promising role and it worth to be considered as a natural substance for ameliorating the oxidative stress and hepatic injury induced by 4-tert-OP compound.
The synergistic effect of numerous environmental endocrine disrupting chemicals (EDCs) has raised research concern among researchers. To extend previous studies, the measured additional potential interactions among bisphenol A (BPA), 4-nonylphenol (NP), 4-tert octylphenol (OP) and isobutylparaben (IBP) in mouse model were observed. Pregnant Swiss-albino mice were treated with binary combined chemicals (5, 50 or 500 mg/kg/bw/day) from gestation day (GD) 1 to 21. Interestingly, maternal exposure to these EDCs caused fluctuation in GD time, live ratio, female/male ratio, body and organ weights of mouse offspring at postnatal day (PND) 1, 21, and 41 days. At most doses early reduced 0.85 to 1.87 GD compared to controls. Besides females/males ratio showed a significant difference in BPA+ OP, BPA+IBP groups. Female body weight at PND 21 and 41, showed a significant reduction at all combined levels, whereas male offspring showed reduction in weight at dose 50 mg/kg/bw/day. The potential effects of synergic estrogenicity detected histopathological abnormities, such as ovary analysis revealed increase of corpora lutea, cystic follicles and an endometrial hypertrophy and morphometric changes in uteri measurement. Taken together, these results provided an additional insight into synergistic effects of EDCs toxicology on reproductive tracts.
4-tert-octylphenol (OP) is an endocrine-disrupting chemical that causes harmful effects to human health. Chlorogenic acid is the major dietary polyphenol present in various foods and beverages. The aim of the present study was to evaluate the protective role of chlorogenic acid in anemia and mineral disturbance occurring in OP toxicity in rats. Thirty-two male albino rats were divided into four equal groups (8 rats/group) as follows. The first (control) group was treated daily with an oral dose of 1 mL saline for two weeks. The second group was treated daily with an oral dose of 60 mg chlorogenic acid/kg body weight for two weeks. The third and fourth groups received daily intraperitoneal (ip) injections with 100 mg OP/kg body weight for two weeks; the fourth group was treated daily with an oral dose of 60 mg chlorogenic acid/kg body weight for three weeks starting one week before OP injections. The results revealed that OP induced significant decreases in hemoglobin, hematocrit, red blood cells, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelet count, white blood cells, lymphocyte and neutrophil percent, transferrin receptor, serum calcium, phosphorous, sodium, potassium, chloride, glutathione-S-transferase, glutathione peroxidase, catalase, glutathione reductase, and superoxide dismutase. Moreover, significant increases in serum hepcidin, ferritin, transferrin, erythropoietin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, urea, creatinine, selenium, zinc, manganese, copper, iron, malondialdehyde, and protein carbonyl levels were found in OP groups. OP exposure also induced cell apoptosis. Chlorogenic acid pretreatment in OP-treated groups restored all the mentioned parameters to approach the normal values. In conclusion, chlorogenic acid protects from anemia and mineral disturbances in 4-tert-octylphenol toxicity by ameliorating oxidative stress and apoptosis.

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Non-Human Toxicity Values
LD50 Mouse ip 25 mg/kg
LD50 Rabbit dermal 1880 mg/kg
LD50 Rat inhalation LD50 Rat oral >2000 mg/kg
LD50 Mouse oral 3210 mg/kg

[1]. 4-tert-Octylphenol Exposure Disrupts Brain Development and Subsequent Motor, Cognition, Social, and Behavioral Functions. Oxidative Medicine and Cellular Longevity, 2020.

[2]. Environmental Water Pollution, Endocrine Interference and Ecotoxicity of 4-tert-Octylphenol: A Review. Rev Environ Contam Toxicol. 2020;248:81-109.

[3]. 17α-ethinylestradiol and 4-tert-octylphenol concurrently disrupt the immune response of common carp. Fish Shellfish Immunol. 2020 Dec;107(Pt A):238-250.

[4]. Effects of crosstalk between steroid hormones mediated thyroid hormone in zebrafish exposed to 4-tert-octylphenol: Estrogenic and anti-androgenic effects. Ecotoxicol Environ Saf. 2024 Jun 1;277:116348.

4-tert-Octylphenol is an alkylbenzene.
alpha-(p-(1,1,3,3-Tetramethylbutyl)phenyl)-omega-hydroxypoly(oxyethylene) is used as a food additive [EAFUS] (EAFUS: Everything Added to Food in the United States. [http://www.eafus.com/]).

alpha-(p-(1,1,3,3-Tetramethylbutyl)phenyl)-omega-hydroxypoly(oxyethylene) belongs to the family of p-Menthane Monoterpenes. These are monoterpenes whose structure is based on the p-menthane backbone.
See also: Tyloxapol (monomer of).

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Mechanism of Action
Environmental contamination has been one of the major drawbacks of the industrial revolution. Several man-made chemicals are constantly released into the environment during the manufacturing process and by leaching from the industrial products. As a result, human and animal populations are exposed to these synthetic chemicals on a regular basis. Many of these chemicals have adverse effects on the physiological functions, particularly on the hormone systems in human and animals and are called endocrine disrupting chemicals (EDCs). Bisphenol A (BPA), 4-tert-octylphenol (OP), and 4-nonylphenol (NP) are three high volume production EDCs that are widely used for industrial purposes and are present ubiquitously in the environment. Bisphenol A is metabolized in the human body to a more potent compound (MBP: 4-Methyl-2, 4-bis (4-hydroxyphenyl) pent-1-ene). Epidemiological and experimental studies have shown the three EDCs to be associated with adverse effects on reproductive system in human and animals. Sex hormone-binding globulin (SHBG) is a circulatory protein that binds sex steroids and is a potential target for endocrine disruptors in the human body. The current study was done in order to understand the binding mechanism of OP, BPA, NP, and MBP with human SHBG using in silico approaches. All four compounds showed high binding affinity with SHBG, however, the binding affinity values were higher (more negative) for MBP and NP than for OP and BPA. The four ligands interacted with 19-23 residues of SHBG and a consistent overlapping of the interacting residues for the four ligands with the residues for the natural ligand, dihydrotestosterone (DHT; 82-91% commonality) was shown. The overlapping SHBG interacting residues among DHT and the four endocrine disruptors suggested that these compounds have potential for interference and disruption in the steroid binding function.

C14H22O

206.3239

206.167

140-66-9

4-tert-Octylphenol-3,5-d2;1173021-20-9

8814

White to off-white solid powder

0.9±0.1 g/cm3

282.3±0.0 °C at 760 mmHg

79-82 °C(lit.)

148.3±8.2 °C

0.0±0.6 mmHg at 25°C

1.501

4.93

1

1

3

15

192

0

ISAVYTVYFVQUDY-UHFFFAOYSA-N

InChI=1S/C14H22O/c1-13(2,3)10-14(4,5)11-6-8-12(15)9-7-11/h6-9,15H,10H2,1-5H3

4-(2,4,4-trimethylpentan-2-yl)phenol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~484.68 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.12 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (12.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)