Absorption, Distribution and Excretion
Tissue concentrations of 4-tert-octylphenol were determined in male and female Sprague-Dawley rats (n=5) at 4 hours and 24 hours after a single oral dose of 125 or 250 mg/kg body weight, and after repeated daily administrations of 25, 50, or 125 mg/kg body weight for 60 days (males) or 35 days (females). Tissue concentrations appeared to be in the single-digit μg/g tissue range. The highest concentrations were observed in the liver after a single oral dose, followed by adipose tissue, kidney, and ovary. The lowest concentrations were observed in muscle tissue. Tissue concentrations of 4-tert-octylphenol appeared to be higher in females than in males. A dose-dependent increase in tissue concentrations of 4-tert-octylphenol was observed after repeated oral administrations. The highest concentrations were observed in adipose tissue and liver. Tissue concentrations in animals repeatedly administered a 125 mg/kg body weight/day dose were compared with those in animals administered a single oral dose of 125 mg/kg body weight. No significant difference was found between single-dose and repeated-dose tissue concentrations, indicating no bioaccumulation of 4-tert-octylphenol. Male or female Sprague-Dawley rats (n=5 per group) were administered 25, 50, or 125 mg/kg body weight/day of 4-tert-octylphenol daily for 57 days (males) or 33 days (females), respectively. Blood samples were collected at 1 hour on day 1 and 1 and 4 hours on the last day after administration. Following repeated exposure, the blood concentrations of 4-tert-octylphenol were higher in female rats (mean increase of 2.26-fold, not significantly different from the control group) and male rats (mean increase of 3.47-fold, significantly different) at the end of the exposure period compared to the control group. One hour after the end of day 1 of exposure, the blood concentration of 4-tert-octylphenol was higher in male rats than in female rats (mean increase of 1.69-fold, not significantly different). Five male or female Sprague-Dawley rats (n=5 per group) were administered a single oral dose of 50, 125, or 250 mg/kg body weight of 4-tert-octylphenol (97% purity), dissolved in propylene glycol. Blood samples were collected within 24 hours after administration. Peak plasma concentrations were reached 2 hours after administration in the 50 mg/kg group, and 1 hour after administration in the 125 or 250 mg/kg groups. The Cmax values for male and female rats were 133, 238, or 386 ng/mL and 106, 290, or 272 ng/mL, respectively. The AUC values for male and female rats were 1235, 2300, or 4264 ng/mL/hr and 1503, 4501, or 7838 ng/mL/hr, respectively. Bioavailability was 26-38% in males and 46-55% in females. The half-life of 4-tert-octylphenol was 5–16.6 hours in males and 8.3–37.9 hours in females. The authors concluded that the half-life determined after oral administration may still be uncertain due to the relatively high concentration of 4-tert-octylphenol in the blood at the last sampling time. Two male Sprague-Dawley rats were administered a single dose of 100 mg/kg body weight of 4-tert-octylphenol propylene glycol solution by gavage. Blood samples were collected within 5 hours after administration. Untreated animals served as a control group. The blood concentration of 4-tert-octylphenol was 730 ng/mL (Cmax) after 1 hour, decreasing to approximately 400 ng/mL after 5 hours. For more complete data on the absorption, distribution, and excretion of 4-(1,1,3,3-tetramethylbutyl)phenol (13 types), please visit the HSDB record page. Metabolites/Metabolites The metabolism of 4-tert-octylphenol was investigated using a liver perfusion method in male Sprague Dawley (SD) rats and Eisai hyperbilirubinemia rats (EHBR) with a solution containing 0.05 mM 4-tert-octylphenol. Metabolites were detected using high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC/MS). This study demonstrates that 4-tert-octylphenol can be metabolized via hydroxylation followed by glucuronidation or glucuronidation alone. The metabolites were identified as hydroxy-4-tert-octylphenol glucuronide, hydroxy-4-tert-octylphenol, tert-octylcatechol glucuronide, 4-tert-octylphenol glucuronide, 4-tert-octylcatechol, and unmodified 4-tert-octylphenol. Glucuronide was excreted into bile (accounting for 38% of the perfused substrate) and detected in the liver tissue of SD rats. In EHBR rats, only 32% of the perfused 4-tert-octylphenol was recovered, with almost all (approximately 68%) remaining in the hepatic veins (rather than in bile or liver). The second part of the study involved the assay of UDP-glucuronyltransferase activity. Yeast cells expressing multiple UDP-glucuronyltransferase isoenzymes (UGT1A1, UGT1A6, UGT1A7, and UGT2B1) were incubated with 4-tert-octylphenol. This assay showed that only the UGT2B1 isoenzyme could metabolize 4-tert-octylphenol, with a maximum reaction rate (Vmax) of 11 nmol/min/mg and a Michaelis constant (Km) of 94 μM. Furthermore, the conversion of 4-tert-octylphenol in rat liver, kidney, intestine, and testicular microsomes, as well as in human liver microsomes, was determined in vitro. The highest conversion rates were observed in the liver, rats, humans, and rat intestine. Vmax and km were measured to be 7.7, 3.8, and 2.75 nmol/min/mg, or 57, 24, and 125 μM, respectively. 4-T-Octylphenol (4-tOP) is an endocrine disruptor. In mammals, it is primarily metabolized to glucuronide by UDP-glucuronyltransferase (UGT). This study used microsomal components to investigate the glucuronidation of 4-tOP in humans, monkeys, rats, and mice in an in vitro system. The kinetics of 4-tOP glucuronidation by liver microsomes followed a Michaelis-Menten equation model in humans and monkeys, and a biphasic model in rats and mice. The K_m, V_max, and CL_int values of human liver microsomes were 0.343 μM, 11.6 nmol/min/mg protein, and 33.8 mL/min/mg protein, respectively. The kinetics of human, monkey, and rat intestinal microsomes conformed to the Michaelis-Menten equation model, while those of mice conformed to the biphasic model. The K_m, V_max, and CL_int values of human intestinal microsomes were 0.743 μM, 0.571 nmol/min/mg protein, and 0.770 mL/min/mg protein, respectively. The order of liver microsome CL_int values estimated by the Eadie-Hofstee plot was: mouse (high affinity phase) (3.0) > human (1.0) = monkey (0.9) > rat (high affinity phase) (0.4); the order of intestinal microsome CL_int values was: monkey (10) > mouse (high affinity phase) (5.6) > rat (1.4) > human (1.0). The percentage of intestinal microsomal CL_int values relative to liver microsomal CL_int values was as follows: monkey (27%) > rat (high affinity phase of liver microsomes) (7.9%) > mouse (high affinity phase of both liver and intestinal microsomes) (4.2%) > human (2.3%). These results indicate significant differences in the ability of UGT enzymes expressed in the liver and intestine to metabolize 4-tert-octylphenol (4-tOP) across different species, suggesting that species differences are closely related to the toxicity of alkylphenols. 4-tert-octylphenol (4-tOP) is an endocrine disruptor. In humans, it is primarily metabolized to glucuronide by UDP-glucuronyltransferase (UGT). This study aimed to assess inter-individual differences in UGT isoenzymes involved in the glucuronidation of 4-tOP in human liver and their potential roles. This study evaluated the glucuronidation activity of 4-tOP in human liver microsomes and recombinant UGT at a wide range of substrate concentrations and analyzed its kinetics. Furthermore, correlation analyses were performed on the activities of 4-tOP with diclofenac or 4-hydroxybiphenyl in mixed and single human liver microsomes. Typical CLint values were: low type 17.8 mL/min/mg protein, medium type 25.2 mL/min/mg protein, and high type 47.7 mL/min/mg protein. Among the recombinant UGTs (13 isoenzymes) tested, UGT2B7 and UGT2B15 exhibited the highest catalytic activity for 4-tOP glucuronidation. Although the Km values of UGT2B7 and UGT2B15 were similar (0.36 μM and 0.42 μM, respectively), the CLint value of UGT2B7 (6.83 mL/min/mg protein) was higher than that of UGT2B15 (2.35 mL/min/mg protein). A strong correlation was observed between the glucuronidation activities of 4-tert-octylphenol (4-tOP) and diclofenac (a probe of UGT2B7) or 4-hydroxybiphenyl (a probe of UGT2B15), with Spearman correlation coefficients (rs) ranging from 0.79 to 0.88. These findings suggest that the glucuronidation of 4-tOP in humans is primarily catalyzed by hepatic UGT2B7 and UGT2B15, and indicate that these UGT isoenzymes play an important and unique role in the detoxification of 4-tOP.

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Biological Half-Life
Five male or female Sprague-Dawley rats were divided into groups and subcutaneously injected with 125 mg/kg of 4-tert-octylphenol (97% purity) DMSO solution. …The half-life of 4-tert-octylphenol was 9.8 hours in males and 39.6 hours in females. ...
A group of 12 female DA/Han rats received a single intravenous injection of 5 mg/kg body weight of 4-tert-octylphenol (98% purity), dissolved in 1,2-propanediol. ...Based on the calculations of this study, the half-life of 4-tert-octylphenol was 36.1 hours.
Another group of 5 male or female Sprague-Dawley rats (n=5 per group) received a single oral administration of 50, 125, or 250 mg/kg body weight of 4-tert-octylphenol (97% purity), dissolved in propylene glycol. ...The half-life of 4-tert-octylphenol in male rats ranged from 5 to 16.6 hours, and in female rats from 8.3 to 37.9 hours. The authors concluded that the half-life determined after oral administration may still have uncertainties due to the relatively high blood concentration of 4-tert-octylphenol at the last sampling. Six male Wistar rats were administered a single intravenous injection of 5 mg of 4-tert-octylphenol (98% purity) polypropylene solution via the tail vein. A group of animals that received only the solvent served as a negative control. In the 4-tert-octylphenol treatment group, peak plasma concentration of 1970 ng/mL was reached immediately after injection, decreased within 30 minutes, and became undetectable after 6-8 hours. The calculated AUC was 0.433 (μg/mL·hr), and the half-life was approximately 310 minutes.

Toxicity Summary
Identification and Uses: 4-(1,1,3,3-Tetramethylbutyl)phenol (tOP) is a white solid used in the synthesis of chemical surfactants. Human Studies: tOP can irritate the skin and eyes. An epidemiological study showed a significant negative correlation between maternal urinary tOP concentration and neonatal birth weight. Animal Studies: tOP can cause eye and skin irritation in rabbits. The subchronic dietary toxicity of tOP was assessed in rats by continuous administration for 3 months. Food intake and mortality were unaffected by treatment at all concentrations. Toxicity symptoms included decreased body weight gain. Hematocrit and thyroxine levels were decreased in female rats. Neonatal exposure to high doses of tOP enhances the incidence of uterine cancer in rats, and the type of uterine tumor is influenced by the duration of neonatal tOP exposure, suggesting that the mechanism of uterine tumor development is related to the duration of neonatal exposure. This study included a reproductive/developmental screening test in rats. Rats were administered tOP by gavage once daily for two weeks before mating, two weeks during mating, and from birth to day 4 after pups, at doses of 125, 250, or 500 mg/kg/day, respectively. Results showed that only the 500 mg/kg/day dose group exhibited mild impaired mating ability and embryonic development, manifested as reduced conception and implantation rates, prolonged gestation, and developmental delay. tOP interfered with uterine contractions in pups. tOP exposure led to dose-dependent oviduct maturation in both male and female frogs. Studies have shown that tOP has estrogen-like effects on cultured mammalian cells. Ecotoxicity studies: tOP is a common environmental pollutant that has been shown to have toxic and estrogen-like effects on mammalian cells. In male voles, continuous 60-day tOP treatment adversely affected the weight and tissue structure of their testes and seminal vesicles. In these tissues, the expression of 3β-hydroxysteroid dehydrogenase and androgen receptors, as well as testosterone levels, were decreased, while the expression of aromatase and estrogen receptor α, as well as estradiol levels, were increased. Short-term exposure to phosphorus oxychloride (tOP) and the natural estrogen 17β-estradiol altered important traits in adult male guppies. Both compounds increased sperm count in ejaculate, reduced the area and color intensity of the orange spot of sexual attraction, and inhibited testicular growth. This study investigated the effects of different concentrations (0, 0.5, 1, 1.5, 2, and 3 mg/L) of phosphorus oxychloride (tOP) on the submerged plant Ceratophyllum demersum. Results showed that the toxic effects of tOP inhibited the growth rate of Ceratophyllum demersum, reduced total chlorophyll content, and increased reactive oxygen species (ROS) levels. tOP treatment significantly increased the activity of antioxidant enzymes, including superoxide dismutase (SOD), guaiacol peroxidase (Guaifenesin peroxidase), glutathione reductase (Glutathione reductase), and ascorbate peroxidase (Ascorbate peroxidase).

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Toxicity Data
LC50 (Rat) < 29,000 mg/m3/4h
Interactions
This study aimed to elucidate the regulatory effect of chicory (Cichorium intybus L.) fruit extract (CFR) on 4-tert-butyl peroxidase (4-tert-OP)-induced oxidative stress and hepatotoxicity in male rats. Rats were divided into four groups and treated for 8 weeks: Group 1: normal control (physiological saline); Group 2: chicory fruit extract group (100 mg/kg); Group 3: 4-tert-butyl peroxidase group; Group 4: 4-tert-butyl peroxidase combined with chicory fruit extract group.
The results showed that the activities of thiobarbituric acid reactants (TBARS), bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) were significantly increased in the livers of rats treated with 4-tert-butylperoxidase (4-tert-OP), while the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase were significantly decreased. On the other hand, the CFR extract effectively regulated these abnormalities induced by 4-tert-OP, as evidenced by a decrease in TBARS levels and a significant improvement in the detected biochemical and antioxidant indicators. Histopathological evidence and observed PCNA and DNA fragmentation further confirmed the detrimental effects of 4-tert-OP and the ameliorative effect of the CFR extract on hepatotoxicity. Therefore, it can be concluded that chicory has good application prospects and is worthy of consideration as a natural substance for alleviating oxidative stress and liver damage induced by 4-tert-octylphenol (4-tert-OP). The synergistic effects of multiple endocrine disruptors (EDCs) have attracted researchers' attention. To expand upon previous studies, this study investigated the potential interactions among bisphenol A (BPA), 4-nonylphenol (NP), 4-tert-octylphenol (OP), and isobutylparaben (IBP) in a mouse model. Pregnant Swiss albino mice were treated with binary combinations of chemicals (5, 50, or 500 mg/kg/bw/day) from day 1 of gestation (GD 1) to day 21. Interestingly, maternal exposure to these EDCs resulted in fluctuations in gestational age, survival rate, sex ratio, body weight, and organ weight in offspring at days 1 (PND 1), 21 (PND 21), and 41 (PND 41) after birth. Early gestation (GD) was reduced by 0.85 to 1.87 days in most dose groups compared to the control group. Furthermore, significant differences in sex ratio were observed between the BPA+OP and BPA+IBP groups. Female offspring showed significantly reduced body weight at days 21 and 41 postnatal time in all combined dose groups, while male offspring showed reduced body weight at a dose of 50 mg/kg/bw/day. Potential synergistic estrogen effects were manifested in histopathological abnormalities, such as increased corpus luteum, increased cystic follicles, endometrial hypertrophy, and uterine morphometric changes in ovarian analysis. In summary, these results provide new insights into the synergistic effects of endocrine disruptors (EDCs) toxicology on the reproductive tract. 4-Ter-Octylphenol (OP) is an endocrine disruptor that can have harmful effects on human health. Chlorogenic acid is a major dietary polyphenol found in various foods and beverages. This study aimed to evaluate the protective effect of chlorogenic acid against anemia and mineral disorders in rats poisoned by organophosphates. Thirty-two male albino rats were randomly divided into four groups (n=8 per group) as follows: Group 1 (control group) received 1 mL of physiological saline orally daily for two weeks; Group 2 received 60 mg/kg body weight of chlorogenic acid orally daily for two weeks; Groups 3 and 4 received 100 mg/kg body weight of organophosphates intraperitoneally daily for two weeks; Group 4 received 60 mg/kg body weight of chlorogenic acid orally daily for three weeks, starting one week before organophosphate injection. Results showed that organophosphates (OP) significantly reduced the levels of hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin content, mean corpuscular hemoglobin concentration, platelet count, white blood cell count, percentage of lymphocytes and neutrophils, transferrin receptor, serum calcium, phosphorus, sodium, potassium, chloride, glutathione S-transferase, glutathione peroxidase, catalase, glutathione reductase, and superoxide dismutase. Furthermore, the OP group showed significantly elevated serum levels of hepcidin, ferritin, transferrin, erythropoietin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, urea, creatinine, selenium, zinc, manganese, copper, iron, malondialdehyde, and protein carbonyl groups. OP exposure also induced apoptosis. Pretreatment with chlorogenic acid in the OP-treated group restored all of the above indicators to near-normal values. In conclusion, chlorogenic acid protects the body from anemia and mineral disorders caused by 4-tert-octylphenol poisoning by alleviating oxidative stress and apoptosis.

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Non-human toxicity values
Mouse intraperitoneal LD50: 25 mg/kg
Rabbit dermal LD50: 1880 mg/kg
Rat inhalation LD50: ≤ 116 mg/L/24 hours/89% purity
Rat oral LD50: >2000 mg/kg
Mouse oral LD50: 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-Tertiary-octylphenol is an alkylbenzene. α-(p-(1,1,3,3-tetramethylbutyl)phenyl)-ω-hydroxypolyoxyethylene is used as a food additive [EAFUS] (EAFUS: United States Food Additives List. [http://www.eafus.com/]). α-(p-(1,1,3,3-tetramethylbutyl)phenyl)-ω-hydroxypolyoxyethylene belongs to the p-menthane monoterpenoid class of compounds. The structure of these monoterpenes is based on the p-menthane skeleton. See also: Tyloxapine (monomer). Mechanism of Action: Environmental pollution has been one of the major drawbacks of the Industrial Revolution. During production and industrial product leaching, numerous synthetic chemicals are continuously released into the environment. Therefore, human and animal populations are frequently exposed to these synthetic chemicals. Many of these chemicals have adverse effects on physiological functions, especially on the hormonal systems of humans and animals; these substances are known as endocrine disruptors (EDCs). Bisphenol A (BPA), 4-tert-octylphenol (OP), and 4-nonylphenol (NP) are three high-yield endocrine disruptors widely used in industry and prevalent in the environment. BPA 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 that these three endocrine disruptors are associated with adverse effects on the reproductive systems of humans and animals. Sex hormone-binding globulin (SHBG), a circulating protein that binds to sex steroids, is a potential target for endocrine disruptors in the human body. This study aimed to investigate the binding mechanism of organophosphates (OP), BPA, nonylphenol (NP), and methylisothiazolinone (MBP) to human sex hormone-binding globulin (SHBG) using computer simulations. The results showed that all four compounds had high binding affinity to SHBG, but the binding affinity values (negative values) of MBP and NP were higher than those of OP and BPA. All four ligands interact with amino acid residues 19-23 of SHBG, and their interacting residues significantly overlap with those of the natural ligand dihydrotestosterone (DHT) (overlap rate 82-91%). The overlap of DHT with these four endocrine disruptors at their SHBG interacting residues suggests that these compounds may interfere with and disrupt the binding function of steroid hormones.

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.)