Absorption, Distribution and Excretion
DINP has extremely low skin absorption rates. … Repeated administration does not result in the accumulation of DINP and/or its metabolites in the blood or tissues. This study investigated the skin absorption of (14)C-DINP in male Fischer 344 rats on pretreated (with unlabeled DINP) and untreated skin. The administration site was sealed after exposure. Under all conditions, the absorption was 2% to 4% of the dose after 7 days. Approximately 93% to 99% of the administered radioactive material was recovered at the administration site. Radioactivity in the feces and intestines of exposed rats indicates that some radioactive material is excreted via the bile route. This study examined the absorption of orally administered (14)C-DINP (dose = 2,500 mg/kg) in conditioned (pretreated with unlabeled DINP) and unconditioned male albino rats. Rats were administered 0.5 mL of radiolabeled DINP via gavage. The expert panel estimated the dose to be approximately 2,500 mg/kg body weight based on the density of DINP and reported rat body weight. Within 72 hours, 85% of the administered dose was excreted in feces, with the majority excreted within the first 24 hours. The remaining dose was excreted in urine (average 12%) or remained in tissues (trace amounts). Therefore, the oral absorption rate was approximately 12%. Male and female Fischer 344 rats received a single or five-day oral administration at doses of 50, 150, or 500 mg/kg, respectively. At least 49% of the single low-dose administration was absorbed. Absorption decreased with a single high-dose administration and with repeated administration of all doses. After five consecutive days of administration of the same dose of unlabeled DINP, albino rats received 0.5 mL of (14)C-DINP (approximately 2500 mg/kg body weight). Three days later, the radioactivity per gram of tissue in all studied tissues did not exceed 0.001% of the administered dose. The highest radioactivity levels were observed in the liver tissue. In male and female Fischer 344 rats that received a single or repeated oral dose (14) of C-DINP, the radioactive material was also rapidly cleared from tissues, but analysis of tissues shortly after exposure (within 1 hour) showed the highest levels of radioactivity in the liver (4.7% of the administered dose), kidneys (0.31%), and blood (1.62%). Small amounts of metabolites were found in fat and testes. No bioaccumulation was observed within 72 hours of administration. For more complete data on absorption, distribution, and excretion of diisononyl phthalate (9 types), please visit the HSDB record page. Metabolites/Metabolites Diisononyl phthalate (DINP) is rapidly metabolized to monoesters and parent alcohol. Following a single oral administration of 14C-DINP to rats, most of the 14C collected in the urine was present as phthalic acid or the side-chain oxidation product of monoesters (MINP). The relative content of phthalic acid in the urine decreased in the high-dose group. Monoesters themselves and diesters were present only in trace amounts. After oral administration of low-dose (50 mg/kg) or high-dose (500 mg/kg) 14C-DINP, the proportions of radioactivity associated with diesters in the feces were 8% and 41%, respectively. This indicates that metabolism reached saturation at high doses. The remaining radioactive material in the feces was associated with monoesters or their side-chain oxidation products. The main metabolites in the liver were monoesters and their side-chain oxidation products. The same metabolites and phthalic acid were also present in the testes. Monoesters and their oxidation products were present in adipose tissue. Repeated exposure experiments showed the presence of similar metabolites in tissues. In summary, in rats, DINP is deesterified to form a monoester, which is further metabolized by oxidation or hydrolysis of the ester side chain to phthalic acid. High doses or repeated administrations appeared to increase the formation of oxidation products, while the amount of hydrolysis to phthalic acid decreased. …Studies were conducted on male and female Fischer 344 rats, who were given a single oral dose of 50 or 500 mg/kg of (14)C-diisononyl phthalate (DINP, CAS 68515-48-0, purity 97-98%). …The clearance of radioactive material in urine and feces was assessed within 72 hours after administration. …High-performance liquid chromatography (HPLC) analysis of urine collected from male rats within 0-8 hours after a single administration of (14)C-DINP showed that most of the radioactive material (up to 28%) corresponded to phthalic acid, with a small amount (up to 7%) eluting at the origin of the chromatogram (polar component 4). Most of the recovered radioactive material (58-83%) eluted as a broad peak, exhibiting stronger polarity than the monoester (monononyl phthalate, MNP). This peak was preliminarily identified as a side-chain oxidation product of MNP (MINPox), which was present in higher concentrations in urine collected between 8 and 24 hours (with reduced recovery of phthalic acid (PA), while the polar component concentration was comparable). Phthalic acid elimination was dose-dependent, decreasing in the urine of rats treated with high doses. Urine analysis results from female rats were similar to those from male rats. Monoesters and diesters were either undetectable or present only in trace amounts in all urine samples. In feces, 8% and 41% of the radioactive material were associated with diesters, respectively, after a single low-dose and high-dose treatment. The remaining radioactive material eluted in the elution regions of MNP and MNPox; phthalic acid was undetectable (high-dose group) or present only in trace amounts (low-dose group). No radioactive material associated with the polar component was detected. Fecal samples from female rats receiving low-dose treatment showed little quantitative difference compared to those from male rats; however, fecal samples from female rats receiving high-dose treatment showed higher levels of maternal compounds and lower levels of oxidative metabolites. Metabolite distribution in the gastrointestinal tract was similar to that in male rats, with 83% of the radioactivity associated with MINPOx after low-dose DINP treatment (small amounts of DINP, MINP, and PA were also recovered). After high-dose treatment, more DINP and less MINPOx were recovered in the gastrointestinal tract. In the liver, regardless of the dose, the main metabolites were MINP and MINPOx. Small amounts of PA were also recovered after low-dose treatment. MINP and PA gradually decreased from 1 hour to 72 hours post-exposure, while MINPOx gradually increased. After high-dose treatment, small amounts of DINP were recovered within 1–4 hours, and only 1% of PA was recovered at 1 hour. The main metabolites recovered in the testes of rats receiving a single dose of (14)C-DINP included monoesters, their oxidation products, and acids; small amounts of polar components were also present. The levels of monoesters recovered from rat testes receiving high doses were slightly higher, while the levels of acids were slightly lower. The parent compound was not detected in either dose group. Fat collected from rats receiving a single low dose showed peaks corresponding to monoesters, their oxidation products, and trace polar components. Diesters were detected only in fat collected from rats receiving high doses. …/1,2-Phenylacetic acid, di-C8-10-branched alkyl ester, rich in C9/…Diisononyl phthalate (DINP, CAS 68515-48-0, purity 97-98%) was studied…In male rats treated with daily oral doses of 50, 150, and 500 mg/kg. Radioactive excretion in urine and feces was assessed up to 72 hours after the last administration. …Studies of the fecal DINP metabolomic profile showed that fecal excretion reflected a balance between unabsorbed DINP and metabolites excreted via bile. In urine, most of the radioactive material (79% to 91%) eluted as a broad peak, corresponding to MINPox. The levels of this metabolite were similar in urine collected at 0 to 8 hours or 8 to 24 hours, but slightly higher in the urine of rats receiving high doses. Small amounts (up to 13%) of phthalic acid were recovered from urine; its excretion was dose-independent after repeated administration. At high dose levels, the polar component was recovered in trace amounts, but at low dose levels, it accounted for 6% of urinary radioactivity. Diesters and monoesters were undetectable or present only in trace amounts at any dose. In feces, radioactive material was distributed among diesters, monoesters, and oxidation products; higher levels of diesters were recovered in the high-dose group. Only trace amounts of phthalic acid and polar components were recovered. Similar distributions were observed in the gastrointestinal tract. The liver contained significant amounts of monoesters and their oxidation products. At subsequent sacrifice time points, most of the radioactive material in the liver (71% to 90%) corresponded to oxidation products. Only trace amounts of phthalic acid and polar components were detected, while diesters were undetectable or present only in trace amounts. Metabolic profiles in the liver were dose-independent. Metabolic profiles in the testes showed that, after high-dose treatment, the content of oxidation products reached up to 89% of the total radioactivity; trace amounts of monoesters and phthalic acid were recovered. Diesters and polar components were undetectable or only occasionally present. The fat of rats treated with five doses contained abundant monoesters and their oxidation products, as well as trace amounts of diesters; phthalic acid and polar components were only occasionally detected. /1,2-Phenylacetic acid, di-C8-10-branched alkyl ester, rich in C9/
For more complete metabolite/metabolite data on diisononyl phthalate (15 in total), please visit the HSDB record page.

Toxicity Summary
Identification and Uses: Diisononyl phthalate (DiNP) is a mixture of phthalate esters with varying lengths of branched alkyl side chains (C8, C9, and C10). DiNP is primarily used in the production of flexible plastics and has replaced di(2-ethylhexyl) phthalate (DEHP) in some plastics, but it is not yet used in medical products. DiNP is widely used in products such as toys, flooring, gloves, straws, garden hoses, and food packaging sealants. Human Exposure and Toxicity: No clinical sensitization or irritation symptoms have been observed in human subjects. Individuals exposed to DiNP shed small amounts of monoisononyl phthalate (MiNP) and other secondary oxidative metabolites. These metabolites can be used to monitor occupational exposure to DiNP and in epidemiological studies. Animal Studies: The key toxicological effect of DINP is considered to be the liver changes observed in multiple studies. In a two-year chronic toxicity study in rats, hepatic cavernous edema was observed in rats, accompanied by elevated serum liver enzyme levels and increases in both absolute and relative liver and kidney weight in both male and female rats. Administration of DINP to rodents resulted in hepatotoxicity and nephrotoxicity. DINP exhibits significant carcinogenicity in rodents, inducing hepatocellular carcinoma in both male and female rats and mice, and monocytic leukemia in both male and female rats. Evidence for carcinogenicity in male rat renal tubular carcinoma is limited. The carcinogenic effect of DINP on rodent liver is associated with peroxisome proliferation and is currently considered irrelevant to humans. DINP appears to induce renal tubular carcinoma via an α2u-globulin mechanism, which is considered a rodent-specific mechanism and unlikely to be relevant to human risk assessments. In a rat developmental study, visceral organ changes (renal pelvis dilation and hydroureter) were observed at doses up to 1000 mg/kg body weight/day. In another rat study, skeletal changes (cervical vertebrae hypoplasia and accessory rib of the 14th rib) were observed. In chronic rat studies, high-dose administration significantly increased relative testicular weight, regardless of whether it was accompanied by an increase in absolute testicular weight and a decrease in body weight. Developmental studies showed that DNIP caused behavioral changes. DINP was not mutagenic in in vitro bacterial mutation assays or mammalian gene mutation assays (with or without metabolic activation), and was not chromosomal breakage-inducing in in vitro CHO cell cytogenetics assays or in vivo rat bone marrow cell assays. This indicates that DINP is not genotoxic in vivo or in vitro. Ecotoxicity studies: The toxicity of most high molecular weight phthalates to Daphnia appears to be due to surface retention or a toxicity pattern not caused by exposure to dissolved aqueous chemicals. This observed toxicity pattern of low molecular weight phthalates, rather than high molecular weight phthalates, is consistent with previously reported results from acute toxicity studies in several aquatic organisms.

---

Toxicity Data
LC50 (Rat)> 4,400 mg/m3/4h

---

Interactions
Phytrates are widely used in flexible plastics and consumer products and have become a prevalent pollutant globally. This study evaluated the acute toxicity and estrogen-endocrine-disrupting activity of butyl benzyl phthalate (BBP), di(n-butyl) phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), di-n-octyl phthalate (DNOP), and mixtures thereof. Using a 72-hour zebrafish embryo toxicity test, the LC50 values for BBP, DBP, and the mixture of six phthalates were found to be 0.72 ppm, 0.63 ppm, and 0.50 ppm, respectively. Even at the highest solubility concentrations, the other four phthalates did not cause embryo mortality exceeding 50%. Typical symptoms of phthalate toxicity include death, tail bending, necrosis, pericardial edema, and tactile unresponsiveness. A 24-hour test using estrogen-responsive ChgH-EGFP transgenic medaka (Oryzias melastigma) embryos showed that BBP possessed estrogenic activity, while DBP, DEHP, DINP, and a mixture of six phthalates exhibited enhanced estrogenic activity, whereas DIDP and DNOP did not show enhancing or anti-estrogenic activity. These findings highlight the developmental toxicity of BBP and DBP, and the estrogen-disrupting endocrine activity of BBP, DBP, DEHP, and DINP in intact organisms, suggesting that the widespread use of these phthalates may pose a potential risk to human health. /Mixtures/
Diisononyl phthalate (DINP) is widely used in polyvinyl chloride (PVC) products and is ubiquitous as an alternative; however, its exposure toxicity remains to be determined. This study investigated DINP-induced oxidative damage and the induction of pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). Oral DINP can induce oxidative damage and inflammatory responses in liver and kidney tissues through the accumulation of reactive oxygen species (ROS), which may be a potential mechanism of its toxicity. These changes may lead to pathological alterations in liver and kidney tissues. Our data suggest that oxidative stress is involved in DINP-induced toxicity, and that co-administration of melatonin has a protective effect against DINP-induced toxicity. Plasticizers are additives used to increase the flexibility or plasticity of their added materials, commonly used in rigid plastics and also as additives in paints and adhesives. They are suspected of interfering with the endocrine system, including the estrogen and thyroid hormone (TH) system. We investigated the thyroid hormone-like and estrogenic activities of a range of commonly used plasticizers and phenolic compounds in vitro, including benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), dioctyl phthalate (DOP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), di(2-ethylhexyl) phthalate (DEHP), di(2-ethylhexyl) adipate (DEHA), 4-tert-octylphenol (tOP), 4-chloro-3-methylphenol (CMP), 2,4-dichlorophenol (2,4-DCP), 2-phenylphenol (2-PP), and resorcinol. Their thyroid hormone-interfering potential was determined by their effect on the proliferation of thyroid hormone-dependent rat pituitary GH3 cells (T-screen). The estrogenic activity of these compounds was evaluated in MVLN cells stably transfected with an estrogen receptor (ER) luciferase reporter vector. In addition, the estrogenic and thyroid hormone (TH) activities of a multi-component mixture of six plasticizers were evaluated. Except for 2-PP, all tested compounds significantly affected GH3 cell proliferation. tOP, BBP, and DBP activated ER transcriptional activity, while DEHP antagonized 17β-estradiol-induced ER function. The mixture significantly induced ER transcriptional activity in an additive manner, but the mixture effect observed in T-screen was lower than expected, suggesting a possible antagonistic effect. In summary, the tested plasticizers and phenolic compounds possess endocrine-disrupting potential, which may be mediated by interference with the estrogen and TH systems. Furthermore, the observed mixture effects highlight the importance of considering the combined effects of compounds when conducting human health risk assessments. /Mixture/

---

Non-human toxicity values
Rabbit dermal LD50 >3.16 g/kg
Rat oral LD50 >10 g/kg
Rat oral LD50 >40000 mg/kg body weight/purity: 98.9% /
Rat oral LD50 >40000 mg/kg body weight/purity: 99.2% /
For more complete non-human toxicity data for diisononyl phthalate (13 items in total), please visit the HSDB record page.

[1]. Exposure to diisononyl phthalate induced an increase in blood pressure through activation of the ACE/ AT1R axis and inhibition of NO production. Toxicol Lett. 2019;309:42-50.

[2]. Chronic toxicity and carcinogenic evaluation of diisononyl phthalate in rats[J]. Fundamental and applied toxicology, 1997, 36(1): 79-89.

According to an independent committee of scientific and health experts, diisononyl phthalate (DINP) may be carcinogenic. Diisononyl phthalate is a diisononyl ester of phenyl-1,2-dicarboxylic acid. It is a plasticizer. It is a phthalate ester and diester. See also: ... See more ...

---

Mechanism of Action
The renal tubular carcinoma observed in male rats exposed to DINP is thought to be caused by cytotoxicity resulting from the accumulation of α2u-globulin in the kidneys... α2u-globulin is secreted from the liver, filtered by the glomeruli, and slowly hydrolyzed in the proximal tubules. Although a covalent, irreversible binding is not required, the chemical or metabolite must physically bind to α2u-globulin to cause kidney disease. When the chemical α2u-globulin complex is filtered by the kidneys, it accumulates in phagolysosomes in the proximal tubule region and produces cytotoxicity, leading to subsequent regenerative proliferation… α2u-globulin does not accumulate in the kidneys of female rats, mice, and NBR rats, does not produce nephrotoxicity or regenerative proliferation, and does not develop renal tumors after exposure to the chemical. …This specific protein appears to be lacking in human kidneys… The specificity of the tumor response in male rats, the lack of genotoxicity, the cytotoxicity and regeneration found in histopathology, the accumulation of α2u-globulin, and the confirmed cell proliferation all strongly support the criteria for demonstrating the α2u-globulin mechanism/DINP renal carcinogenesis…
A study using SV 129 PPARα gene knockout mice investigated the role of peroxisome proliferator-activated receptor α (PPARα) in the hepatic response to DINP… Male and female SV 129 PPARα knockout mice (-/-), SV 129 PPARα (+/+), and B6C3F1 mice were fed a control diet or a diet containing 8000 ppm DINP for 1 or 3 weeks, respectively. One week after exposure, liver weight increased in both male and female SV 129 PPARα (+/+) and B6C3F1 mice, while the increase in liver weight disappeared in SV 129 PPARα knockout (-/-) mice after one week of exposure. Western blot analysis of liver protein extracts showed that after 3 weeks of exposure, acyl-CoA oxidase and CYTP450 4a protein expression was upregulated in the livers of female PPARα (+/+) mice, while no upregulation was observed in the livers of female PPARα (-/-) mice. Furthermore, the study found altered expression of some genes involved in drug metabolism and protein transport in the livers of PPARα (+/+) female mice, while no such alterations were observed in the livers of PPARα (-/-) mice. These data support the hypothesis that DINP, like other peroxisome proliferators such as DEHP, induces liver effects through a PPARα-dependent mechanism.

C26H42O4

418.61

418.308

28553-12-0

590836

Colorless liquid

1.0±0.1 g/cm3

463.3±18.0 °C at 760 mmHg

-48ºC

214.9±19.6 °C

0.0±1.1 mmHg at 25°C

1.487

9.04

0

4

18

30

416

0

O(C(C1=C([H])C([H])=C([H])C([H])=C1C(=O)OC([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H]

HBGGXOJOCNVPFY-UHFFFAOYSA-N

InChI=1S/C26H42O4/c1-21(2)15-9-5-7-13-19-29-25(27)23-17-11-12-18-24(23)26(28)30-20-14-8-6-10-16-22(3)4/h11-12,17-18,21-22H,5-10,13-16,19-20H2,1-4H3

bis(7-methyloctyl) benzene-1,2-dicarboxylate

ENJ 2065; Baylectrol 4200; Diisononyl phthalate

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 (~238.9 mM; with ultrasonication)

Solubility in Formulation 1: ≥ 5 mg/mL (11.94 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 DMSO stock solution (50.0 mg/mL) to 900 μL of corn oil and mix well.

---

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