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Description of key information

4-Isopropylbiphenyl, 4-MIPB, [CAS No. 7116-95-2] is a representative position isomer of the target compound, MIPB isomer mixture [CAS No.25640-78-2] accounting for about 45% of MIPB. Thus it may serve as model and marker substance for the ADME complex. Metabolism was determined to proceed in two steps. First, the isopropyl side chain is hydroxylated at C1 or C2 to the corresponding alcohol followed in part by further oxidation to carboxylic acid. In a second step, the biphenyl ring system can be hydroxylated with resulting products being conjugated for excretion.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic and metabolism studies were performed using either a single isomer (mostly 4-, para isomer) of (1-methylethyl)-1,1'-biphenyl  (isopropylbiphenyl, MIPB) or a mixture of 3- and 4-isopropylbiphenyl as present in the technical product. Results are generally the same not requiring separate consideration of different isomers. Information from one isomer applies to the total substance.

Absorption

4-Isopropylbiphenyl is easily absorbed from the gastrointestinal tract as demonstrated after oral administration to rats. Uptake is quantitative and parent compound and metabolites are present in blood already after 0.5 hours with peak levels at about 4 hours (Sullivan 1978).

Distribution

48 hours after oral administration of radiolabelled 4-isopropylbiphenyl, radioactive was found mostly in liver (5.25 µg equiv./g), fat (4.73 µg equiv./g), and kidney (0.94 µg equiv./g). In other tissues, lower amounts were found (from 0.63 to 0.05 µg equiv./g) - tissues in decreasing order: blood, lung, heart, spleen, muscle, and brain). Isopropylbiphenyl and/or metabolites seem to be sequestered in fatty tissue and then released at slower rates into the blood stream for ultimate metabolism and excretion (Sullivan 1978.

Metabolism

Two major steps were identified in the metabolic pathway of isopropylbiphenyl. In a first step, biotransformation takes place at the isopropyl side chain (oxidation to alcohols and subsequently also to carboxylic acid). In a second step, the aromatic biphenyl ring system is hydroxylated, probably at the 4' position. These hydroxybiphenyl derivatives can be conjugated and excreted.

Metabolic transformations at the isopropyl side chain occur via two pathways. In one pathway, the primary carbon of the isopropyl side chain (C1) is oxidised. The resulting alcohol I could not be isolated in vivo. It is considered an intermediate in formation of the carboxylic acid II which was identified in blood. The second pathway is characterised by oxidation of the tertiary carbon atom (C2) of the isopropyl side chain. The resulting tertiary alcohol III was found in blood. The corresponding carboxylic acid as subsequent oxidation product could not be identified and does not seem to be generated.

In the blood of rats the following metabolites of 4-isopropylbiphenyl were found.

Circulating metabolites:

- 2-(biphenyl-4-yl)propionic acid (II), (major metabolite) (following also named propionic acid) (resulting from pathway 1).

- 2 (biphenyl-4-yl)propan-2-ol (III) (minor metabolite) (following also named propan-2-ol) (resulting from pathway 2)

- 2-hydroxy-2-(biphenyl-4-yl)propionic acid (major metabolite) (IV) (following also named hydroxypropionic acid (product of combined pathway 1 and 2)

In urine and bile of rats, except one very minor metabolite, only ring hydroxylated products were identified.

Excreted metabolites:

- 2-(4'-OH-biphenyl-4-yl)propionic acid (V) (major metabolite) (derivative of propionic acid)

- 2-(4'-OH-biphenyl-4-yl)propan-2-ol (VI) major metabolite (derivative of propan-2-ol)

- 2-(4'-OH-biphenyl-4-yl)propanol (VII) (very minor metabolite (derivative of primary oxidation product (alcohol) at C1 of isopropyl side chain)

- 2-hydroxy-2-(4'-OH-biphenyl-4-yl)propionic acid (VIII) (very minor metabolite) (derivative of hydroxpropionic acid)

- 4'OH-4-isopropylbipheny (IX) (very minor metabolite) (ring hydroxylated parent compound)

- 2-hydroxy-2-(4'-OH-biphenyl-4-yl)propanol (X) (very minor metabolite (dialcohol at C1 and C2 of isopropyl side chain, not identified in blood)

It is noteworthy that one of the major metabolites in blood (hydroxpropionic acid IV), is found in urine/bile only in a very minor amount. In rats, this metabolite is not or only minutely excreted neither as itself nor as ring hydroxylated product. In further studies, it was found that this metabolite is sequestered in the kidney of rats forming calculi and causing severe nephrotoxicity.

General principles of metabolism (primary and secondary step, pathway 1 and pathway 2) are the same in other species than rats. But preferences in metabolic pathways and number and amount of metabolites formed may be different. In addition to rats, metabolism was studied in dogs, monkeys and man. In the following table, the metabolites identified for the four species are compiled. They are differentiated in circulating (blood) and excreted (urine/bile). In rats, excreted metabolites were conjugated. For other species, this information is not reported.

 

 

Rat

Dog

Monkey

Man

blood
(serum)

propionic acid (II) (+)

propan-2-ol (III)

propionic acid (II) (+)

propionic acid (II)

 

hydroxy-propionic acid (IV) (+)

hydroxy-propionic acid (IV)

propanol (+-)

 

 

propan-2-ol (III) (+-)

 

propan-2-ol (III) (+-)

 

excreted
(urine/bile)

(OH-)propionic acid (V) (+)

hydroxy-propionic acid (IV)

propan-2-ol (III)

(OH-)propan-2-ol (VI)

 

(OH-)propan-2-ol (VI) (+)

(OH-)propan-2-ol (VI)

propionic acid (II)

(di-OH-)propan-2-ol

 

(OH-)propanol (VII) (--)

 

(OH-)propan-2-ol (VI)

(OH-)propene

 

(OH-)hydroxy-propionic acid (VIII) (--)

 

3-hydroxy-propionic acid

propionic acid (II)

 

(OH-)hydroxy- propanol (X) (--)

 

 

(OH-)propionic acid (V)

Explanation to the table above:

With (OH-) the phenolic hydroxy-substituent at the biphenyl ring system is characterised while hydroxy- denotes the alcoholic OH group at C2 of the three carbon side chain. The biphenyl ring system is also attached to this carbon atom. (+) indicates a major metabolite in the respective compartment, (-) a minor one. If abundance is not indicated, the order is decreasing within the medium.

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Rat is the only species among the tested species that is not able to excrete metabolites but only after ring hydroxylation and conjugation. In other species, some of the metabolites can be excreted without further ring hydroxylation. Intermediate metabolites are indicated by excretion of metabolites not present in blood.

Hydroxy-propionic acid IV is only formed in rats and dogs. In dogs it can be excreted unchanged not leading to accumulation. In monkey and man it could not be detected even if both pathways (oxidation at C1 and C2) are utilised.

Observation of renal toxicity in rats caused by sequestration of hydroxy-propionic acid in kidney is restricted to this species as in the other species investigated, this metabolite is directly excreted (dog) or not generated at all (monkey, man).

Excretion

After oral or intraperitoneal administration of radiolabelled isopropylbiphenyl, ca. 85 % of radioactivity was excreted into urine and bile/faeces within 48 h. After oral administration, excretion in urine was ca. 40%, in bile/faeces ca. 45-48%. No radioactivity was found in air expired by rats within 48 h after administration.

Special considerations related to renal toxicity in rats

There is experimental evidence that high doses of the 4-isopropyl isomer are nephrotoxic in rats, related to accumulation of a particular metabolite predominantly formed in this species (see above and endpoint study records in IUCLID Sect. 7.1.1 "Toxicokinetics": Sullivan et al. 1977/1978). Based on pharmacokinetic investigations into the species-specific metabolism as well as chronic toxicity studies in monkey and dog, 4-IPB failed to induce the development of nephrotoxicity in monkey and dog (short communication in Sullivan et al. 1977, p. 39). Further investigations into the human-specific metabolism of 4-IPB demonstrated a similarity to that of the dog. The synopsis of all results, metabolic/toxicokinetic as well as toxicological, resulted in the conclusion that 4-IPB would not demonstrate nephrotoxicity in humans (see Sullivan et al. 1977, p. 40/41).