4-mesyl-2-nitrotoluene

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: assessment

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented assessment of toxicokinetic behaviour of the substance. Further experimental data has become available since the assessment was made.

Objective of study:

other: general toxicokinetic assessment

Qualifier:

no guideline required

Principles of method if other than guideline:

Theoretical assessment of available toxicokinetic data.

GLP compliance:

no

Details on absorption:

Based upon its structure, molecular weight and Log P value, reasonable absorption of orally administered 4-mesyl-2-nitrotoluene across the gastrointestinal mucosa would be expected. Reduction of the nitro group to the amine, a predominant biotransformation reaction, is likely to occur in the intestinal tract prior to absorption, as a consequence of metabolism by the intestinal micro flora. Some absorption of this reduced molecule would be expected. Evidence of oral absorption is seen in acute and repeat dose toxicity studies, where an oral gavage dose of 1000mg/kg and above resulted in the deaths of dosed animals. In a sub acute (28 day) oral gavage study there was evidence of systemic toxicity at doses of 150 and 250 mg/kg/day with treatment-related increases in liver weight and decreased testis and epididymis weights, matched by histopathological effects. However the extent of absorption of an orally administered cannot be concluded from the reported data.
There was no evidence of any dermal penetration of 4-mesyl-2-nitrotoluene in the rat or rabbit studies, despite occlusion of the application sites, which would have promoted any absorption. However, the moderate positive dermal sensitisation result in the guinea pig study indicates that there was some absorption through skin in this species, although the extent of such absorption could not be assessed.

Details on distribution in tissues:

The molecular weight of 4-mesyl-2-nitrotoluene is below the biliary exclusion limit in the rat. Consequently, it would not be excreted directly in bile. Target organ toxicity, an effect on the testes in both acute and repeat dose studies, is evidence that either 4-mesyl-2-nitrotoluene or metabolite is systemically bioavailable.

Details on excretion:

The aqueous solubility of any absorbed 4-mesyl-2-nitrotoluene would allow its direct urinary excretion. The size of the molecule would preclude its excretion via bile in the rat. Excretion would therefore be unabsorbed material in the faeces and 4-mesyl-2-nitrotoluene or its metabolites in the urine. Excretion by both routes would be expected to be rapid.

Rapid excretion of absorbed material is supported by information from the 28 day oral study in the rat. A slight effect on the functional observational battery/motor activity in rats, possibly indicative of a mild pharmacological effect of the compound throughout the dosing period, was evident on day 28. The recovery in the functional observational battery on day 29, allowing for a 24 hour period without dosing, indicates that the compound has a mild, transient pharmacological effect, which is indicative of rapid clearance of the absorbed dose from systemic circulation.

Details on metabolites:

Based on the physicochemical properties of 4-mesyl-2-nitrotoluene an oral dose can be assumed to be absorbed and may be subject to biotransformation to promote its excretion. Reduction of the nitro group to the amine would be expected to be a predominant biotransformation reaction, but, this is more likely to occur in the intestinal tract prior to absorption, as a consequence of metabolism by the intestinal micro flora. Some absorption of this reduced molecule would be expected. The methyl sulphonyl moiety will probably remain intact, so metabolism is likely to involve the reduction of the nitro moiety to the amine and the progressive oxidation of the ring methyl group to the alcohol and the carboxylic acid, the increased polarities of which would promote urinary excretion, although both would also be subject to conjugation. Ring hydroxylation is also possible, which would also increase polarity. No direct evidence of the metabolism of the molecule is available from the toxicity studies conducted.

4-Mesyl-2-nitrotoluene(C₈H₉NO₄S) is a white to off-white powder with a molecular weight of approximately 215g/mol. It is modestly soluble in water (370 mg/L) and possesses a Log P value of 0.94 at 40°C.

Conclusions:

Interpretation of results (migrated information): no data

Executive summary:

Based upon its structure, molecular weight and Log P value, reasonable absorption of orally administered test substance across the gastrointestinal mucosa would be expected. Toxicity studies have shown evidence for absorption and for systemic exposure to the test substance and/or its metabolites following oral administration of the test substance for up to 90 days. Evidence of toxicity, based primarily upon weight changes in specific organ weights supported by histopathological changes, was noted at dose levels of 150 mg/kg/day. In a one generation reproduction study an adverse effect on organ function was also noted. Although there was no evidence of any dermal penetration in the rat and rabbit, following occluded application of the test substance, the moderate dermal sensitisation result in the guinea pig demonstrated that some test substance was absorbed though the skin in this species.

 

The aqueous solubility of any absorbed test substance would allow its direct urinary excretion. Its molecular weight is below the biliary exclusion limit in the rat, consequently, it would not be excreted directly in bile. The absorbed test substance molecule may therefore be subject to biotransformation to promote its excretion. Reduction of the nitro group to the amine would be expected to be a predominant biotransformation reaction, but, this is more likely to occur in the intestinal tract prior to absorption, as a consequence of metabolism by the intestinal micro flora. Some absorption of this reduced molecule would be expected. The methyl sulphonyl moiety will probably remain intact, so metabolism is likely to involve the reduction of the nitro moiety to the amine and the progressive oxidation of the ring methyl group to the alcohol and the carboxylic acid, the increased polarities of which would promote urinary excretion, although both would also be subject to conjugation. Ring hydroxylation is also possible, which would also increase polarity. No direct evidence of metabolism of the test substance was noted in any of the toxicity studies conducted.

 

The test substance would not be excreted in the bile as its molecular weight is below the biliary excretion limit in the rat. Hence excretion of absorbed test substance and/or its metabolites would be via the urine and unabsorbed material would be excreted in the faeces. Both the absorbed and unabsorbed portions of the oral dose would be expected to be excreted fairly rapidly. This was confirmed by information from the 28 day oral gavage study where rapid recovery of an effect on motor activity was noted after one day without dosing.

Description of key information

Assessment of toxicokinetics based on structure and available toxicity studies, Jones 1999

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Absorption: Based upon its structure, molecular weight and Log P value, reasonable absorption of orally administered 4-mesyl-2-nitrotoluene across the gastrointestinal mucosa would be expected. Reduction of the nitro group to the amine, a predominant biotransformation reaction, is likely to occur in the intestinal tract prior to absorption, as a consequence of metabolism by the intestinal micro flora. Some absorption of this reduced molecule would be expected. Evidence of oral absorption is seen in acute and repeated dose toxicity studies, where an oral gavage dose of 1000 mg/kg and above resulted in the deaths of dosed animals. In a sub-acute (28 day) oral gavage study there was evidence of systemic toxicity at doses of 150 and 250 mg/kg/day with treatment-related increases in liver weight and decreased testis and epididymis weights, matched by histopathological effects. However the extent of absorption of an orally administered dose cannot be concluded from the reported data.

There was no evidence of any dermal penetration of 4-mesyl-2-nitrotoluene in the rat or rabbit studies, despite occlusion of the application sites, which would have promoted any absorption. However, the moderate positive dermal sensitisation result in the guinea pig study indicates that there was some absorption through skin in this species, although the extent of such absorption could not be assessed.

Distribution: The molecular weight of 4-mesyl-2-nitrotoluene is below the biliary exclusion limit in the rat. Consequently, it would not be excreted directly in bile. Target organ toxicity, an effect on the testes in both acute and repeated dose studies, is evidence that either 4-mesyl-2-nitrotoluene or some metabolite is systemically bioavailable.

Metabolism: Based on the physicochemical properties of 4-mesyl-2-nitrotoluene an oral dose can be assumed to be absorbed and may be subject to biotransformation to promote its excretion. Reduction of the nitro group to the amine would be expected to be a predominant biotransformation reaction, but, this is more likely to occur in the intestinal tract prior to absorption, as a consequence of metabolism by the intestinal micro flora. Some absorption of this reduced molecule would be expected. The methyl sulphonyl moiety will probably remain intact, so metabolism is likely to involve the reduction of the nitro moiety to the amine and the progressive oxidation of the ring methyl group to the alcohol and the carboxylic acid, the increased polarities of which would promote urinary excretion, although both would also be subject to conjugation. Ring hydroxylation is also possible, which would also increase polarity. No direct evidence of the metabolism of the molecule is available from the toxicity studies conducted.

Excretion: The aqueous solubility of any absorbed 4-mesyl-2-nitrotoluene would allow its direct urinary excretion. The size of the molecule would preclude its excretion via bile in the rat. Excreted material would therefore be unabsorbed material in the faeces and 4-mesyl-2-nitrotoluene or its metabolites in the urine. Excretion by both routes would be expected to be rapid.

Rapid excretion of absorbed material is supported by information from the 28 day oral study in the rat. A slight effect on the functional observational battery/motor activity in rats, possibly indicative of a mild pharmacological effect of the compound throughout the dosing period, was evident on day 28. The recovery in the functional observational battery on day 29, allowing for a 24 hour period without dosing, indicates that the compound has a mild, transient pharmacological effect, which is indicative of rapid clearance of the absorbed dose from systemic circulation.

Bioaccumulation Potential: Based on the structure, molecular weight and Log P value, NMST would be expected to be absorbed across the gastrointestinal mucosa and evidence from both single and repeated dose studies in rats supports this. No data on tissue distribution are available but the compound would be expected to be readily excreted via the urine. The reversal within 24 hours of a mild pharmacological effect seen following 28 days of daily dosing is evidence of the rapid clearance from the body. Overall the substance is considered to have a low potential for bioaccumulation.

Discussion on absorption rate: This information is not available.