N,N-dimethyl-p-toluidine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer reviewed journals

Data source

Reference

Reference Type:

publication

Title:

Disposition of the test chemical in rats and mice

Author:

Dix et.al

Year:

2007

Bibliographic source:

Journal of Toxicology and Environmental Health, Part A: Current Issues, 2007

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

The objective of the study was to assess the rates and routes of excretion and tissue distribution of [14C]test chemical-derived radioactivity in F344 rats.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dimethyl-p-toluidine

EC Number:

202-805-4

EC Name:

N,N-dimethyl-p-toluidine

Cas Number:

99-97-8

Molecular formula:

C9H13N

IUPAC Name:

N,N,4-trimethylaniline

Test material form:

liquid

Details on test material:

- Name of test material: Benzenamine, N,N,N-trimethyl-
- Common Name: N,N-Dimethyl-p-toluidine
- Molecular formula: C9H13N
- Molecular weight: 135.209 g/mol
- Smiles notation: c1(N(C)C)ccc(C)cc1
- InChl: 1S/C9H13N/c1-8-4-6-9(7-5-8)10(2)3/h4-7H,1-3H3
- Substance type: Organic
- Physical state: liquid
- Purity: Greater than 99%.

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories; Raleigh, NC
- Age at study initiation: approx 10-12 weeks of age
- Weight at study initiation: Body weight ranges were 180–267 g (male rats), 157–178 g (female rats)
- Housing:From 1 d prior to dosing until sacrifice animals were housed individually in all-glass metabolism cages
- Diet (e.g. ad libitum): Animals were fed Teklad certified rodent diet (W) 8728C (Harlan Teklad, Madison, WI) ad libitum,
- Water (e.g. ad libitum): Muncipal Water supplu, ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Oral dose formulations contained [14C]test chemical and non-radiolabeled test chemical in 10% aqueous Alkamuls EL-620 (Rhodia, Cranbury, NJ). Alkamuls EL-620 (also known as PEG-30 castor oil) was used as an emulsifier. The target dose levels were 2.5, 25, and 250 mg/kg body weight administered in a dose volume of 5 ml/kg for rats. Animals received approximately 5–25 μCi of radioactivity.

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

Duration and frequency of treatment / exposure:

daily

Doses / concentrations

Remarks:

2.5,25,250 mg/kgbw - for male rats
25 mg/kgbw - female rats

No. of animals per sex per dose / concentration:

4 male rats/dose group - 2.5, 25,250 mg/kgbw
4 female rats - 25 mg/kgbw

Control animals:

not specified

Positive control reference chemical:

no data available

Details on study design:

no data available

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, serum or other tissues, cage washes, bile : The following tissues were excised and weighed: samples of blood, adipose, muscle, and skin, as well as the following organs and glands in their entirety: brain, cecum (with contents), heart, kidneys, large intestine (with contents), liver, lung, small intestine (with contents), spleen, stomach (with contents), testes, thyroid, urinary bladder, and uterus. Blood and tissues were solubilized in Soluene- 350, neutralized, bleached as necessary, and analyzed for total radioactivity by LSC. The stomach with contents,
cecum with contents, small and large intestines with contents, tail (iv studies only), and residual carcass were solubilized in ethanolic sodium hydroxide. Weighed aliquots of each digestate were neutralized, bleached, and analyzed for total radioactivity
- Time and frequency of sampling:
- Other: Urine and feces were collected separately from each animal into receptacles cooled on dry ice. Urine was collected at 6, 12, and 24 h; feces were collected at 12 and 24 h. Bladder urine was also collected from the euthanized animals and added to the last urine collection. At the end of each collection interval, the metabolism cages were rinsed with water or ethanol (after the terminal collection only), and the rinsates were analyzed for total 14C content as described for urine. Recovery of radioactivity in the rinsate was added to the recovery of radioactivity in urine at the corresponding time point. Weighed aliquots of urine were analyzed directly for total radioactivity. Aliquots of feces were mixed with an approximately equal mass of water, homogenized, and solubilized in Soluene-350. The solubilized samples were neutralized and decolorized as described earlier before analysis for total radioactivity by LSC.

Statistics:

Means (reported to three significant figures) and standard deviations are presented. Recovery of radioactivity in a given matrix (i.e., urine, feces, VOCs, 14CO2, and tissues), expressed as percent of administered dose, were analyzed using analysis of variance with the Tukey post test for pairwise multiple comparisons (SigmaStat, version 3.1; Systat Software, Inc., Point Richmond, CA). A p value of <0.05 was considered significant. For male–female comparisons at the mid oral dose within a species, recovery of radioactivity in a given matrix was analyzed using a t-test.

Results and discussion

Main ADME results

Type:

excretion

Results:

[14C]test chemical-derived radioactivity was rapidly absorbed and excreted at oral doses up to 25 mg/kg. Excretion in urine accounted for approximately 88–94% in rats in the 2.5- and 25-mg/kg dose groups.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

[14C]test chemical-derived radioactivity was rapidly absorbed and excreted at oral doses up to 25 mg/kg. Excretion in urine accounted for approximately 88–94% in rats in the 2.5- and 25-mg/kg dose groups. The balance of the administered dose was recovered in feces and tissues, with little excreted as exhaled VOCs.

Details on distribution in tissues:

For all doses in disposition studies, approximately 1–2% of the administered dose was present in liver 24 h after dosing

Details on excretion:

[14C]test chemical-derived radioactivity was rapidly absorbed and excreted at oral doses up to 25 mg/kg. Excretion in urine accounted for approximately 88–94% in rats in the 2.5- and 25-mg/kg dose groups. The balance of the administered dose was recovered in feces and tissues, with little excreted as exhaled VOCs.

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

At the 250-mg/kg oral dose (aqueous), all rats showed signs of decreased activity, piloerection, blinking eyes, and hunched posture within 10–15 min of dosing.Decreased food and water intake also were observed, but all animals were clinically normal by 24 h.

Applicant's summary and conclusion

Conclusions:

At the 250-mg/kg oral dose (aqueous), all rats showed signs of decreased activity, piloerection, blinking eyes, and hunched posture within 10–15 min of dosing.Decreased food and water intake also were observed, but all animals were clinically normal by 24 h.[14C]test chemical-derived radioactivity was rapidly absorbed and excreted at oral doses up to 25 mg/kg. Excretion in urine accounted for approximately 88–94% in rats in the 2.5- and 25-mg/kg dose groups. The balance of the administered dose was recovered in feces and tissues, with little excreted as exhaled VOCs. Recovery of radioactivity in the various matrices, including feces and tissues, was similar for the 2.5-mg/kg dose regardless of route of administration.

Executive summary:

The objective of the study was to assess the rates and routes of excretion and tissue distribution of [14C]test chemical-derived radioactivity in F344 rats. Oral dose formulations contained [14C]test chemical and non-radiolabeled test chemical in 10% aqueous Alkamuls EL-620 (Rhodia, Cranbury, NJ). Alkamuls EL-620 (also known as PEG-30 castor oil) was used as an emulsifier. The target dose levels were 2.5, 25, and 250 mg/kg body weight administered in a dose volume of 5 ml/kg for rats. Animals received approximately 5–25 μCi of radioactivity. A single oral (2.5, 25, or 250 mg/kg) dose of [14C]DMPT (1–25 mCi) was administered in an aqueous vehicle to male and female Fischer 344 rats. The following tissues were excised and weighed: samples of blood, adipose, muscle, and skin, as well as the following organs and glands in their entirety: brain, cecum (with contents), heart, kidneys, large intestine (with contents), liver, lung, small intestine (with contents), spleen, stomach (with contents), testes, thyroid, urinary bladder, and uterus. Blood and tissues were solubilized in Soluene- 350, neutralized, bleached as necessary, and analyzed for total radioactivity by LSC. The stomach with contents, cecum with contents, small and large intestines with contents, tail (iv studies only), and residual carcass were solubilized in ethanolic sodium hydroxide. Weighed aliquots of each digestate were neutralized, bleached, and analyzed for total radioactivity.Urine and feces were collected separately from each animal into receptacles cooled on dry ice. Urine was collected at 6, 12, and 24 h; feces were collected at 12 and 24 h. Bladder urine was also collected from the euthanized animals and added to the last urine collection. At the end of each collection interval, the metabolism cages were rinsed with water or ethanol (after the terminal collection only), and the rinsates were analyzed for total 14C content as described for urine. Recovery of radioactivity in the rinsate was added to the recovery of radioactivity in urine at the corresponding time point. Weighed aliquots of urine were analyzed directly for total radioactivity. Aliquots of feces were mixed with an approximately equal mass of water, homogenized, and solubilized in Soluene-350. The solubilized samples were neutralized and decolorized as described earlier before analysis for total radioactivity by LSC. At the 250-mg/kg oral dose (aqueous), all rats showed signs of decreased activity, piloerection, blinking eyes, and hunched posture within 10–15 min of dosing.Decreased food and water intake also were observed, but all animals were clinically normal by 24 h.[14C]test chemical-derived radioactivity was rapidly absorbed and excreted at oral doses up to 25 mg/kg. Excretion in urine accounted for approximately 88–94% in rats in the 2.5- and 25-mg/kg dose groups. The balance of the administered dose was recovered in feces and tissues, with little excreted as exhaled VOCs. Recovery of radioactivity in the various matrices, including feces and tissues, was similar for the 2.5-mg/kg dose regardless of route of administration.