Benzene, C10-13-alkyl derivs.

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

6 Aug 1992 to 25 Feb1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Gathering information on ADME parameters of UVCB in vivo is particularly challenging because of technical difficulties with radiolabeling of the test substance. Therefore, the ADME properties of a representative substance, 2-phenyldodecane, were examined as surrogate for the whole UVCB substance.

Objective of study:

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

A single intravenous dose of test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose, 0.5, 4, 8, 24, 72, and 96 hrs post-dose. Whole body autoradiography was done for 1 animal of each sex at 0.5, 4, 8, 24, and 96 hrs after dosing.

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

yes

Species:

rat

Strain:

other: Crl: CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Ltd
- Age at study initiation: 8 weeks of age
- Weight at study initiation: males 201 -2 65 g, females 178 - 220 g
- Housing: individual all-glass cages suitable for collecting urine and feces, identified with ear notching
- Individual metabolism cages: yes
- Diet: SQC Rat and Mouse Maintenance Diet No. 1, Expanded, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 40 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 6 Aug 1992 to 25 Feb 1993

Route of administration:

intravenous

Vehicle:

other: ethanol: polyethylene glycol 400 (5:95, v/v)

Details on exposure:

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Test material was tested for stability for 24 h using TLC

Duration and frequency of treatment / exposure:

1 intravenous injection

Dose / conc.:

1 mg/kg bw/day

Remarks:

1 mg/kg bw equals 10 μCi

No. of animals per sex per dose / concentration:

5

Control animals:

no

Details on dosing and sampling:

- Tissues and body fluids sampled: Urine and faeces were collected using suitable vessels surrounded by solid CO2. Cage washings and cage debris were also collected. Whole-body autoradiography was done for 1 animal of each sex at 0.5, 4, 8, 24, and 96 hrs after dosing. Sections obtained include the exorbital lachrymal gland or ovaries, intra-orbital lachrymal gland, Harderian gland, adrenal gland, thyroid, and brain and spinal cord.
- Time and frequency of sampling: Urine and faeces: pre-dose, 0.5, 4, 8, 24, 72, and 96 hrs post-dose
- Method type(s) for identification: Liquid scintillation counting and TLC, urine and faeces were pooled by time point and sex
- Limits of detection and quantification: for LSC the limit of detection was twice the background disintegration rate obtained from the measurement of the pre-dose samples.

Details on distribution in tissues:

Highest levels were observed early in the liver and kidneys. The radioactivity was widely distributed early in the experiment, but was largely gone by 24 hrs after dosing. The Steno's gland, however, still contained radioactivity. Tissues with high lipid content and those with oily secretions still showed low but persistent radioactivity. No radioactivity was noted in the blood after 4 hrs in males, and 8 hrs in female.

Details on excretion:

79.88 % of the test substance was excreted by male rats, and 85.87 % by the female rats within 96 hrs. The main route of excretion was the urine (75.97 % female, 57.94 % males) and mostly within the first 24 hrs (72.15 % female, and 53.19 % males). The amount excreted in the faeces was 8.865 % for males and 5.285 % in females.

Metabolites identified:

no

Details on metabolites:

Parent compound was a major component of radiation in the faeces. The test compound appeared to be rapidly eliminated from the body via the urine. Up to 9 different metabolites were resolved by TLC. A volatile fraction that was most likely parent compound was noted at the first time point. This was no longer evident at later time points.

No clinical signs were observed during the experiment.

Conclusions:

The test substance was rapidly eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.

Executive summary:

A single intravenous dose of test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose, 0.5, 4, 8, 24, 72, and 96 hrs post-dose. Whole body autoradiography was done for 1 animal of each sex at 0.5, 4, 8, 24, and 96 hrs after dosing. No clinical signs were observed during the study. The test substance was rapidly eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

11 Sep 1992 to 4 Feb 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Gathering information on ADME parameters of UVCB in vivo is particularly challenging because of technical difficulties with radiolabeling of the test substance. Therefore, the ADME properties of a representative substance, 2-phenyldodecane, were examined as surrogate for the whole UVCB substance.

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

A single oral dose of test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose 4, 8, 24, 72 and 96 hrs post-dose. Whole body autoradiography was done for 1 animal of each sex at 4, 8, 24 and 96 hrs after dosing.

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

yes

Species:

rat

Strain:

other: Crl: CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Ltd.
- Age at study initiation: 8 weeks of age
- Weight at study initiation: males 252 - 283 g, females 182 - 208 g
- Housing: individual all-glass cages suitable for collecting urine and feces, identified with tail marking
- Individual metabolism cages: yes
- Diet: SQC Rat and Mouse Maintenance Diet No. 1, Expanded, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 40 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 11 Sep 1992 to 4 Feb 1993

Route of administration:

intravenous

Vehicle:

other: ethanol: polyethylene glycol 400 (5:95, v/v)

Details on exposure:

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Test material was tested for stability for 24 hrs using TLC

Duration and frequency of treatment / exposure:

Single oral dose

Dose / conc.:

1 mg/kg bw/day

Remarks:

1 mg/kg bw equals 10 μCi

No. of animals per sex per dose / concentration:

5

Control animals:

no

Details on dosing and sampling:

- Tissues and body fluids sampled: Urine and faeces were collected using suitable vessels surrounded by solid CO2. Cage washings and cage debris were also collected. Whole-body autoradiography was done for 1 animal of each sex at 4, 8, 24 and 96 hrs after dosing. Sections obtained include the exorbital lachrymal gland or ovaries, intra-orbital lachrymal gland, Harderian gland, adrenal gland, thyroid, and brain and spinal cord. Brown and white fat samples were taken from animals sacrificed at 48 and 96 hrs. Brown fat was pooled as there was insufficient brown fat from single animals.
- Time and frequency of sampling: Urine and faeces: pre-dose, 4, 8, 24, 72, and 96 hrs post-dose
- Method type(s) for identification: Liquid scintillation counting and TLC, urine and feces were pooled by time point and sex
- Limits of detection and quantification: for LSC the limit of detection was twice the background disintegration rate obtained from the measurement of the pre-dose samples.

Details on absorption:

A minimum of 50 % of the dose was absorbed.

Details on distribution in tissues:

Highest levels of labeled material were observed early in the liver and kidneys. The radioactivity was widely distributed early in the experiment, but was largely gone by 24 hrs after dosing. The Steno's gland, however, still contained radioactivity. Tissues with high lipid content and those with oily secretions still showed low but persistent radioactivity.

Details on excretion:

Most of the test substance was eliminated within 24 hrs. Maximum rate of excretion was between 8 and 24 hrs. 74.99 % was eliminated in males, and 88.52 % in females. Most was eliminated via the urine (49.40 % males, and 55.71 % females). The amount excreted via the faeces was 19.25 % in males and 26.04 % in females.

Metabolites identified:

yes

Details on metabolites:

Metabolites included either 4-phenyl pentoic acid or 4-phenyl pentylthioamide.

No clinical signs were observed during the experiment.

Conclusions:

The test substance was rapidly absorbed and eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.

Executive summary:

A single oral dose of test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose 4, 8, 24, 72, and 96 hrs post-dose. Whole body autoradiography was done for 1 animal of each sex at 4, 8, 24, and 96 hrs after dosing. No clinical signs were observed during the study. The test substance was rapidly absorbed and eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

20 Oct 1992 to 5 Feb 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Gathering information on ADME parameters of UVCB in vivo is particularly challenging because of technical difficulties with radiolabeling of the test substance. Therefore, the ADME properties of a representative substance, 2-phenyldodecane, were examined as surrogate for the whole UVCB substance.

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

A single dermal dose of 200 μL test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose 4, 8, 24, 72, and 96 hrs post-dose. Whole body autoradiography was done for 1 animal of each sex at 4, 8, 24, and 96 hrs after dosing. Cold traps were used to collect any test substance that volatilized.

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

yes

Species:

rat

Strain:

other: Crl: CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Ltd.
- Age at study initiation: 8 weeks of age
- Weight at study initiation: males 237 - 272 g, females 190 - 212 g
- Housing: individual all-glass cages suitable for collecting urine and faeces, identified with ear notching
- Individual metabolism cages: yes
- Diet: SQC Rat and Mouse Maintenance Diet No. 1, Expanded, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 40 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20 Oct 1992 to 5 Feb 1993

Route of administration:

intravenous

Vehicle:

ethanol

Details on exposure:

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Test material was tested for stability for 24 hrs using TLC

TEST SITE:
- Area of exposure: dorso-lumbar area, 100 x 75 mm
- Type of wrap if used: A 4 cm diameter glass ring was glued to the clipped area and secured using Vetrap. The test substance was applied, and the vehicle allowed to evaporate. Afterwards, a nylon mesh was glued to the surface, and fresh vetrap applied.
- Time intervals for shavings or clippings: area was clipped the day before dosing

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 200 μL (approx. 2 mg of test substance, 50 μCi)
- concentration (if solution): 10 mg/mL, equivalent to 1 % (w/v) solution in ethanol

Duration and frequency of treatment / exposure:

Single dermal application

No. of animals per sex per dose / concentration:

5

Control animals:

no

Details on dosing and sampling:

- Tissues and body fluids sampled: Urine and faeces were collected using suitable vessels surrounded by solid CO2. Cage washings and cage debris were also collected. Whole-body autoradiography was done for 1 animal of each sex at 4, 8, 24, and 96 hrs after dosing. A back-wash was done prior to necropsy. Sections obtained include the exorbital lachrymal gland or ovaries, intra-orbital lachrymal gland, Harderian gland, adrenal gland, thyroid, and brain and spinal cordal expired air was collected in cold traps. The cold traps were changed pre-dose, 4, 8, and 24 hrs post-dose. Collection ended at 48 hrs.
- Time and frequency of sampling: Urine and faeces: pre-dose, 4, 8, 24, 72, and 96 hrs post-dose.
- Method type for identification: Liquid scintillation counting and TLC, urine and fseces were pooled by time point and sex.
- Limits of detection and quantification: for LSC the limit of detection was twice the background disintegration rate obtained from the measurement of the pre-dose samples.

Details on absorption:

A minimum of 10 % (male) and 8 % (female) of the dose was absorbed. The majority of the test substance remained on the skin through the end of the study.

Details on distribution in tissues:

Highest levels of radiation were found in the liver, gastro-intestinal tract, kidneys, and bladder. Levels increased through 24 hrs, then remained constant. Radioactivity continued to be found in tissues with high lipid content, such as the skeletal or brown fat tissues, and those with oily secretions throughout the study.

Details on excretion:

Excretion was primarily through the urine, though there was some excretion through the faeces. 10.58 % of the test substance was excreted in males, and 7.95 % in females. 7.668 % was excreted through the urine in males, and 6.129 % by females. The excretion rate in urine was greatest between 24 and 48 hrs post-dose. 2.004 % was excreted through the faeces in males, and 0.889 % in females. No radioactivity was detected in the cold traps. Most of the radioactivity was recovered in the back wash, and the remainder at the dose site.

Metabolites identified:

no

Details on metabolites:

Extensive and rapid metabolization occurred. Very little parent compound was found in the feces and urine at any time point.

No clinical signs were observed during the experiment.

Conclusions:

The test substance was poorly absorbed through the skin with only 8 - 10 % being absorbed. The test substance was rapidly eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid and mostly complete, and it was eliminated mostly through the urine.

Executive summary:

A single dermal dose of 200 μL test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose 4, 8, 24, 72, and 96 hrs post-dose. Whole body autoradiography was done for 1 animal of each sex at 4, 8, 24, and 96 hrs after dosing. Cold traps were used to collect any test substance that volatilized. No clinical signs were observed during the study. The test substance was poorly absorbed through the skin, with only 8 -10 % being absorbed. The test substance was rapidly eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.

Description of key information

- Absorption: intravenous or oral absorption was more than 50 %, absorption via the skin was 8 - 10 %.

- Distribution: the distribution of radioactivity was widespread with the highest levels in the liver and kidney but was largely gone 24 hrs after dosing, though some remained in the fatty tissues and tissues with high lipid content or with oily secretions.

- Metabolism: metabolism was rapid and several metabolites have been resolved using TLC.  The substance was rapidly eliminated from the majority of tissues.

- Excretion: rapid elimination mostly via the urine and to a lesser extent in the faeces (in particular when the exposure is oral).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Three basic toxicokinetic studies were performed in rats:

(1) A single intravenous dose of test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose, 0.5, 4, 8, 24, 72, and 96 hours post-dose. Whole body autoradiography was done for 1 animal of each sex at 0.5, 4, 8, 24, and 96 hours after dosing. No clinical signs were observed during the study. The test substance was rapidly eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.

(2) A single oral dose of test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose 4, 8, 24, 72, and 96 hours post-dose. Whole body autoradiography was done for 1 animal of each sex at 4, 8, 24, and 96 hours after dosing. No clinical signs were observed during the study. The test substance was rapidly absorbed and eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.

(3) A single dermal dose of 200 μL test substance was given to 5 male and 5 female rats. Samples of urine and faeces were taken at pre-dose 4, 8, 24, 72, and 96 hours post-dose. Whole body autoradiography was done for 1 animal of each sex at 4, 8, 24, and 96 hours after dosing. Cold traps were used to collect any test substance that volatilized. No clinical signs were observed during the study. The test substance was poorly absorbed through the skin, with only 8 -10 % being absorbed. The test substance was rapidly eliminated from the majority of tissues, though some remained in fatty tissues. Metabolism of the test substance was rapid, and it was eliminated mostly through the urine.