Alcohols, C11-14-iso-, C13-rich

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

toxicokinetics

Test guideline

Qualifier:

no guideline available

Test material

Test material information

Constituent 1

Reference substance name:

Alcohols, C11-14-iso-, C13-rich

EC Number:

271-235-6

EC Name:

Alcohols, C11-14-iso-, C13-rich

Cas Number:

68526-86-3

Molecular formula:

CnH2n+1OH (n = 11 to 14)

IUPAC Name:

Branched alcohols, C11-14, C13 rich

Details on test material:

- Name of test material (as cited in study report): Exxal 13
- Physical state: clear colorless liquid
- Stability under test conditions: stable at room temperature
- Storage condition of test material: room temperature

Radiolabelling:

yes

Remarks:

7,10-Dimethyl-1-undecanol, [7-14C]- and 6,9-Dimethyl-1-decanol, [6-14C]- were synthesized for use as representative radiolabeled tracer molecules of Isotridecanol (referred to as [14C]-isotridecanol equivalents).

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

This species and strain of animal is recognized as appropriate for repeat-dose toxicity studies. The Sprague Dawley rat was utilized because it is a widely used strain for which significant historical control data are available. The number of animals used was the minimum necessary to yield scientifically meaningful results.

Sex:

male/female

Details on test animals or test system and environmental conditions:

Dose-range finding phase:
- Source: Charles River (Raleigh, NC, US)
- Age at study initiation: Approximately 7 weeks old
- Weight at study initiation: Dose range-finding phase (233-280g males, 143-202g females); radiolabeled dosing phase (307-334g males);
- Housing: For the dose range-finding phase, all animals were housed 2 to 3 per cage by sex in clean, solid bottom cages (the animals were temporarily separated as necessary to allow for the performance of protocol-specified activities); for the radiolabeled dosing phase, all animals were housed individually in clean, stainless steel, wire-mesh cages suspended above cage-board. Following administration of [14C]-isotridecanol equivalents, all animals were housed individually in wire-mesh cages suspended above cage-board or Nalgene-type metabolism cages for up to 168 hours. Solid-bottom or group housing was not appropriate for radiolabeled studies where the study objectives (quantitative analysis of test substance exposure by individual animal) could be compromised by test substance exposure from bedding or from other animals
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 (ad libitum); during acclimation, individual animals were offered DietGel® to maintain the health status of the animals. Use of non-certified diet gel packs did not have an adverse impact on the quality or integrity of the data or the outcome of the study as diet gel packs are a commercially available food that is commonly regarded as safe and is widely used in veterinary practices.
- Water (e.g. ad libitum): Reverse osmosis-treated water, ad libitum (except when animals were in Nalgene-type cages when water was provided from water bottles)
- Acclimation period: 13 days for dose range-finding phase; at least 5 days for radiolabeled dosing phase

ENVIRONMENTAL CONDITIONS:
- Temperature: 65.4°F to 72.8°F (18.6°C to 22.7°C)
- Humidity: 29.8% to 57.0%
- Air changes (per hr): 10 air changes per hour, 100% fresh air
- Photoperiod: 12 hours fluorescent light followed by 12 hours of darkness; the light/dark cycle was interrupted for protocol-specified activities as needed

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

Dose range-finding phase: once daily oral gavage of test substance (study day 0-12)
Radiolabeled dosing phase: once daily oral gavage of unlabeled test substance and [14C]-isotridecanol equivalents (100 uCi/kg) on study day 13

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Remarks:

Test substance; dose range-finding phase

Doses / concentrations 2

Dose / conc.:

400 mg/kg bw/day (actual dose received)

Remarks:

Test substance; dose range-finding phase

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

Test substance; dose range-finding phase

Doses / concentrations 4

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Remarks:

Test substance; pharmacokinetic and excretion mass balance phases day 0-12

Doses / concentrations 5

Dose / conc.:

50 mg/kg bw (total dose)

Remarks:

[14C]-isotridecanol equivalents (100uCi/kg); pharmacokinetic and excretion mass balance phases, study day 13

Doses / concentrations 6

Dose / conc.:

400 mg/kg bw/day (actual dose received)

Remarks:

Test substance; pharmacokinetic, excretion mass balance, and tissue distribution phases day 0-12

Doses / concentrations 7

Dose / conc.:

400 mg/kg bw (total dose)

Remarks:

[14C]-isotridecanol equivalents (100uCi/kg); pharmacokinetic, excretion mass balance, and tissue distribution phases, study day 13

No. of animals per sex per dose / concentration:

Dose range-finding phase (vehicle control, 150mg/kg/day, 400mg/kg/day, 1000mg/kg/day): 5M/5F
Pharmacokinetic phase (50mg/kg/day, 400mg/kg/day): 6M/6F
Excretion mass balance phase (50mg/kg/day, 400mg/kg/day): 3M
Tissue distribution phase (400mg/kg/day): 6M

Control animals:

yes, concurrent vehicle

Details on study design:

The objectives of this study were to evaluate the potential toxicity, pharmacokinetics, excretion and tissue distribution of Isotridecanol when administered daily by oral gavage to Sprague Dawley rats for 14 consecutive days for a subset of animals (potential toxicity) and for 13 consecutive days followed by 14C-isotridecanol equivalents oral gavage administration for another subset of animals (pharmacokinetics, excretion and tissue distribution) on dosing day 14.

Dose range-finding phase: Isotridecanol in the vehicle (corn oil) was administered orally by gavage once daily for 14 consecutive days to 3 groups (150, 400, and 1000 mg/kg/day) of Crl:CD(SD) rats. All animals were observed twice daily for mortality and moribundity. Detailed physical examinations were performed 1 week prior to randomization, on the day of randomization, and weekly during the study period. Clinical examinations were performed at the time of dose administration and at 1–2 hours after dose administration. Individual body weights and cage food weights were recorded. Clinical pathology parameters (hematology, coagulation, serum chemistry, and urinalysis) were analyzed for all animals on the day of the scheduled necropsy (Day 14). Complete necropsies were conducted on all animals, selected organs were weighed, and frozen samples of the kidney and liver were collected for possible future analysis at the scheduled necropsy. Selected tissues were examined microscopically from all animals in the control and 1000 mg/kg/day groups at the scheduled necropsy. In addition, target tissues (kidney and liver) and gross lesions were examined microscopically from all animals in the 150 and 400 mg/kg/day groups at the scheduled necropsy. A single blood sample was collected from all surviving animals at the scheduled necropsy (Day 14) for possible future plasma analysis.

Radiolabeled dosing phase: Isotridecanol in the vehicle (corn oil) was administered orally by gavage once daily for 13 consecutive days (Days 0–12) and a single oral gavage dose of [14C]-isotridecanol equivalents (target of 100 μCi/kg) in the vehicle was administered on Day 13 to 5 groups of Crl:CD(SD) rats. Dosage levels were 50, 400, 50, 400, and 400 mg/kg/day for pharmacokinetic, excretion mass balance, and tissue distribution, respectively. The pharmacokinetic phase consisted of 6 animals/sex/group, the excretion mass balance phase consisted of 3 males per group, and the tissue distribution [quantitative whole body autoradiography (QWBA)] phase consisted of 6 males. For toxicology assessment, all animals were observed twice daily for mortality and moribundity. Individual body weights were measured throughout the study. For the pharmacokinetic phase, blood samples were collected from 3 animals/sex/group/time point at approximately 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hours after dose administration on Day 13 for radioactivity analysis by liquid scintillation counting (LSC). For the excretion mass balance phase, urine samples were collected from all animals for approximately 0–6, 6–12, and 12–24 hours and then every approximately 24 hours through 168 hours after dose administration, and feces samples were collected from all animals for approximately 0–12 and 12–24 hours and then approximately 24 hours through 168 hours after dose administration on Day 13. The amount of radioactivity in the urine, feces, and cage rinse or wash samples was analyzed by LSC. For the tissue distribution (QWBA) phase, blood samples were collected from 1 animal/time point at approximately 0.5, 1, 4, 8, 24, and 168 hours after dose administration on Day 13. The whole blood and plasma samples were analyzed for the amount of radioactivity by LSC. Following each animal’s final blood collection, selected tissues were sectioned to determine the amount of radioactivity in the tissues using QWBA.

Dosage levels were selected based on evidence of structurally related substances and acute toxicity data on the test substance; the low dosage level was expected to be the no-observed-effect level (NOEL). A single dose acute toxicity test conducted by the Sponsor concluded that the LD50 was greater than 2000 mg/kg and a 7-day repeat-dose study concluded that the LD50 was greater than 1000 mg/kg for this test substance. In a 2-week oral study, 5 male rats were dosed orally (gavage) with 144 mg/kg/day (1mmol/kg/day) of isononanol following a 1-week acclimation.4,5 Animals were sacrificed after 14 days and blood was analyzed for plasma cholesterol and triglycerides. The liver was removed for histopathological analysis, analysis of catalase, and CN-insensitive palmitoyl CoA oxidation. Testicular weight was also determined. The rats did not develop testicular atrophy, liver enlargement, hepatic peroxisome induction, or hyperlipidemia. The no-observed-adverse-effect level (NOAEL) for Isooctanol was set at the limit dose of 144 mg/kg/day. Data from a 7-day oral repeat dose study with 2-ethylhexanol reported that animals treated with 1000 mg/kg body weight/day had a decreased body weight, and increased liver, stomach, and kidney weights. However, animals administered 330 and 100 mg/kg body weight/day showed no changes. Therefore, the high dosage level was expected to produce some effects.

Statistics:

Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals or cages (N) used to calculate the mean. Statistical analyses were not conducted if the number of animals was 2 or less. Comparative statistics were not performed on the data from the radiolabeled dosing phase due to the absence of a control group. Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex. Body weight, body weight change, food consumption, clinical pathology, and organ weight data were subjected to a parametric one-way ANOVA7 to determine intergroup differences. If the ANOVA revealed statistically significant (p < 0.05) intergroup variance, Dunnett's test was used to compare the test substance-treated groups to the control group.

Results and discussion

Preliminary studies:

The analyzed dosing formulations contained 87.7% to 99.3% of the test substance which was within the protocol-specified range of target concentrations for suspensions (85% to 115%), were homogeneous. The test substance was not detected in the analyzed vehicle formulation that was
administered to the control group.

The radio-HPLC analyses of the dosing solutions performed prior to and after completion of dosing showed two peaks in the radiochromatogram, consistent with the use of both 6, 9-Dimethyl-1-decanol, [6-14C]- and 7, 10-Dimethyl-1-undecanol, [7-14C]- to model the in vivo disposition of Isotridecanol. Overall, at least 97.3% of the radioactivity was attributed to the two test materials. There was no significant change in the total radioactivity attributed to the test materials between the predose and postdose analyses; therefore, stability over the dosing period was demonstrated.

The analyzed radiolabeled dosing formulations contained 101% and 102% of the test substance which was within the protocol-specified range of target concentrations for suspensions (85% to 115%) and were homogeneous. In addition, the mean radioactivity of [14C]-isotridecanol equivalents was 106% and 109% of the target.

Main ADME results

Main ADME results 1

Type:

absorption

Results:

At 50mg/kg: plasma Cmax (18.7ug/g 8h post-dose males, 21.4 ug/g 6h post-dose females); AUClast (502 h*ug/g males, 492 h*ug/g females); T1/2 (31.1h males, 29.5h females)

Main ADME results 2

Type:

absorption

Results:

At 400mg/kg: plasma Cmax (136ug/g 8h post-dose males, 164 ug/g 6h post-dose females); AUClast (3750 h*ug/g males, 3710 h*ug/g females); T1/2 (29.6h males, 32.5h females)

Main ADME results 3

Type:

absorption

Results:

At 400mg/kg (QWBA phase): whole blood AUClast (4380h*ug/g)

Main ADME results 4

Type:

absorption

Results:

At 400mg/kg (QWBA phase): plasma Cmax (176 ug/g 8h post-dose); AUClast (5890 h*ug/g)

Main ADME results 5

Type:

distribution

Results:

Cmax: 1,990,000 ng/g (adrenal gland)

Main ADME results 6

Type:

distribution

Results:

Cmax: 1,060,000 ng/g (stomach)

Main ADME results 7

Type:

distribution

Results:

Cmax: 873,000 ng/g (small intestine)

Main ADME results 8

Type:

distribution

Results:

Cmax: 335,000 to 404,000 ng/g (kidney, all sections)

Main ADME results 9

Type:

distribution

Results:

Cmax: 379,000 ng/g (liver)

Main ADME results 10

Type:

distribution

Results:

Cmax: 632,000 ng/g (pancreas)

Main ADME results 11

Type:

distribution

Results:

Cmax: 441,000 ng/g (spleen)

Main ADME results 12

Type:

distribution

Results:

Cmax: 320,000 ng/g (harderian gland)

Main ADME results 13

Type:

distribution

Results:

At 400mg/kg: Tmax generally <8h (exception is fat tissue, Tmax 24h post-dose); AUClast reflected Cmax ranking of tissues

Main ADME results 14

Type:

excretion

Results:

At 50mg/kg: 62% radioactivity recovery from excreta in males (61.5-64.2% range); of this total percentage of 62%, 68% was recovered in urine, 15% in feces, 17% in carcass at 168h postdose.

Main ADME results 15

Type:

excretion

Results:

At 400mg/kg: 65% radioactivity recovery from excreta in males (63-67% range); of this total percentage of 65%, 62% was recovered in urine, 24% in feces, 14% in carcass at 168h postdose.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Pharmacokinetic profiles were comparable to the tissue distribution plasma data acquired from male rats during the QWBA phase of the study. The half-life (T1/2) could not be calculated because fewer samples were collected after Cmax (relative to the animals in the pharmacokinetic phase dosed with 400mg/kg/d).

Also during the QWBA phase, the whole blood Cmax measured after 13 doses of non-radiolabeled isotridecanol and a single oral dose of [14C]-isotridecanol equivalents to Crl:CD(SD) rats in the tissue distribution phase at 400 mg/kg was 120 μg/g at 8 hours postdose. This corresponds to approximately 1.8% of the dose circulating in whole blood at Tmax. The ratio of whole blood to plasma exposure to [14C]-isotridecanol-equivalents was approximately 0.74, demonstrating some distribution of isotridecanol into blood cells. The AUClast increased 7.3-fold over an 8-fold increase in dose for males and 7.7-fold for females. The data indicate that exposure to [14C]-isotridecanol equivalents is dose-proportional over the dose range examined.

Details on distribution in tissues:

After 13 doses of non-radiolabeled isotridecanol, followed by a single oral dose of [14C]-isotridecanol equivalents to Crl:CD(SD) rats in the tissue distribution phase at 400 mg/kg, [14C]-isotridecanol and/or its metabolites were broadly distributed and detected by QWBA in all tissues for at least 168 hours postdose, with the following exception: [14C]-isotridecanol equivalents were only detected in the eye up to 8 hours postdose, and in the lung and uveal tract to 24 hours postdose.

The Cmax for [14C]-isotridecanol-derived radioactivity was highest in the adrenal gland followed by the tissues expected from extensive absorption following oral administration, including the stomach, small intestine, kidney, and liver, but also the pancreas, spleen, and harderian gland. The lowest activity was observed in the muscle, bone (femur), skin, testes, and eye (lens) (≤ 100,000 ng/g). The remaining tissues had concentrations of approximately 119,000 to 265,000 ng/g.

The Tmax was generally 8 hours postdose or less. Exposure, as measured by AUClast, reflected the same general ranking of tissues, i.e., highest in small intestine, adrenal gland, liver, stomach, pancreas, harderian gland, kidney, and spleen, but also with significant exposure to the fat (highest at 30,900,000 h·ng/g), large intestine, thyroid, and thymus. Exposure was lowest in the muscle, testes, lung, uveal tract, and eye (lens) (< 3,710,000 h·ng/g). As calculated using AUClast, the tissue:plasma ratios were highest for the fat, small intestine, adrenal gland, liver, and stomach and ranged from 2.5- to 5-fold higher than plasma exposure. Remaining tissue:plasma ratios were < 2, demonstrating limited affinity for all tissue types. Where tissue half-lives could be calculated with reasonable certainty, they were 52 to 69 hours.

Details on excretion:

After 13 doses of non-radiolabeled isotridecanol, followed by a single oral dose of [14C]-isotridecanol equivalents to rats in the excretion mass balance phase at 50 mg/kg, a total of approximately 62% of the administered radioactivity was recovered in the excreta collected from male rats. Recovery is consistent with the excretion measured after a single dose of isotridecanol. In that study the remaining radioactivity (up to 35%) was recovered in the expired air for a total recovery of administered radioactivity of 86% to 94%. It is reasonable to assume that the remaining radioactivity in this study was eliminated in the expired air, as well. The majority of the elimination occurred in the first 24 hours postdose; however, some radioactivity was still detected in both urine and feces collected at 168 hours postdose.

After 13 doses of non-radiolabeled isotridecanol, followed by a single oral dose of [14C]-isotridecanol equivalents to rats in the excretion mass balance phase at 400 mg/kg, a total of approximately 65% of the administered radioactivity was recovered in the excreta collected from male rats. The remaining radioactivity is attributed to the expired air. The majority of the elimination occurred in the first 24 hours postdose; however, some radioactivity was still detected in both urine and feces collected at 168 hours postdose.

Metabolite characterisation studies

Metabolites identified:

not measured

Remarks:

Metabolites are being identified in a follow-up study (2018).

Any other information on results incl. tables

All animals survived to the scheduled necropsy, for both the dose-finding phase and the pharmacokinetic phase.

Dose Range-Finding Phase:

Clinical observations: There were no test substance-related clinical observations.

Body weights: Unaffected by test substance administration.

Food consumption: Unaffected by test substance administration.

Clinical pathology:

Hematology and coagulation: Test substance-related generally statistically significantly lower mean absolute lymphocyte, monocyte, eosinophil, and basophil counts were noted in all test substance-treated group males when compared to the control group. These changes were considered nonadverse. There were no test substance-related effects on coagulation parameters or other test substance-related effects on hematology parameters. However, statistically significantly lower mean white blood cell counts were noted in all test substance-treated group males and a statistically significantly lower mean prothrombin time was noted in the 1000 mg/kg/day group females compared to the control group. These differences were not considered test substance-related because the control group values were slightly higher and the direction of change was not toxicologically relevant. Statistically significant findings that involved percentage leukocyte differential counts were not itemized above, and were not considered toxicologically important because absolute cell counts are more relevant for interpretative purposes.

Serum chemistry: There were no test substance-related effects on serum chemistry parameters. Differences in serum chemistry parameters, some of which attained statistical significance, were not considered test substance-related and were attributed to biologic variation because they were sporadic, similar to differences among control group values, lacked a clear dose-response, and/or were of a magnitude of change commonly observed in rats under similar study conditions.

Urinalysis:

Test substance-related high mean urine volume was noted in the 1000 mg/kg/day group males. The finding correlated with non human-relevant kidney histopathology.

Macroscopic Examination: No observations associated with administration of test substance.

Organ Weights:

Test substance-related, statistically significant, higher mean liver weights (absolute and relative to brain and final body weights) were noted in the 1000 mg/kg/day group males and the 400 and 1000 mg/kg/day group females. Statistically significant higher mean liver weights (relative to final body weight) were noted in the 150 and 400 mg/kg/day group males as well. These alterations were accompanied by histopathologic correlates of hepatocellular hypertrophy.

Test substance-related, statistically significant, higher mean kidney weights (relative to final body weights) were noted in the 400 and 1000 mg/kg/day group males. This was most likely secondary to xenobiotic metabolism related to microsomal enzyme induction; however there were no histopathologic correlations.

Statistically significant, lower mean thymus weights (absolute and relative to brain and final body weights) were noted in the 1000 mg/kg/day group males. These alterations demonstrated a dose-response relationship but were without any histopathologic correlates. The cause of this change was not evident, and was considered non-adverse.

Test substance-related, and statistically significant, lower mean brain weight (absolute) was noted in the 1000 mg/kg/day group females with a dose-response relationship but without any histopathologic correlates. The cause of this change was not evident, and was considered non-adverse.

There were no other test substance-related effects on organ weights.

Microscopic Examination:

Test substance-related histopathologic findings were noted in the liver of the 400 and 1000 mg/kg/day group males and females and in the kidney of the 150, 400, and 1000 mg/kg/day group males.

In the liver, hepatocellular hypertrophy was noted in the 400 and 1000 mg/kg/day group males and females and characterized by increased cytoplasm of hepatocellular epithelial cells. This was observed most often with the centrilobular and midzonal hepatocytes. Cytoplasm was typically homogenous and eosinophilic. These findings were consistent with centrilobular cytochrome enzyme induction. These findings were not considered adverse based on the absence of additional test substance-related histopathologic findings in the liver and absence of test substance-related alterations in mean liver enzyme values.

In the kidney, hyaline droplet accumulation was noted in the 150, 400, and 1000 mg/kg/day group males and characterized by the presence of one to few, round to ovoid or angular, bright eosinophilic bodies within the cytoplasm of the S2 segments of proximal tubules. Occasionally the hyaline droplet was surrounded by clear space, consistent with an intracytoplasmic vacuole. Degeneration/necrosis and regeneration of the proximal tubule were noted in the 400 and 1000 mg/kg/day group males. Degeneration/necrosis was characterized by individual or few grouped epithelial cells, with fragmented cytoplasm and pyknotic nuclei, which were occasionally sloughed into the tubule lumen while regeneration was characterized by slightly enlarged individual tubule epithelial cells with a faint basophilic cytoplasm and, occasionally, mitotic figures. Granular casts were noted in the 400 and 1000 mg/kg/day group males and characterized by individually dilated tubules in the medulla, lined by flattened epithelial cells, which contain granular eosinophilic debris. The findings were consistent with α-2μ-globulin nephropathy, a phenomenon unique to male rats following exposure to xenobiotics, and has been reported in male Fischer 344 rats following tert-butyl alcohol administration. The tubule degeneration/necrosis and regeneration were most likely secondary to hyaline droplet accumulation and not a direct test substance effect. A review of xenobiotics known to cause α-2μ-globulin nephropathy identified single cell necrosis in the S2 segment of kidneys as an associated finding and tubular regeneration and atrophy have been associated with tert-butyl alcohol induced α-2μ-globulin nephropathy. Additionally, granular casts have been considered a hallmark feature of α-2μ-globulin nephropathy. Degeneration/necrosis of tubules accompanied mild to moderate hyaline droplet accumulation but was not observed with minimal hyaline droplet accumulation. Findings in the kidney of male rats were considered adverse at 400 and 1000 mg/kg/day but nonadverse at 150 mg/kg/day. However, α-2μ-globulin nephropathy is male rat specific and not considered relevant to humans.

There were no other test substance-related histopathologic findings.

Applicant's summary and conclusion

Executive summary:

A 14 day dose range-finding study with a separate toxicokinetic phase (pharmacokinetics, excretion, tissue distribution) was conducted to assess the toxicokinetics and toxicity of isotridecanol. Oral administration of isotridecanol to rats at dosage levels of 150, 400, and 1000 mg/kg/day for 14 consecutive days resulted in test substance-related adverse tubule degeneration, necrosis, and regeneration, granular casts, and hyaline droplet accumulation of the kidneys in the 400 and 1000 mg/kg/day group males. Additionally, nonadverse test substance-related hyaline droplet accumulation of the kidney was noted in the 150 mg/kg/day group males and hepatocellular hypertrophy of the liver was noted in the 400 and 1000 mg/kg/day group males and females. Histopathologic kidney findings were consistent with α-2μ-globulin nephropathy, a phenomenon unique to male rats following exposure to xenobiotics, and is not considered relevant to humans. Test substance-related higher kidney weights were noted in the 400 and 1000 mg/kg/day group males and was most likely secondary to xenobiotic metabolism related to microsomal enzyme induction. Nonadverse lower thymus weight was noted in the 1000 mg/kg/day group males and nonadverse lower brain weight was noted in the 1000 mg/kg/day group females. Also, nonadverse test substance-related lower absolute lymphocyte, monocyte, eosinophil, and basophil counts were noted in all test substance-treated group males and high urine volume was noted in the 1000 mg/kg/day group males. Therefore, the no-observed-adverse-effect level (NOAEL) was considered to be 150 mg/kg/day. No macroscopic changes were observed in any reproductive tissues evaluated in either males or females in the dose range-finding study (cervix, epididymides, ovaries with oviducts, prostate, seminal vesicles, testes, uterus, or vagina), nor were weight changes observed in any of the reproductive tissues evaluated (epididymides, ovaries with oviducts, prostate with seminal vesicles, uterus).

In addition, oral administration of Isotridecanol for 13 consecutive days and a single dose of [14C]-isotridecanol equivalents to rats at dosage levels of 50 and 400 mg/kg/day was well tolerated. Isotridecanol was nearly completely absorbed following oral administration and excreted primarily in the urine. The majority of the [14C]-isotridecanol equivalents were excreted in the first 24 hours postdose. There appeared to be little affinity for whole blood cells or any tissues types. Tissue concentrations were highest in the tissues associated with oral administration and urinary excretion, but [14C]-isotridecanol equivalents and/or its metabolites were also detected in notable concentrations in other tissues. [14C]-isotridecanol equivalents were still present in almost all tissues after 168 hours postdose. Overall, the exposure to tissues was generally usually low or equivalent relative to the plasma.