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Reference
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:
other: GLP-compliant study, available as unpublished report, no restrictions, adequate for assessment
Objective of study:
distribution
Principles of method if other than guideline:
Other: Monsanto Company internal method.
Study conducted in general accordance with GLP Standards with the following exceptions:
- The stability of the test substance, neat and after mixing with carrier, was not determined; however stability can be inferred from Benzene, mono-C10-13-alkyl derivs., distn. residues studies.
- Characterization of the test substance was not conducted according to the standards.
- Characterization and stability data for reference substances were not developed according to the standards.
These deviations should not impact the interpretation of the study.
GLP compliance:
yes (incl. certificate)
Radiolabelling:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: approximately seven to ten weeks of age
- Weight at study initiation: 200-350 gm
- Housing: one per cage
- Diet (e.g. ad libitum): ad libitum (Purina Certified (#5002) Laboratory Rodent Chow )
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least ten days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72+2 °F
- Humidity (%): 35-60%
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Rats were gavaged using a 2 mL syringe fitted with a straight Perfectum 16 or 18 gauge, 2-inch animal feeding needle (Popper and Sons, inc., New Hyde Park, NY). The dose was contained in approximately 1.1-1.6 mL of solution.

VEHICLE
- Concentration in vehicle: 65.2 mg/g



Duration and frequency of treatment / exposure:
single dose
Dose / conc.:
300 mg/kg bw/day
No. of animals per sex per dose:
Nine male rats per dose level
Control animals:
not specified
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, liver, kidney, intestinal contents and carcasses
Details on absorption:
Absorption was not determined in this study. However, the minimum amount absorbed, calculated as the amount of radioactivity excreted in the urine plus the amount of radioactivity in the organs and carcass, was approximately 31.9% (normalized data) of the administered dose 8 hours after gavage.
Details on distribution in tissues:
The gut contents, followed by the carcass and liver, contained the majority of hydrogenated terphenyl derived radioactivity 8 hours after administration. Within 48 hours the radioactivity in the gut contents had declined by a factor of 10, while the radioactivity in the feces had increased, suggesting that most of the material in the feces was composed of unabsorbed parent compound.
Based on a per gram concentration basis, greater than 1% of the dose/per gram of gastrointestinal contents was detected in the gut 8 hours after gavage. Although almost ten times more material was observed in the carcass compared to the liver there was little difference when the % dose was expressed as per gram of tissue (0.22 and 0.37% administered dose/gram, respectively, liver and carcass). The large proportion of dose in the carcass was due to its larger mass compared to the liver.
Details on excretion:
The greatest amount of radioactivity was found in the intestinal contents 8 hours after an oral dose of hydrogenated terphenyl at 300 mg/kg, with the faces representing the major route of elimination. After 48 hours the amount detected in the feces had increased to approximately 75% of the administered dose and at 168 hours greater than 85% of the dose had been excreted by fecal elimination. Approximately 11 % of the administered dose was excreted in the urine over the 168 hour observation period.
Elimination of hydrogenated terphenyl derived radioactivity best fit a 1 compartment model. The half-lives for elimination via the urine and feces were estimated to be 23.0 and 13.0 hours, respectively. The whole body elimination reflected that of the feces and the half-life was estimated to be 14.0 hours.

Liver and kidney weights liver weights were significantly increased above control liver weights only in animals administered 300 mg/kg of hydrogenated terphenyl.

The test material was not readily absorbed and did not appear to accumulate in rat body tissues following a single gavage dose of 300 mg/kg.  Very little radiolabel was evident in the kidney and liver 48 hours after gavage. Generally the test material appeared to have little effect on AHH or ECOD activity following single exposure, although some statistically significant changes in enzymatic activity were noted.

Conclusions:
Interpretation of results: no bioaccumulation potential based on study results
Hydrogenated terphenyl was not readily absorbed and did not appear to accumulate in body tissues following a single gavage of 300 mglkg. The fecal half-life was about 13 hours and the urinary half-life was about 23 hours. The whole body half-life was estimated to be about 14 hours and the primary route of elimination was via the feces. Very little radiolabel was evident in the kidney and liver 48 hours after gavage and little enzyrne induction was noted in these tissues.

Executive summary:

Hydrogenated terphenyl was not readily absorbed and did not appear to accumulate in body tissues following a single gavage of 300 mg/kg in male rats. The fecal half-life was about 13 hours and the urinary half-life was about 23 hours. The whole body half-life was estimated to be about 14 hours and the primary route of elimination was via the feces. Very little radiolabel was evident in the kidney and liver 48 hours after gavage and little enzyrne induction was noted in these tissues.

Description of key information

300 mg/kg bw Terphenyl, hydrogenated were administered by gavage to Sprague-Dawley rats. Absorption was not determined in this study. However, the minimum amount absorbed, calculated as the amount of radioactivity excreted in the urine plus the amount of radioactivity in the organs and carcass, was approximately 31.9% (normalized data) of the administered dose 8 hours after gavage. Hydrogenated terphenyl was not readily absorbed and did not appear to accumulate in body tissues following a single gavage.

0, 100, or 300 mg/kg bw Terphenyl, hydrogenated were administered by gavage to Sprague-Dawley rats. Hydrogenated terphenyl did not appear to be extensively absorbed after a single oral dose of 300 mg/kg (30%), there is no bioaccumulation potential based on study results

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
30
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
60

Additional information

A key study was performed with hydrogenated terphenyl to determine the disposition and localization in rats as a function of dose and time, and to determine the effects on liver and kidney microsomal drug-metabolizing enzymes following oral and inhalation administration (Hotz & Brewster, 1990). In this study, hydrogenated terphenyl was administered to male Sprague Dawley rats as either a single oral dose at 0,100, or 300 mg/kg body weight, or as a single 6 hour inhalation exposure of 0 or 350 mg/m3, or in the diet at concentrations of 0, 100, 500 or 5000 ppm, or as a repeated inhalation exposure for 6 hours/day for 14 days at 0, 25, 250, at 1200 mg/m3. Ethoxycoumarin-o-deethylase (ECOD) and aryl hydrocarbon hydroxylase (AHH) activities were determined in liver and kidney S-9 preparations.

Little change in body weight was observed in animals administered hydrogenated terphenyl via the diet except at 5000 ppm. The body weight gain of animals exposed to hydrogenated terphenyl via inhalation decreased in a dose dependent manner over the 2 week exposure period and was significantly different from control at both 250 and 1200 mg/m3. Absolute liver weights from animals administered 5000 ppm in the diet or 250 mg/m3 or 1200 mg/m3 via inhalation were 30 to 70% higher than control liver weights.

Single oral and inhalation exposures to hydrogenated terphenyl produced little or no induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity. However, hepatic AHH activity in animals administered 5000 ppm in the diet, and in animals repeatedly exposed to 250 mg/m3 or 1200 mg/m3 via inhalation, was significantly increased above that of control animals. Ethoxycoumarin-o-deethylase (ECOD) activity in the inhalation and diet groups was increased only in animals receiving the highest doses of hydrogenated terphenyl. In general, renal AHH activity was statistically decreased at high exposure levels, whereas renal ECOD activity appeared to be slightly but not significantly increased compared to controls, regardless of route or length of exposure. Hydrogenated terphenyl produced less induction of microsomal enzymes in the kidney than in the liver for both AHH and ECOD.

Dietary and inhalation exposures produced similar induction patterns in both ECOD and AHH activity However, animals exposed to hydrogenated terphenyl via inhalation demonstrated a greater hepatic inductive effect than did animals exposed to hydrogenated terphenyl via the diet. This effect may be due to greater absorption of hydrogenated terphenyl after inhalation exposure compared to that after dietary exposure.

Results from the disposition study indicated that hydrogenated terphenyl did not appear to accumulate in the body tissues and did not appear to be extensively absorbed after a single oral dose of 300 mg/kg. Whole body elimination was approximately 47 hours and occurred primarily via the feces. Absorption was estimated to be approximately 30% of the administered dose. Of this, 1/3 was eliminated in the urine over the 168 hour observation period. The major route of elimination for hydrogenated terphenyl appeared to be the feces.

In summary, approximately 30% of an oral dose of hydrogenated terphenyl was absorbed from the gastrointestinal tract, there was little accumulation in tissues, and the whole body half-life was less than 1 day. Induction of drug metabolizing enzymes was evident only at the 2 highest doses and the liver was more sensitive to the enzyme inducing effects of hydrogenated terphenyl than was the kidney. ECOD activity was affected to a greater extent than was AHH activity and inhalation produced a greater effect than did dietary exposure.

In addition, supporting literature data were available on mice that were exposed by inhalation for 4 or 7 hours to radioactive (partial) hydrogenated terphenyl at 10µCi/mL . Clearance of the radiolabel from the respiratory tract was complete within 24 hours. Radioactivity in the gut, which was significantly increased immediately after inhalation, was reportedly equivalent to control values within 24 hours of compound administration. No accumulation was noted in the gut, kidney, and liver since radioactivity levels 24 hours after the final exposure were similar for mice exposed once compared with mice exposed for five consecutive days.Mice were also exposed by oral administration to radioactive (partial) hydrogenated terphenyl at 100µCi/mL and demonstrated radioactivity in the gut, liver, and kidney. The radioactivity was maximal at 4 to 5 hours after administration and steadily disappeared to background levels within 7 days.

No additional data on absorption, besides the estimated oral absorption of 30% after gavage of 300 mg/kg hydrogenated terphenyl in rats, is available. In consequence, absorption rates can be estimated by physico-chemical parameters, as indicated in ECHA’s guidance R.7c. Relevant parameters are:

 

Endpoint

Hydrogenated Terphenyl

Appearance

Clear pale yellow liquid at 20°C and 1013 hPa

Molecular weight

236 - 248 g/mol

Melting point

-24°C

Boiling point

342°C

Density

1.013 (relative)

Vapour pressure

0.00174 hPa @ 20°C

Partition coefficient

> 6.5

Water solubility

Max. 0.061 mg/L

Skin Irritation

Not irritating (Draize test)

Eye Irritation

Not irritating (Draize test)

 

In general, based on the physico-chemical parameters, the poor oral absorption is feasible.

The substance is non-volatile, making exposure via inhalation limited. For the e.g. accidentally inhaled amount, In general, either a prolonged exposure due to deposition and subsequent absorption or immediate absorption by micellular solubilisation has to be assumed. The latter mechanism may be of particular importance for highly lipophilic compounds (LogPow >4), particularly those that are poorly soluble in water (1 mg/l or less) and is hence the only relevant here. To be readily soluble in blood, a gas, vapour or dust must be soluble in water and increasing water solubility would increase the amount absorbed per breath. However, the gas, vapour or dust must also be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate log P value (between -1 and 4) would be favourable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. Hence, with a logPow of >6.5 and a virtually non-existing water solubility, the absorption of this fraction which may not be subjected to ciliary clearance can be considered as very limited by the rate at which the substance partitions out of the fluid in the lung surface.

For absorption of deposited material similar criteria as for GI absorption can be applied. So it can be estimated that the absorption via inhalation would be similar to the one via the oral route. In addition, according to the Reference preliminary Technical Guidance Document (reference p-TGD), Chapter 3, Human health hazard assessment, Part of Preliminary TGD, it is proposed, in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. So a worst case inhalation absorption of 60% will be assumed, most likely overestimating the actual absorption.

 

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. Above a logPow of 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. The substance is not irritating, so no additional, absorption-enhancing factors need to be regarded.

For the substance a QSAR-based model published by DERMWIN, taking into account molecular mass and log Kow, estimated a dermal permeability constant Kp of 30.4 cm/h. Similar to the approach taken by Kroes et al. (2007), the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated, resulting in dermal absorption of 0.001854 µg/cm²/h. Generally, this value, i.e. <0.01 µg/cm²/h, is considered to indicate a dermal absorption of approximately 1% (Mostert and Goergens, 2011). Therefore, the calculated dermal uptake indicates that the substance has a very potential for dermal absorption. However, according to ECHA’s Guidance Chapter R.7c: Endpoint specific guidance Version 2.0 – November 2014, the lowest default dermal absorption value is 10%, so this value will be chosen for further assessment as a worst case scenario, also most likely overestimating the actual absorption.