4-(1,1,3,3-tetramethylbutyl)phenol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17.07.1995 - 27.07.1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP, comparable to guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1996

Materials and methods

Objective of study:

distribution

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Version / remarks:

(The study was designed according to scientifically accepted procedures and according to validated and standardized methods, developed in the testing facility.)

Principles of method if other than guideline:

The OCT concentrations in tissues were determined by a gas chromatographic method, using a mass selective detector. OCT was extracted with methyl tert.-butyl ether and p-tert.-butyl phenol (BUT) was used as internal standard. The limit of detection under the conditions of this study was determined to be in the range of 5 - 10 ng/g tissue.

GLP compliance:

yes (incl. QA statement)

Remarks:

MINISTERIUM FÜR UMWELT, RAUMORDNUNG UND LANDWIRTSCHAFT DES LANDES NORDRHEIN-WESTFALEN

Test material

Test material information

Constituent 1

Reference substance name:

4-(1,1,3,3-tetramethylbutyl)phenol

EC Number:

205-426-2

EC Name:

4-(1,1,3,3-tetramethylbutyl)phenol

Cas Number:

140-66-9

Molecular formula:

C14H22O

IUPAC Name:

4-(2,4,4-trimethylpentan-2-yl)phenol

Details on test material:

- Name of test material (as cited in study report): p-(1,1,3,3-tetramethylbutyl)-phenol (Octylphenol PT, OCT)
- Substance type: pure substance
- Physical state: solid, white - slight yellowish
- Analytical purity: appr. 98 %
- Impurities (identity and concentrations): no data
- ID-No.: 0637/81611; internal number.: 0125
- Production date of the lot/batch: 24.01.1994; stability > 1 year
- Storage condition of test material: room temperature, darkness
- Density: 0,95 g/cm³ (20°C)
- Solubility in water: 4 mg/l (20°C)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Fa. Harlan-Winkelmann, D-33167 Borchen
- Age at study initiation: no data
- Weight at study initiation: 200-220 g
- Fasting period before study: No fasting period before administration
- Housing: Groups of five in Makrolon cages Type IV
- Diet: ad libitum, Ssniff R10 - laboratory standard rat diet (in pellet form), Fa. Ssniff, Spezialfutter GmbH, D-59494 Soest.
- Water: groups I - IV ad libitum, Fa. Gelsenwaser, D-45721 Haltern; group V tap water saturated with OCT ad libitum
- Acclimation period: animals were acclimated under study conditions except administration for a minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3°C
- Humidity (%): 30-70 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): artificial light; 12/12

Administration / exposure

Route of administration:

other: : oral: gavage and drinking water (repeated application)

Vehicle:

polyethylene glycol

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): Solutions of the test material in the vehicle for the gavage application were prepared once. The concentrations of the test substance were determined after preparation of the solutions, at the mid and at the end of the study.
- Storage temperature of food: room temperature, dark

VEHICLE
- Justification for use and choice of vehicle (if other than water): used in comparable studies
- Concentration in vehicle: 50 mg OCT/ml (for 50 mg/kg dose group, gavage application); 200 mg OCT/ml (for 200 mg/kg dose group, gavage application);

For the treatment of group V, a saturated solution of OCT in tap water was prepared weekly (day 1 - 14 of application) or once (day 15 - 28 of application), respectively, by dissolving a surplus of OCT in tap water, stirring overnight, and removal of unsoluble residues by filtration.
The concentrations of these solutions were determined weekly.

Duration and frequency of treatment / exposure:

After acclimatization the animals of group I and II received gavage applications of 50 or 200 mg/kg b.w. OCT once per day for 14 consecutive days.
Other animals received drinking water satured with OCT for 14 and 28 days, respectively.

Doses / concentrations

Remarks:

Doses / Concentrations:
Repeated gavage application: 50 mg/kg resp. 200 mg/kg bw
drinking application ad libitum: mean concentration = 8.39 mg/l / standard deviation = 1.182 mg/l (for average doses see Table 6 in annexed document)
One control groups received the vehicle only, another control group received pure water.

No. of animals per sex per dose / concentration:

Group I : 5 animals : 50 mg/kg bw gavage
Group II : 5 animals : 200 mg/kg bw gavage
Group III : 5 animals : vehicle control group (gavage)
Group IV : 5 animals : drinking water control group
Group V : 5 animals : about 8 mg/l drinking water (satured solution)

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

no

Details on study design:

- Rationale for animal assignment: there are not enough data in mammals. To complete a former study, the same animals (Wistar rats) were chosen.

Details on dosing and sampling:

Schedules for blood sampling in the oral gavage dose groups see: "Any other information on materials and methods incl. tables 2

Statistics:

Statistical evaluations (average, standard deviation) were performed using the PC Software Microcal Origin Vers. 3.5 (Microcal Software Inc.).

Results and discussion

Preliminary studies:

Three preliminary studies showed low bioaccumulation and a high degree of detoxification by glucuronidation and sulfation of OCT.

Main ADME results

Main ADME results 1

Type:

distribution

Results:

After oral gavage OCT is detectable in different tissues.

Main ADME results 2

Type:

distribution

Results:

The OCT drinking water group had no OCT in any tissue.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

50 mg/kg dose group: OCT was detected in liver tissue and fat of 3/5 animals treated for 14 days with 50 mg/kg. The mean OCT concentrations measured were about 10 and 7 ng/g tissue for fat and liver, respectively. No OCT was detected in the remaining tissues analyzed.

200 mg/kg dose group: OCT was detected in all tissues of animals treated for 14 days with 200 mg/kg per gavage. The OCT concentration was highest in fat tissue (about 1285 ng/g tissue). In liver, kidney and muscle tissue the OCT concentrations measured were about 87, 71 or 43 ng/g tissue, respectively. Low concentrations of about 9 or 7 ng/g tissue were measured in brain and lung tissue, respectively.
For mean OCT concentration in different tissues see table 5 and figures 1 and 2 of annexed document.

Drinking water group: OCT was detectable in muscle and kidney of one single animal (#21) receiving OCT via drinking water for 14 days. No OCT was measured in any other tissue of animals receiving OCT over a period of 14 or 28 days, nor in animals of the recovery group. The reason for detecting OCT in muscle and kidney tissue, but no other tissue including fat, of one single animal after 14 day drinking water application is unknown. Since OCT is highly lipophilic the highest concentration is expected in fat tissue. Due to the fact that OCT was not detectable in fat tissue and not in animals of the 28 day group this finding is considered to be negligible.

Blood concentration: The OCT concentration in blood sampled at sacrifice of animals of the drinking water group was determined. Although the blood volume used for analysis was increased up to 5 ml, OCT was not detected in concentrations above the limit of detection, which was about 1 ng/ml blood. This results confirm the findings of the previous study BT-95/0125 where OCT was not detected in blood sampled from animals receiving OCT via drinking water for up to 28 days.

Transfer into organs

Test no.:

#1

Transfer type:

other:

Observation:

distinct transfer

Metabolite characterisation studies

Metabolites identified:

not measured

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results male rats
Concentration of up to 1285 ng OCT/g fat were detected in male rats after repeated oral gavage of 200 mg OCT/kg bw. At this dose group OCT was also detected in other tissues, but not in testes. After repeated oral gavage of 50 mg OCT/kg bw, only trace levels (7 - 10 ng/g tissue) of OCT were detected and only in fat and liver tissue of 3/5 animals.
After drinking water application (800 pg/kg bw/day) for up to 28 days OCT was not detected in any tissue or blood sample.

Executive summary:

In a toxicokinetic study p-(1,1,3,3-tetramethylbutyl)-phenol (Octylphenol PT, OCT) (98 %) was administered to 3 groups of 5 male Wistar rats by repeated gavage at dose levels of 0, 50, 200 mg/kg bw. Another group received OCT saturated water (appr. 8 mg/l) ad libitum.

At the 200 mg/kg bw group OCT was detected in any tissue tested despite testes. The maximum concentration was 1285 ng OCT/g measured in fat. After administration of 50 mg/kg bw traces of OCT (7-10 ng/g tissue) were found in fat and liver tissue. No accumulation of OCT occurs in animals of the drinking water group.

 

This toxicokinetics study in rats is classified acceptable and satisfies essential requirements for a toxicokinetics study (OECD 417) in rats. The study does not cover the total endpoint information, but is only the fourth part of a series of four supplementary studies.