Phenol, 4-methyl-, reaction products with dicyclopentadiene and isobutylene

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

February – May 2000

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Performed in accordance with common test guidelines in compliance with GLP.

Qualifier:

according to guideline

Guideline:

other: OECD No. 417 (1984) & ECETOC Technical Report No. 46 (1992)

Deviations:

no

Principles of method if other than guideline:

none

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

other: BRL-HAN Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd (CH-4414 Fuellinsdorf, Switzerland)
- Age at study initiation: Males: 6 weeks; Females: approximately 8 weeks
- Weight at study initiation: Males 142-167 g; Females: 151-170 g
- Fasting period before study: Prior to dosing, rats were fasted overnight (approximately 17 hours)
- Housing: Groups of 1-3 rats in Makrolon cages (type 3) during acclimation and in all-glass metabolism cages 1 day prior to treatment and during
the experiment
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40--70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: 18 February, 2000 To: 15 March, 2000

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): once
- Mixing appropriate amounts with (Type of food): not applicable
- Storage temperature of food: not described

VEHICLE
- Justification for use and choice of vehicle (if other than water): not provided
- Concentration in vehicle: 3.0 mg/ml
- Amount of vehicle (if gavage): 1 ml/100 g body weight
- Lot/batch no. (if required): 000209 (radiolabelled test substance)
- Purity: Radiochemically pure (test substance)

HOMOGENEITY AND STABILITY OF TEST MATERIAL: The stability was confirmed by comparison of the chromatographic pattern by HPLC analysis of the formulated test item before and after treatment. No homogeneity testing.

Duration and frequency of treatment / exposure:

Single dose with a recovery period of 168 hours

Remarks:

Doses / Concentrations:
30 mg/kg body weight

No. of animals per sex per dose / concentration:

4 males and 4 females

Control animals:

no

Positive control reference chemical:

no

Details on study design:

- Dose selection rationale: not provided
- Rationale for animal assignment (if not random):not applicable

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, eyes, heart, lung, liver, gastro-intestinal tract (with contents), thymus, spleen, adrenal glands, kidney, gonads, brain, thyroid gland, pancreas, partial samples of muscle, bones (femur), skin (back region) and fat and residual carcass, cage washes
- Time and frequency of sampling: urine and feces sampling at 24, 48, 72, 96 and 168 hours after administration; blood and tissue sampling after 168 hours
- Other: none

METABOLITE CHARACTERISATION STUDIES not applicable

Statistics:

no

Preliminary studies:

not performed

Details on absorption:

The data suggest that a large proportion of test material is not absorbed, but passes through the gastro-intestinal tract with very small amounts being absorbed. However, there are data suggestive of biliary excretion (see below) in which case there could be significant absorption.

Details on distribution in tissues:

At 168 hours the total amount of residual radioactivity in blood, tissues/organs and the remaining carcass was approximately 1.5% and 2.4% of the administered dose in males and females, respectively. Elevated amounts of radioactivity were found in the gastro-intestinal tract (males:0.15%, females: 0.24%), and liver (males:0.09%; females: 0.13%). Taking into account the amount of radioactivity in the feces from 96 to 168 hours (males: 0.59%; females 0.78%), excretion of absorbed radioactivity into feces via bile was likely. Highest levels of radioactivity in males were found in fat, liver, adrenal gland and epididymides. Highest levels of radioactivity in the females were found in fat, ovaries and liver.

Details on excretion:

Mainly via feces (90% of administered radioactivity within the first 48 hours for both genders), negligible amounts via urine (0.1-0.2% of administered radioactivity mainly within first 48 hours).

Metabolites identified:

not measured

Details on metabolites:

none

none

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
14C-Wingstay was rapidly eliminated following single oral administration to rats. Within the first 48 hours, 90% of administered radioactivity was excreted via the faeces .

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

other: available information

Adequacy of study:

key study

Study period:

June - August 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non GLP-assessment report

Objective of study:

other: toxicokinetic assessment

Qualifier:

no guideline required

Principles of method if other than guideline:

Assessment of all available data

GLP compliance:

no

Species:

other: none

Strain:

other: none

Route of administration:

other: oral, dermal and inhalation

Vehicle:

unchanged (no vehicle)

Details on exposure:

see assessment

The water solubility of Lowinox®CPL is very low (0.01 mg/L). Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that Lowinox®CPL will show a high systemic exposure after oral administration (1). However, its highly lipophilic character (log Po/w 7.17 – 8.17) indicates that uptake by micellular solubilisation may be of particular importance. Lowinox®CPLwith its hydroxyl (OH) groups is potentially ionisable, and ionized substances do not readily diffuse across biological membranes. Also the relative high molecular weight of Lowinox®CPL (MW 700) is not favourable for absorption. For risk assessment purposes oral absorption of Lowinox®CPL is set at 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

 

Once absorbed the highly lipophilicLowinox®CPL(log P >6) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Due to its lipophilicity,Lowinox®CPL may be present at higher concentrations in breast milk than in blood/plasma, and exposure of neonates via nursing to mother’s milk may have toxicological significance. Lowinox®CPLmay tend to concentrate in adipose tissue and depending on the conditions of exposure may accumulate in individuals that are frequently exposed (e.g. daily at work) Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance.Lowinox®CPLwith its hydroxyl (OH) groups may be conjugated as glucuronides and excreted in the bile and potentially undergo enterohepatic circulation.

 

The very low vapour pressure (< 3.2 x 10^-5Pa) and the high boiling point (Decomposition > 300°C) indicate that Lowinox ®CPL is not available for inhalation as a vapour, but Lowinox ®CPL particles have the potential to be inhaled by humans (96.5% < 45 µm) . Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract. Lowinox ®CPL particles depositing in the nasopharyngeal region could be coughed or sneezed out of the body or swallowed. Dusts depositing in the tracheo-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed. The low water solubility of Lowinox ®CPL indicates a potential for accumulation, since the substance will not dissolve easily into the mucus lining of the respiratory tract and will not be transported out of the respiratory tract. Micellular solubilisation may be of particular importance for the highly lipophilic Lowinox ®CPL particles (log P7.17 – 8.17), which may have a longer half-life within the lungs. However a small amount may be taken up by phagocytosis and transported to the blood via the lymphatic system. Lowinox ®CPL dusts depositing in the alveolar region would mainly be engulfed by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. For risk assessment purposes the inhalation absorption of Lowinox ®CPL is set at 100%.

Lowinox®CPLmay penetrate the lipid rich stratum corneum but with a log P value of7.17 – 8.17, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may even be slow. At a molecular weight above 500 the molecule may also be too large for dermal uptake. AlthoughLowinox®CPLmay persist in the stratum corneum, it will eventually be cleared as the stratum corneum is sloughed off. With a molecular mass above 500 and log P outside the range [-1, 4],the data meet the criteria for 10% dermal absorption as given in the Guidance for the implementation of REACH (2) The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

Conclusions:

Interpretation of results (migrated information): other: see conclusions
For risk assesment purposes, the oral absorption is set at 50%.
For risk assessment purposes the inhalation absorption is set at 100%.
For risk asssessment purposes the dermal absorption is set at 10%.

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

Based on the available information the following absorption values were derived:

Absorption oral (rat) = Absorption oral (human) = 50%

Absorption dermal (human) = 10%

Absorption inhalation (human) = 100%