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Reference
Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979-02-27 to 1979-04-25
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
Four animals per group were treated with the test article for 28 days and autopsied. The following organs and tissues of each animal were then used for residue analysis: Liver, Brain, Eyes, Blood, Fat of testes, Storage fat tissue.
GLP compliance:
no
Remarks:
prior to GLP
Species:
rat
Strain:
other: Tif: RAIf (SPF)
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not indicated
- Age at study initiation: 7 to 8 weeks old at the starting date of administration
- Fasting period before study: overnight
- Housing: groups of 4 in special Macrolon cages (type 3, equiped with wire inset)
- Diet: rat food - NAFAG, Gossau SG, ad libitum
- Water: ad libitum
- Acclimation period: for a minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 10
- Photoperiod (hrs dark / hrs light): 14/10

IN-LIFE DATES: From: 1979-03-29 To: 1979-04-25
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
2%
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The test substance was suspended.
- Before treatment the suspension was homogeneously dispersed with an Ultra-Turrax and during treatment it was kept stable with a magnetic stirrer.

VEHICLE:
- Carboxymethyl-cellulose 2 % (CMC)
- Volume: 5 mL/kg
Duration and frequency of treatment / exposure:
28 days, daily administration
Dose / conc.:
0.025 mg/kg bw/day
Dose / conc.:
0.25 mg/kg bw/day
No. of animals per sex per dose / concentration:
4 (see table below)
Control animals:
yes, concurrent no treatment
Details on dosing and sampling:
PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: Liver, Brain, Eyes, Blood, Fat of testes, Storage fat tissue.
- Time and frequency of sampling: after 1, 7, 14 and 28 days

Analytical determination of the test article in the test material:
The test material was homogenized after addition of a measured amount of water using a high speed homogenizer. The slurry was then extracted with
n-hexane and the water free solvent measured using a fluorescence spectrophotometer.
Excitation wave length: 373 nm
Emission wave length: 400 - 450 nm
Type:
distribution
Results:
No accumulation of test material took place in the organs and tissues being examined.
Metabolites identified:
no

With regard to the detection limits given in the table below no accumulation of the test article took place in the organs and tissues being examinated after 1 day of treatment. In respect of this results, samples of autopsy data taken after 7, 14 and 28 days of treatment were not analyzed.

Organ / Tissue Dose Level (mg/kg bw) Test material ng/g (ppb)
Blood 0.025 < 5
0.25 < 5
Liver 0.025 < 30
0.25 < 30
Storage Fat Tissue 0.025 < 30
0.25 < 30
Fat of testes 0.025 << 50
0.025 << 50
0.25 << 50
0.25 << 50
Eyes 0.025 < 5
0.25 < 5
Brain 0.025 < 5
0.25 < 5

No animal died during the study. The body weight gain of all treated animals was comparable to that of the controls. No toxic signs or symptoms were seen during the study. No substance related gross organ changes were seen.

No toxic signs or symptoms and no mortalities were seen during the study. The test material has therefore practically no toxicity to male rats by the this route of administration at the dose levels 0.25 mg/kg and 0.025 mg/kg.

Description of key information

Based on physico-chemical characteristics, absorption via oral and dermal route will most likely occur on a very small scale. In congruence with this statement, oral application of the test substance to several species demonstrates that there is no evidence for a significant adsorption and metabolism. A rapid excretion of the higher molecular test substance is assumed via feces.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic assessment

The test substance is a yellow/greenish powder with a molecular weight of approximately 430. The water solubility is reported as < 10µg/L at 20°C at pH 6.3 and the log Pow was measured to be greater than 6.5 at 23°C at pH 6.1 and was calculated to be 8.6 at 25°C by a QSAR model. Except for a distribution study, no studies are available investigating the toxicokinetic properties of the test substance. Absorption, metabolism and excretion are therefore assessed based on physico-chemical properties and on available toxicity studies.

Absorption

Absorption through the gastrointestinal tract is favored for molecules with a molecular weight below 500; molecular weights above 1000 are not easily absorbed (ECHA GD 7c, 2008). The test article’s molecular weight is therefore in the absorbable range. However, an additional limiting factor for gastrointestinal absorption is the water solubility. Water-soluble substances will readily dissolve in the fluids of the GI tract (ECHA GD 7c, 2008). The test article’s solubility in water is very low, therefore limiting the dissolving in GI fluids and hindering its contact with the mucosal membrane for subsequent absorption. Passive diffusion is also not very likely to happen because of the high log Pow (> 4) of the test substance. Direct uptake via aqueous pores is also unlikely since it is favorable for substances with a molecular weight of < 200. Based on the physic-chemical properties, micellular solubilisation might be a potential absorption pathway for the test article. However, in an acute toxicity study in rats no mortality was observed after oral administration of test substance even at the high dose of 10000 mg/kg. Furthermore, no systemic toxicity was observed when the test article was fed to Beagle dogs for 90 days at daily dose levels of up to 50000 ppm, equivalent to an average daily intake of 1571 mg/kg for males and 1682 mg/kg for females. Similarly, when given to rats for 90 days, only minimal liver weight increases were reported in animals of the high dose levels (> 700 mg/kg). Based on these findings, a very low absorption profile for the substance is postulated.

 

For chemicals with a molecular weight < 100 dermal uptake is favored, while chemicals with a molecular weight > 500 have low potential to penetrate the skin (ECHA GD 7c, 2008). Highly lipophilic substances (log P 4-6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. In conclusion, a dermal uptake of the test substance is expected to be low. This is in line with the available guinea pig maximization test (Stillmeadow, 1994). None of the tested animals were sensitized after dermal exposure, therefore not giving any indication for dermal penetration.

 

Exposure to vapors is not of relevance as the substance has a very low vapor pressure (8.1E-10 Pa at 25°C, calculated). Particle size distribution analysis showed that 98% of the analyzed material was smaller than 100 µm and 26.2% of the substance was found in particles smaller than 10 µm. These data demonstrate that the test substance can be inspired and may reach the alveolar region upon dust inhalation. However, in an acute inhalation study, rats were exposed for 4 hours to a test atmosphere containing 1820 mg/m3 of the test article. No mortalities and no toxic symptoms were observed, indicating that absorption after inhalation is low. This is in line with the Log Pow of the test substance, which is not in the range between -1 and 4 favorable for absorption after inhalation. Particles deposited in the nasopharyngeal region will most likely be coughed or sneezed out and particles deposited in the trachea-bronchial region will be cleared by mucocilliary mechanisms and swallowed. Dust particles reaching the alveolar region will mainly be engulfed by alveolar macrophages and cleared via the ciliated airways or the lymphatic drainage. In conclusion, the test article can be inspired in the form of dust, however, as indicated by the acute inhalation toxicity study and based on the very low solubility, particles are expected to be absorbed with low efficiency.

Distribution

In an in vivo accumulation study test material was given orally to groups of 4 male rats for 28 consecutive days at concentrations of 0, 0.025 and 0.25 mg/kg body weight followed by necropsy and quantitative analysis of target tissue. Test article levels measured in blood, liver, fat, eyes and brain did not exceed 50 ng/g tissue. It was concluded that no accumulation of test material took place in the organs and tissues examined. In two long-term cancer studies in mice and rat, minor accumulation of test article in adipose tissue was reported which was somewhat reduced after 26 weeks withdrawal from treatment, although still evident.

Metabolism

Based on the structure of the molecule it may be metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase the compound’s hydrophilicity. The test substance is most likely not enzymatically activated during metabolism. This assumption is supported by the result of several mutagenicity studies in which cytotoxicity of the parent (test) substance was not higher as compared to metabolic activated test substance.

Excretion

The test substance is expected to be absorbed only in small amounts and is presumably rapidly excreted via the feces. Potential metabolites are either excreted via feces or urine, depending on their molecular size and water solubility after phase II metabolism.

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