Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
Refer to analogue justification document provided in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Type:
absorption
Results:
91.54% / 92.96% (males /females) of dose excreted via urine while 6.69 / 4.35% (males / females) found in faeces; thus, the absorption rate is estimated to be 91.54 / 92.96% in males / females, respectively (source, CAS 59-50-7, key rel.1, Rudolph 2009)
Type:
distribution
Results:
< 1% of the administered dose was recovered in the carcass and GI tract (source, CAS 59-50-7, key rel.1, Rudolph 2009)
Type:
distribution
Results:
no recovery of the test material in the liver tissue at any time point or dose; isolated values above the detection limit in the fatty tissue (source, CAS 59-50-7, rel.1, Schmidt & Bomhard 1981)
Type:
metabolism
Results:
urine: at least 5 metabolite fractions (two major fractions 37-39% and 41-47% of the dose, respectively), 6 - 11% of dose unchanged parent compound; faeces: almost completely unchanged (3 - 5% of the dose) (source, CAS 59-50-7, key rel.1, Rudolph 2009)
Type:
metabolism
Results:
2 highly polar metabolites detected (source, CAS 59-50-7, rel.2, Schmidt 1980)
Type:
excretion
Results:
99.03% (males) and 98.94% (females) excreted via urine and faeces within 7 days after administration (source, CAS 59-50-7, key rel.1, Rudolph 2009)
Type:
excretion
Results:
mean excretion via urine was 60.5% (67.2% after correction by recovery rate) within 72 h; excretion via faeces was low (0.24% within 24 h (0.40% after correction by recovery rate), not detectable thereafter) (source, CAS 59-50-7, rel.2, Schmidt 1980)

Description of key information

Absorption, distribution, excretion and metabolism, oral, rat (OECD 417):

absorption: the test material is mainly excreted via urine and thus it is absorbed to a high extent

distribution: no retention of compound related residues in organs or tissues of the animals

excretion: rapid excretion during the first 24 h after administration; completed after 7 days; mainly via urine

metabolism: 4 and 5 metabolites in urine of males and females, respectively; 4 metabolites in faeces of males and females, respectively

Accumulation in liver tisue and/or fatty tissue:

Liver tissue: no retention of compound related residues in the liver detected

Fatty tissue: occasionally values above the detection limit without relation to the dose or the time of exposure

Excretion in urine and faeces, metabolism in urine:

rapid excretion via urine mainly during the first 24 h after administration (67.2%); low excretion via faeces (0.40%); 2 highly polar metabolites detected in urine

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There are no data available regarding toxicokinetic of sodium p-chloro-m-cresolate (CAS 15733-22-9). The assessment was therefore based on studies conducted with the analogue substance p-chloro-m-cresol (CAS 59-50-7) as part of a read across approach, which is in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

The toxicokinetic behavior (absorption, distribution, excretion) and metabolism of the source substance p-chloro-m-cresol was investigated in the Wistar HanRcc:WIST rat according to OECD Guideline 417 (1984) and in compliance with GLP (Rudolph, 2009). The test compound was radiolabelled with 14C in the phenol moiety of the molecule. A group of 4 male and 4 female rats received the test substance at a single dose of 300 mg/kg bw orally via gavage suspended in polyethylene glycol (PEG 400) as vehicle. The excretion of radioactivity in urine, faeces and expired air was measured in daily intervals up to 7 days after administration. The animals were sacrificed 7 days after dosing and residues of the test material were determined in selected organs and tissues. The metabolite pattern was investigated in urine and faeces extracts.

Between 121.48% and 119.46% of the administered dose were recovered from measurement of the total radioactivity in males and females, respectively. All mean values were normalized to a recovery of 100%. Rapid excretion mainly via urine was observed after oral administration. Within 24 h 85.21% and 84.30% of the administered dose was excreted in urine of male and female rats, respectively. During the same period of time 3.70% and 1.44% was excreted via faeces of male and female rats, respectively. The radioactivity excreted in the expired air was low (< 1% of the administered dose). Almost the complete administered dose was excreted after 7 days (99.03 and 98.94% in males and females, respectively). Less than 1% of the test material was detected in the remaining carcass and GI-tract. Extensive metabolism of the test material was identified in urine and faeces and excretion of respective metabolites was mainly via urine. The urinary metabolite pattern consisted of at least 5 metabolite fractions dominated by 2 major fractions (37-39% and 41-47% of the dose, respectively). Unchanged parent compound accounted for 4.97% and 11.35% of the administered dose in urine of males and females, respectively. In the fecal metabolite pattern the major fraction was found as unchanged parent compound (3-5% of the dose) while 4 metabolites in negligible amounts (< 1%) were detected in both sexes. The metabolite pattern was very similar for both sexes with some quantitative differences. Thus, under the conditions of this study, after oral administration of the radiolabeled test material to male and female Wistar rats, the recovery of radioactivity in urine, faeces, expired air and cage wash was almost complete. The radioactivity was mainly recovered in urine and to a lower extent in faeces but to a negligible extent in the expired air.

In a further study the potential of thesource substance p-chloro-m-cresolto accumulate in fatty tissue and /or liver tissue was investigated (Schmidt & Bomhard, 1981). Three groups of 12 male Wistar TNO/W74 rats received oral doses of 150, 500 or 1500 ppm of the test substance in the diet over 1, 4, 8 or 13 weeks. The liver as well as samples of fatty tissue from the abdominal cavity were removed from 3 animals per dose group 1, 4, 8 and 13 weeks after start of administration. The samples were homogenized and extracted with hexane before derivatisation with heptafluorobutyric acid anhydride for gas chromatography with electrochemical detection. Detectable concentrations of the test substance were not found in any of the liver samples (> 10 nmol/g). In the fatty tissue samples, concentrations of the test substance were occasionally above the detection limit of 4 nmol/g. No correlation was found between the applied dose and the amount of test substance in the samples. No cumulative effect was observed. Thus, under the conditions of the study, the test substance did not accumulate in liver and fatty tissues.

The excretion of the source substance p-chloro-m-cresolin urine and faeces of rats as well as the quantity of metabolites in urine was further assessed after single oral administration (Schmidt, 1980). Five male Wistar II rats received a single oral dose of 300 mg/kg bw via gavage and were housed individually in metabolism cages. Urine samples were taken at 4, 8, 24, 32, 48 and 72 hours after application and analysed by HPLC-UV. Faeces were collected at 24, 48 and 72 hours after application and measured by GC-ECD. In addition, the urine samples were analysed by TLC to identify potential metabolite. The major excretory route was via the urine with 67.2% recovery of the applied dose. The excretion was rapid within the first 24 h after application. Low concentrations were also detected up to 72 h. The faeces represent a minor excretory route, with only 0.40% recovery of the applied dose within 24 h post-dosing. Two highly polar metabolites were found in the urine samples after TLC analysis. Since these metabolites were not included in the calculation of the recovery they might be the explanation for the low recovery rate of around 68% and might account for the remaining 30%. Under the conditions of the study, the test substance is eliminated rapidly and extensively from the body; the urine was identified as the main way of excretion.