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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
19 Oct 1986 to 20 May 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Version / remarks:
1982
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2-chloroethoxy)-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamoyl]benzene-1-sulfonamide
EC Number:
617-298-9
Cas Number:
82097-50-5
Molecular formula:
C14H16ClN5O5S
IUPAC Name:
2-(2-chloroethoxy)-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamoyl]benzene-1-sulfonamide
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Wistar
Remarks:
KFM-WIST (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 7 - 8 weeks of age
- Weight at study initiation: 150 - 200 g
- Housing: Groups of 3 rats in Makrolon type-4 cages with standard soft wood bedding during acclimatisation and treatment with unlabelled test substance. During the metabolism studies rats were held individually in all-glass metabolism cages.
- Diet: Ad libitum.
- Water: Tap water. Ad libitum
- Acclimatisation: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 37.5 - 70
- Air changes per hour: 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 19 Oct 1986 To: 20 May 1987

Administration / exposure

Route of administration:
other: Intravenous or oral
Details on exposure:
Male and female rats were orally or intravenously treated with a single high (300 mg/kg bw/day) or low (0.5 mg/kg bw/day) dose level of the test substance.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrationsopen allclose all
Dose / conc.:
300 mg/kg bw (total dose)
Remarks:
Group 1: oral administration in males
Dose / conc.:
0.5 mg/kg bw (total dose)
Remarks:
Group 2: oral administration in males
Dose / conc.:
0.5 mg/kg bw/day (actual dose received)
Remarks:
Group 3: oral administration in females
Dose / conc.:
300 mg/kg bw (total dose)
Remarks:
Group 4: oral administration in females
Dose / conc.:
0.5 mg/kg bw (total dose)
Remarks:
Group 5: intravenous administration in males
Dose / conc.:
0.5 mg/kg bw (total dose)
Remarks:
Group 6: intravenous administration in females
Dose / conc.:
0.5 mg/kg bw (total dose)
Remarks:
Group 7: oral administration in males
Dose / conc.:
0.5 mg/kg bw (total dose)
Remarks:
Group 8: oral administration in females
No. of animals per sex per dose / concentration:
Group 1: 5 males
Group 2: 5 males
Group 3: 5 females
Group 4: 10 females

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The test substance was readily absorbed based on calculated excretion values (74.5 - 96.45 %).
Details on distribution in tissues:
The residual radioactivity levels found in organs/tissues, being after 96 hours below the limit of quantification (LOQ) for the low dose level (0.5 mg/kg) and in the order of LOQ (spleen, brain, fat, adrenal glands, thyroid gland) up to 0.88 mg/g (skin, chest) for the high dose level (300 mg/kg). After repeated administered at the low dose level, no radioactivity was retained in organs and tissues of male and female rats.
Details on excretion:
Excretion mainly via the urine representing in male rats, on average, 74.0 and 80.0 % of the radioactivity administered for the high and low dose level, respectively. The corresponding values in females were 74.4 and 85.1 %. Excretion via the faeces ranged for all experiments,  on average, from 0.3 to 13.9 %.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Analysis of the metabolite patterns in urine, faeces and liver showed mainly the presence of the parent molecule, ranging from 65.7 - 84.9 % of the dose administered. Besides the test substance itself, 12 urinary metabolites (6.6 - 8.1 %), and 8 faecal meta­bolites (1.2 - 2.9 %) were identified.

Any other information on results incl. tables

BALANCE STUDY ON THE RAT AFTER SINGLE ORAL ADMINISTRATION


Balances and excretion patterns:


Excretion mainly proceeded via the urine representing in male rats, on average, 74.0 and 80.0 % of the radioactivity administered for the high and low dose level, respectively. The corresponding figures in females were 74.4 and 85.1 %.


The excretion patterns demonstrated a rapid elimination of absorbed radioactivity since already 24 hours after the administration, on average, 41.8 to 75 8 % of the radioactivity administered were found in the urine. Furthermore, it can be stated that urinary excretion was higher at the low dose levels than at the high dose levels. No influence of sex on absorption/urinary excretion was observed.


Excretion via the faeces ranged for all experiments,  on average, from 0.3 to 13.9 %. Additional radioactivity resulting from excretion via urine and faeces was found in the cage wash ranging, on  average, from 5.8 to 12.1 %.


Only very small amounts of radioactivity were found in the intestinal tracts (<0.1 %), in the residual carcass (<0.1-0.3 %), in organs/tissues (<0.1 %) and in the expired air (<0.01 %).


Total recoveries of radioactivity ranged, on average, from 92.9 to 101.8 % of the radioactivity administered.


In conclusion, the test substance was highly absorbed by male and female rats and thereafter rapidly and almost completely excreted.


Residual radioactivity in organs/ tissues/ blood:


Males high target dose level (300 mg/kg):


The residual radioactivity in organs/tissues, blood and plasma was low 96 hours after the administration of U-14C-labelled test substance. Except for liver (0.31 mcg/ g), kidney (0.68 mcg/g), pancreas (0.23 mcg/g), stomach (0.15 mcg/ g), intestinal tract (0.22 mcg/g), skin (0.29-0.88 mcg/g), carcass (0.41 mcg/g), blood (0.74 mcg/g) and plasma (1.09 mcg/g), all other organs and tissues were below or at the limit of quantification.


Females high target dose level (300 mg/kg):


Residual radioactivity in females was very similar to that observed in males, i.e. only liver, kidney, intestinal tract, ovary/uterus, skin, carcass, blood and plasma, significant but low amounts of radioactivity were detected (Tables 19 and 25). The reasons for these low amounts of residual radioactivity still found were mainly due to a not totally completed excretion process. Residual radioactivity observed in the skin was considered to be due to contaminations from urine and faeces.


Males and females: low target dose level (0.5 mg/kg):


The residual radioactivity levels in all organs/tissues, blood and plasma were below or at the limit of quantification. In conclusion, practically no radioactivity was retained 96 hours after the administration of the low dose level, and only small amounts were found at the high dose level in organs/tissues etc. involved in the excretion process. Therefore, it can be assumed that increasing the depuration period at the high dose level would also result in a complete elimination of residual radioactivity.


 


BALANCE STUDY ON THE RAT AFTER SINGLE INTRAVENOUS ADMINISTRATION


Balances and Excretion Patterns:


Urinary excretion was very rapid and high accounting already after 8 hours in males and females orally exposed to a target dose level of 0.5 mg/kg for 88.2 and 86.5 %, respectively. Finally after 96 hours, on average, 98.2 and 92.1 % were excreted via the urine by males and females, respectively.


Excretion via the faeces was in males and females 7.2 and 2.3 %, respectively. Additional radioactivity was collected in the cage washes (2.7 and 3.1 %).


Radioactivity found in the residual carcass and organs/tissues was 0.2 and <0.1 % of the radioactivity administered to male rats, respectively. For females, the corresponding figures were 0.1 and <0.1 %. Practically no radioactivity was found in the intestinal tract (<0.1 %) of males and females.


Total recoveries were, on average, 97.6 - 108.3 %.


When compared with the oral study, it can be stated that the total excretion and the ratio of  radioactivity excreted via the urine and faeces were of the same order of magnitude. Based on these findings, it can be concluded for the oral study that the amount of radioactivity appearing in the feces most probably originated from biliary excretion. Therefore, a complete absorption of the test substance from the gastro-intestinal tract can be assumed after oral administration.


Residual radioactivity in organs/ tissues/ blood:


When compared with the oral study, again no residual radioactivity was found in organs, tissues and in blood/plasma, i.e. all values were below the limit of quantification.


 


EXCRETION OF RADIOACTIVITY AFTER REPEATED (14X) ORAL ADMINISTRATION OF THE UNLABELLED TEST SUBSTANCE FOLLOWED BY A SINGLE ORAL ADMINISTRATION OF THE 14C­ LABELLED TEST SUBSTANCE


Excretion patterns:


Males: On average, 91.5 and 7.9 % of the radioactivity administered were excreted via the urine and faeces, respectively. Further, mainly urinary radioactivity was collected via the cage wash (4.4 %). Therefore, the total excreted radioactivity was 103.8 %. Only negligible amounts of radioactivity were found in the intestinal tract, residual carcass and organs/tissues. The total recovery was, on average, 104.0 %.


Females: Here, 82.0, 6.6 and 14.4 % of the radioactivity administered were collected in the urine, faeces and cage wash. Based on these figures, total excretion accounted for 103.0 %. Residual radioactivity in the intestinal tract, residual carcass and organs/tissues ranged from <0.1 - 0.1 %. The total recovery was, on average, 103.1 %.


When compared with the corresponding single oral administration study, a more rapid absorption/ elimination of radioactivity could be stated, i.e. absorption/elimination half-lives were about 8 hours and 24 hours for the repeated oral and single oral route of administration, respectively. These data indicate an adaptation of the rat to the test article after repeated oral administration resulting in a more pronounced urinary excretion rate.


Residual radioactivity in organs/ tissues/ blood and plasma:


The residual radioactivity was for males and females in all organs and tissues below the limit of quantification. In conclusion, residue data observed were not different from those obtained after single oral administration of U-14C-labelled test substance.


 


METABOLITE PATTERNS


Urine:


There was a presence of up to 8 metabolites (Ul - U7.2) in the 0-48 hour urine samples of rats exposed to a single oral, single intravenous dose of U-14C-labelled test substance, and to a repeated dose (14x) of unlabelled test substance followed by a single dose of U-14C-labelled test substance.


Metabolite U6:


It is by far the most prominent radioactive fraction was U6 identified by co-chromatography on TLC to be test substance itself. Its amount ranged in the various 0-48 hour urine samples from 65.7 to 84.9 % of the radioactivity administered.


Metabolite U1:


Besides the parent molecule, one major, polar metabolite fraction (U1) was found in all urine samples, ranging from 1.3 % (females: single oral high dose) to 9.3 % (males: single intravenous administration). However, when the latter fraction was isolated (males: single oral, high dose) and submitted to TLC in the polar solvent system 79, it was separated into at least 6 metabolites (Ul 1 - Ul.6). Only one minor fraction (U1 2) behaved on TLC identical to reference test substance. All other metabolites were found to be unknown.


Metabolite U2:


Metabolite U2 was an unknown metabolite present in almost all urine samples of the various experiments, ranging from 0.7 to 4.0 %.


Metabolite U3:


Metabolite U3 was a minor metabolite mainly occurring in the 0-48 hour urine samples of rats exposed to a single oral dose of the test substance. Its amount ranged from 0.5 to 1.0 %. It was also detected in urine of males exposed to the repeated oral dose (2.6 %). After isolation by TLC, U3 was identified by co­chromatography was shown.


Metabolite U4:


Metabolite U4 was mainly found in the urine of males exposed to a single low and high dose level, in urine of females treated with the high dose level and in the urine of males intravenously treated with (U-14C)-labelled test substance. It re­presented a minor, unknown metabolite accounting for 0.3 % to 2.9 %.


Metabolite U5:


Metabolite US was a minor, unknown metabolite only found in the urine of males and females exposed to a high, single oral dose of the test substance. The corresponding amounts of U5 were 0.3 % and 0.1 % of the radioactivity administered.


Metabolite U7.1:


Metabolite U7.1 was found in all urine samples of the various groups. It was unknown and its amount ranged from 0.8 to 4.9 %


Metabolite U7.2:


Metabolite U7.2 was only found in the urine of males of the high, single oral dose level study, of females of the intravenous and in the urine of males and females of the repeated oral study. It ranged from 0.6 to 2.8 % of the dose administered. By co-chromatography, the identity of U7.2 was shown. In conclusion, analysis of the various urine samples showed no significant difference of the metabolite patterns in the various groups, i.e. neither the sex and dose level, nor the route of administration influenced the metabolism of the test substance by the rat.


Extractability of radioactivity:


Between 84.2 and 90.5 % of the radioactivity found in faeces was extractable.


Patterns of metabolites in extractables of faeces:


Up to 11 metabolites (F1.1 – F8.2) were found in the extractables of faeces at varying amounts. The most prominent metabolites found in extractables of all treatment groups were F1.1 and F6. Their corresponding amounts ranged from 0.4 to 2.3 % (F1.1) and from 0.7 to 9.6 % (F6 = test substance). All other metabolites ranged, as far as found, from 0.1 to 3.1 % of the dose administered. Based on the TLC­ behaviour in at least two solvent systems, the identity of most faecal metabolites with urinary metabolites U1 - U7.2 could be shown.


Liver and kidney extractability:


The extractability of liver and kidney tissues of rats of groups 1 and 2 (males, females: single oral, high dose level) is discussed. Extractables accounted for 24.0 and 58.9 % of the radioactivity present in the liver of males and females, respectively. These figures corresponded to 0.10 and 0.21 mg parent equivalents per kg of tissue fresh weight.


In kidney of males and females, extractables accounted for 15.4 and 17.7 % of the radioactivity present in the kidney tissues. These figures corresponded to a residual radioactivity level of 0.12 and 0.11 mg/kg.


Non-extractables of males and females were in the liver 0.30 and 0.14 mg/kg and in the kidney 0.68 and 0.50 mg/kg, respectively.


Metabolite pattern:


No analyses could be performed with the extractable radioactivity of kidney of males and females and of the liver of males due to the very low amount of radioactivity present.


Extractables of the liver tissues of female rats were submitted to further analyses. After clean-up, 58.1 % of the radioactivity extracted were recovered corresponding to 34.2 % of the radioactivity present in the liver. This figure corresponded to a residual radioactivity of 0.12 mg/kg.


Analysis by TLC showed the presence of 2 metabolites (L1 and L2) accounting for 0.10 and 0.02 mg/kg. Metabolite fraction L1 proved to be the parent molecule and metabolite L2 was an unknown metabolite.

Applicant's summary and conclusion

Conclusions:
The rat metabolism study has shown that the test substance was almost quantitatively absorbed from the gastrointestinal tract by male and female rats. Absorption was rapid after single oral administration, reaching its maximum about 24 hours after the administation. After repeated oral administration, an even more rapid absorption rate was observed, indicating an adaptation of the rats to the test substance as shown by the urinary excretion rates. The major route of excretion was via the urine. Smaller amounts were excreted via the faeces. Elimination of radioactivity was very rapid as shown by the urinary excretion patterns. The half-lives observed were about 24, 8 and less than 8 hours for the single oral, re­peated oral and intravenous route of excretion.
At the low, single oral dose level, residual radioactivity was in almost all organs/tissues, blood and plasma below the limit of quantification. Even when the test substance was repeatedly administered at the low dose level, no radioac­tivity was retained by the animals. At the high target dose level (300 mg/kg), higher levels of residual radioactivity were observed in organs and tissues, indicating that the capacity of the animals to eliminate the test substance de­creased.
Analysis of the metabolite patterns in urine, extractables of faeces and liver showed that mainly the parent molecule was excreted. Besides the parent molecule, a variety of minor metabolites was excreted, i.e. up to at least 12 urinary metabolites and up to at least 8 faecal me­tabolites. No significant difference in the metabolite pat­terns was observed for the various treatment groups, indi­cating that neither the dose level and sex or the routes and rates of administration influenced the metabolism of the test substance by the rat.
Executive summary:

The objectives of the study were to follow the absorption, distribution, excretion and metabolism of the 14C-labelled molecule after single and repeated oral and single intra­venous administration of the test substance at 2 dose levels to male and female rats. For this purpose, the levels of radioactivity appearing in the expired air, urine, faeces, blood and organs/tissues were followed in various separate experiments. Furthermore, the radioactivity appearing in various fractions (liver, kidney, urine and faeces) was characterised by appropriate methods.


The study has shown that the test substance was almost quantitatively absorbed from the gastrointestinal tract of male and female rats. Elimination of radioactivity was rapid and almost quantitative as shown by the urinary/faecal excre­tion rates (the elimination half-life was about 24 hours) and the residual radioactivity levels found in organs/tissues, being after 96 hours below the limit of quantification (LOQ) for the low target dose level (0.5 mg/kg) and in the order of LOQ (spleen, brain, fat, adrenal glands, thyroid gland) up to 0.88 mcg/g (skin, chest) for the high target dose level (300 mg/kg). The latter values indicated a decrease in the elimination capacity of the animals. When the test substance was repeatedly administered at the low target dose level, no radioactivity was retained in organs and tissues of male and female rats. Furthermore, it was shown that repeated oral administration (14x) of the test substance at the low target dose level resulted in a more rapid urinary excretion rate but had no influence on the routes of excretion and on the metabolic capacity of the rat. Analysis of the metabolite patterns in urine, extractables of faeces and extractables of liver showed mainly the presence of the parent molecule, ranging from 65.7 % up to 84.9 % of the dose administered. In faeces, the amount of the test substance ranged from 0.7 % to 9.6 %. Besides the test substance itself, a variety of minor metabolites was ex­creted, i.e. up to at least 12 urinary metabolites totally accounting for 6.6 - 8.1 %, and up to at least 8 faecal meta­bolites totally accounting for 1.2 - 2.9 %. Analysis of ex­tractable radioactivity from liver tissues again showed mainly the presence of the parent molecule besides negligible amounts of one unknown metabolite.