O-isopropyl ethylthiocarbamate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Dithiocarbamates are related compounds to Thionocarbamate.

Objective of study:

metabolism

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.36 (Toxicokinetics)

Deviations:

yes

Remarks:

Distribution was not investigated.

GLP compliance:

yes

Radiolabelling:

yes

Remarks:

14C-Ziram

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River, US
- Age at study initiation: 44 days (m); 51 days (f)
- Weight at study initiation: 149-169 g (m); 145-162 g (f)

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Duration and frequency of treatment / exposure:

Single and multiple (15 days daily) application

Remarks:

Doses / Concentrations:
Single: 15 and 352 mg/kg
Multiple: 15 mg/kg (14x nonradiolabeled; 1x radiolabeled)

No. of animals per sex per dose / concentration:

5

Control animals:

yes, concurrent vehicle

Details on dosing and sampling:

- Tissues and body fluids sampled: air, urine, faeces, blood, several organs

The CO2 trapping solution and the volatile traps were collected at 0-4, 4-8, 8-12, and 12-24 h following administration of the radiolabeled Ziram and daily thereafter for a total of 4 days. Urine and faeces samples were collected at 0-6, 6-12, and 12-24 hours after the radiolabeled dose and daily thereafter for a total of 7 days. Urine and faeces were collected in plastic containers surrounded by ice. At the end of the collection period, the animals were anesthetized with halothane and exsanguinated by cardiac puncture. Blood (2 to 5 mL) was collected and weighed in heparinized tubes and saved for radioanalysis. After sacrifice the cages were washed with a 1.0% trisodium phosphate solution which was saved for analysis.

Details on absorption:

The mean 14C recovery ranged from 79% to 92% of the total doses administered.

Details on distribution in tissues:

The mean total radioactivity retained in the tissues and carcasses ranged from 1.11% to 1.92% of the total dose administered. For the low dose groups, the residue levels in the blood and tissues ranged from 0.05 to 2.5 ppm (µg 14C-Ziram equivalents/g sample). The highest levels were found in blood, liver, kidney, heart, lungs, spleen and thyroid gland.

Details on excretion:

The majority of the radioactivity was found in urine (17% to 35%), faeces (9% to 18%), and expired air (36% to 53%). The rate of elimination was relatively fast; the majority of the radioactivity was eliminated within 48 hours after dosing.
No apparent sex-related differences were observed for 14C elimination or distribution for any of the treated groups.

Metabolites identified:

yes

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
Dithiocarbamates are related compounds to Thionocarbamate .
The mean total radioactivity retained in the tissues and carcasses ranged from 1.11% to 1.92% of the total dose administered. For the low dose groups, the residue levels in the blood and tissues ranged from 0.05 to 2.5 ppm (µg 14C-Ziram equivalents/g sample). The highest levels were found in blood, liver, kidney, heart, lungs, spleen and thyroid gland.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of IPETC/O-isopropyl ethylthiocarbamate . Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of IPETC/O-isopropyl ethylthiocarbamate .

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

observation period should be 7 days or until 95% of the administered dose has been excreted, whichever comes first

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[2-14C]isopropanol

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: distilled, deionized water

Duration and frequency of treatment / exposure:

single dose exposures and repeated-dose exposure (for 8 days)

Remarks:

Doses / Concentrations:
Single dose of 300 mg/kg bw, single dose of 3000 mg/kg bw, and repeated dose of 300 mg/kg bw for 8 days

No. of animals per sex per dose / concentration:

4 animals/sex/group

Control animals:

no

Preliminary studies:

An oral dose-range finding study was conducted. From the data collected from the dose-range finding study it was concluded, through consultations with the sponsor that a nominal dose of 3 g isopropanol per kg body weight would be considered a toxic dose and that a nominal dose of 0.3 g isopropanol per kg body weight would be a nontoxic dose. These dosing concentrations were used for the definitive oral studies.

Details on absorption:

Low dose:
Following the oral administration of 300 mg IPA/kg bw, radiolabel was absorbed and appeared in the blood very rapidly. The radiolabel was then eliminated less quickly from the central vascular compartment, but levels still had declined by 10-fold 18 h following dose administration. IPA also appeared in the blood extremely rapidly and disappeared with nearly equal rapidity. IPA concentration in the blood decreased nearly 10-fold during the 6 h following dose administration.

High dose:
The concentration of radiolabel in the blood of rats that had received 3000 mg IPA/kg bw increased very rapidly following dosing, reaching peak levels 2 to 4 h following dosing. The concentration of radiolabel did not, however, drop off as rapidly as following the low dose. The concentration of radiolabel remained relatively high for several hours following attainment of peak levels. The concentration then decreased slowly during the 30 h following dose administration. The concentration of radiolabel in the blood decreased only about 3-fold during the interval from 6 to 30 h following dosing. This is in sharp contrast to the rapid decrease in concentration observed following a single low dose.

The concentration of IPA In the blood following the high oral dose increased rapidly following dose administration, but then decreased fairly rapidly following attainment of the highest levels.

Repeated dose:
The concentration of total radioactivity, IPA and acetone in the blood of rats administered 8 consecutive doses of 300 mg IPA/kg bw/day is virtually indistinguishable from the time course of a single oral dose of 300 mg IPA/kg bw/day. This result indicates that the disappearance of radiolabel from the blood along with absorption and disappearance of both IPA and acetone from the blood are not the consequence of inducible processes and are unaffected by repeated administration of the parent compound.

Details on distribution in tissues:

Low dose:
Following the 300 mg/kg bw oral dose, liver, kidney, skin, and adipose tissue from both male and female rats had the highest concentrations of radiolabel and also had significantly elevated TBR. Since liver and kidney are tissues which conduct oxidative metabolism of xenobiotics these tissues might be expected to have elevated residual concentrations of radiolabel. Adipose tissue and skin are not metabolic tissues, but may serve as a passive depot for lipophillic chemicals such as acetone. In addition, ovarian tissue was observed to have a significantly elevated TBR value, but contained only a tiny fraction (0.01%) of the dose. No other tissues were observed to have unexpectedly high concentrations of radiolabel.

High dose:
Following an oral dose of 3000 mg of IPA/kg bw, adipose tissue, liver and kidney were observed to have the highest concentrations of residual radioactivity, just as in the low dose study. The TBR of adipose tissue following 3000 mg IPA/kg bw was lower than that observed following the low dose. In female rats, the ovarian tissue had an elevated TBR value as had been observed following the low dose, but contained a very small fraction of the total dose. No other tissues had elevated amounts of residual radioactivity. There were no observable differences in the distribution of residual radioactivity in the tissues of male and female animals.

Repeated dose:
The tissue distribution observed in both sexes following multiple dosing was similar to that observed after a single dose at the low dose level. The same tissues, i.e., liver, skin, kidney, and adipose tissue, had the highest concentrations of residual radioactivity and elevated TBR, as was observed for the single dose study.

Details on excretion:

Low dose:
Radiolabel was excreted very rapidly following oral administration of 300 mg [14C]IPA/kg bw. Male and female rats had eliminated 84% of the total dose 24 h following dosing. IPA was eliminated very rapidly following a relatively rapid absorption phase. The exhaled breath was the major route of elimination for both sexes. The bulk of excretion in the breath occurred as volatile organic compounds, which accounted for over 55% of the dose. Approximately 26% of the administered radioactivity was recovered from the exhaled breath as radiolabeled carbon dioxide.

Slightly more than 5% of the administered radiolabel was excreted in the urine. Less than 1% of the dose was excreted in the feces. The extremely small amount of radiolabel appearing in the feces indicates that absorption of the dose from the gut was nearly complete and no enterohepatic circulation of IPA or its radiolabeled metabolites was occurring.

High dose:
IPA and its radiolabeled metabolites were eliminated somewhat less rapidly following 3000 mg IPA/kg bw than after the low dose. Male and female rats had excreted approximately 65 and 93% of the dose 24 h and 72 h after dosing, respectively.

Total elimination as volatile organics in breath averaged 70% of the dose 72 h following administration of the dose. Offsetting that increase, in comparison to the low dose, exhalation of radiolabeled carbon dioxide fell to just over 15% of the administered dose over the 72 h interval following dose administration.

Urinary excretion of radiolabel averaged just under 8% of the dose, over the 72 h following dose administration. This was slightly higher than observed to occur following the low oral dose but is probably not significant of any fundamental difference in the disposition of the parent IPA. Fecal elimination of radiolabel was very low (<1%) for both sexes indicating that absorption of the dose was nearly complete. The slower rate of excretion of radiolabel at this dose level expressed as a fraction of the administered dose may indicate that either absorption or elimination is not as rapid due to the very large dose. However, the amounts of IPA and its metabolites absorbed and excreted during the first 24 h measured on a molar basis after the high dose of IPA were much larger than in the low dose study. No significant difference in the rates or routes of excretion of radiolabel between males and females was observed. It should be noted when considering the meaning of these results that this dose of IPA was somewhat toxic. Motor impairment and ataxia was observed within several hours of dosing and persisted for several hours. Such motor impairment could compromise the animal’s ability to drink normally for a short time following dose administration. These narcotic-like effects of the high dose of IPA could have resulted in a transient decrease in the respiration rate. Such a decrease in respiration might account for the somewhat slower excretion observed. Female rats seemed to recover somewhat more quickly than did the male rats.

Repeated dose:
Repeated administration of the low oral dose did not seem to affect the overall rate of elimination of radiolabel. The breath was again the major route of elimination with organic volatiles in the breath accounting for the majority of radiolabel exhaled.

Urine and feces remained very minor routes for elimination of radiolabel, comparable to that found in the single low dose study. Overall excretion of radiolabel was as fast following repeated dosing as that after a single dose. Absorption of IPA was greater than 95% for both sexes. No effect of repeated administration on the rates and routes of excretion of radiolabel could be discerned. As with the studies described above, no significant differences in the rates and routes of elimination of radiolabel were detected between males and females.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 1.3 hr (for males and females); (blood, single dose of 300 mg/kg bw)

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 6.8 hr (males) and 4.0 hr (females); (blood, single dose of 3000 mg/kg bw)

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 1.7 hr (for both males and females); (blood, repeated dose of 300 mg/kg bw)

Test no.:

#1

Toxicokinetic parameters:

Cmax: 344 μg-eq/g (males) at 1 hr and 321 μg-eq/g (females) at 2 hr (blood, single dose of 300 mg/kg bw)

Test no.:

#1

Toxicokinetic parameters:

Cmax: 2214 μg-eq/g (males) at 6 hr and 2280 μg-eq/g (females) at 2 hr (blood, single dose of 3000 mg/kg bw)

Test no.:

#1

Toxicokinetic parameters:

Cmax: 272 μg-eq/g (males) at 0.5 hr and 3 hr and 258 μg-eq/g (females) at 1 hr (blood, repeated dose of 300 mg/kg bw)

Metabolites identified:

yes

Details on metabolites:

Following the low oral dose, the majority of the administered radiolabel (55%) was excreted in the exhaled breath as volatile compounds. These volatile compounds were found to be composed entirely of radiolabeled acetone in the 24 h following the oral administration of 300 mg IPA/kg bw. No parent compound was detected in these samples indicating that the metabolic conversion of IPA to acetone is quite efficient. Small amounts of acetone and IPA were excreted in the urine during the 24 h following the low oral dose but since the rats only eliminated an average of five percent of the dose in the urine this does not account for a large proportion of the dose. Approximately 75-80% of the radiolabel eliminated in the urine following the low oral dose is accounted for by a metabolite identified as isopropyl glucuronic acid.

Following the high oral dose approximately three-quarters of the radiolabel trapped from the breath as volatile compounds was found to be acetone while the remaining quarter was found to be radiolabeled IPA. This finding is consistent with the notion proposed above that following the high oral dose ADH activity may have been saturated. This would be expected to lead to the delay in peak blood levels of acetone that were observed. This would also be expected to result in increased excretion of the unchanged parent compound since it remained in the blood relatively longer due to delayed metabolic transformation.

During the 24 h following the high oral dose a slightly greater fraction of the dose was excreted in the urine than occurred following the low oral dose. In this case the distribution of the radiolabel present changed slightly in that approximately 19% of the radiolabel was accounted for by acetone, with approximately 15% accounted for by. IPA. The same unknown metabolite, found to be common to all doses and routes accounted for about 65% of the radiolabel present in the urine or just over 5% of the total dose.

The distribution of metabolites trapped as volatile compounds from the exhaled breath was changed by repeated administration of IPA. Acetone, accounted for all of the radiolabel that was found in the exhaled breath as volatile organics. This observation is interesting due to the fact that overall exhalation of radiolabeled volatile organics did not change from that observed following a single oral dose of 300 mg IPA/kg bw.

Excretion of radiolabel in the urine accounted for approximately 5% of the administered dose on the average. During the first 24 h acetone comprised about 17% of this, on the average. As was the case following the single low dose males excreted a small amount of radiolabeled IPA in the urine whereas females did not excrete a detectable amount.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
No bioaccumulation potential based on study results for Propan-2-ol (Isopropyl alcohol).
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of IPETC/ O-isopropyl ethylthiocarbamate Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of IPETC/O-isopropyl ethylthiocarbamate .

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of IPETC/ O-isopropyl ethylthiocarbamate. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of IPETC/ O-isopropyl ethylthiocarbamate.

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[2-14C]isopropanol

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, NC)
- Age at study initiation: 7 to 9 weeks old
- Weight at study initiation: 98 to 225 g
500 ppm group: mean bw at the time of dosing = 122 g (females) and 163 g (males)
5000 ppm group: mean bw at the time of dosing = 125 g (females) and 188 g (males)
- Fasting period before study: not reported
- Housing: Housed in specially designed, polycarbonate restrainers
- Individual metabolism cages: Animals were housed in restrainers.
- Diet (e.g. ad libitum): Certified Purina Rodent Chow (5002), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: Rats were quarantined in polycarbonate cages for at least 7 days prior to initiation of each study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C (72 ± 3°F)
- Humidity (%): 50 ± 20%
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

Single exposure for 6 hours

Remarks:

Doses / Concentrations:
500 (low dose) and 5000 ppm (high dose) (actual concentrations were averaged to be 476 and 4960 ppm, respectively)

No. of animals per sex per dose / concentration:

4 animals/sex/group

Control animals:

no

Positive control reference chemical:

None.

Details on study design:

- Dose selection rationale: A dose-range finding study was performed prior to the initiation of the study (see preliminary studies section below).

Details on dosing and sampling:

PHARMACOKINETIC STUDY (absorption, distribution, and excretion)
- Tissues and body fluids sampled: urine, feces, blood, breath, and tissues
- Time and frequency of sampling: Urine and feces were collected at 8, 24, 48, and 72 hours following exposure. Timed blood samples were collected at intervals during and after exposure. Following final excreta collection, selected tissues were obtained and analyzed for total radioactivity.

Statistics:

Statistical analysis was not performed.

Preliminary studies:

A dose-range finding study was performed prior to the initiation of the study. After exposure to 3100 ppm, the animals exhibited some loss of balance, but did not show any body weight depression or loss of appetite. After exposure to 770 and 230 ppm essentially no dose-related symptoms were observed. It was suggested that a high dose for the definitive studies be chosen near 6700 ppm, no lower than 3100 ppm, and a low dose be chosen in the 230 ppm to 770 ppm range.

Details on absorption:

The concentration of radiolabel in the blood increased rapidly following the initiation of inhalation exposure at either concentration. The concentration of radiolabel appeared to still be rising at the end of the exposure to 500 ppm but appeared to have plateaued by the end of the exposure to 5000 ppm IPA. The peak levels attained by the end of the exposure to 5000 ppm were almost exactly 10 times the levels attained following inhalation of 500 ppm. This indicates that absorption is not dose dependent in this range of concentrations. Radiolabel was found to disappear rapidly from the blood following cessation of inhalation exposure. Parent IPA appeared in the blood quickly following the start of exposure to either of the concentrations of IPA vapor studied. Parent IPA concentration in the blood was found to decrease very fast following cessation of the 500 ppm exposure. IPA concentration in the blood dropped more slowly following the end of exposure to 5000 ppm IPA than following the 500 ppm exposure.

Details on distribution in tissues:

In general, IPA and its radiolabeled metabolites were widely distributed among the tissues following nose only inhalation exposure to nominal concentrations of 500 and 5000 ppm. Tissue to blood ratio (TBR) values observed in the tissues of male and female rats following exposure to 500 ppm indicate that even though tissue distribution was broad, clearance from the tissue compartment was uniform and nearly complete. No evidence was observed to indicate that IPA or its radiolabeled metabolites accumulated in any tissue with the possible exception of adipose tissue, kidney, liver, and ovarian tissue, which had moderately elevated TBR values. Following inhalation of 5000 ppm, elevated TBR values in adipose.tissue, liver kidney and ovary were observed. Approximately 5% of the absorbed dose was found in the residual carcass 72 h following the low Inhalation whereas less than 1.5% was found in the carcass of animals that had been exposed to 5000 ppm 168 h following the start of inhalation exposure.

Details on excretion:

Following nose only inhalation of IPA at the wide range of concentrations studied the breath is, by far, the predominant route of excretion of radiolabel by both sexes. The excretion of the absorbed dose was rapid, with greater than 90% of the absorbed radiolabel being excreted from the breath, urine, and feces within 72 h of the beginning of the inhalation exposure. Exhalation in the breath accounted for a total of about 83% of the absorbed dose at the low exposure level while it accounted for just under 88% following the high exposure level. Even though total excretion of radiolabel in the breath was practically the same following either inhalation exposure, the distribution of radiolabel that appeared in the breath was dramatically different. Following exposure to 500 ppm males and females exhaled an average of 49% of the absorbed radiolabel as carbon dioxide in the breath. Following exposure to 5000 ppm, only 22% of the radiolabel present in the exhaled breath was found to be 14CO2. While the exhaled breath was the major route of excretion following both exposure levels, urine was a minor route of elimination of radiolabel and excretion in the feces was negligible.

In general no significant differences were observed between male and female animals within the same study in the rates and routes of elimination of radiolabel absorbed during inhalation exposure. On a relative basis the radiolabel absorbed during the low exposure was excreted somewhat more slowly than occurred following the high exposure.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 0.8 hrs (males) and 0.9 hrs (females) (blood; dose of 500 ppm)

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 2.1 hrs (males) and 1.8 hrs (females) (blood; dose of 5000 ppm)

Test no.:

#1

Toxicokinetic parameters:

Cmax: 116 μg-eq/g (males) and 125 μg/g (females) at 6 hrs (blood; dose of 500 ppm)

Test no.:

#1

Toxicokinetic parameters:

Cmax: 1258 μg-eq/g (males) and 1449 μg/g (females) at 6 hrs (blood; dose of 5000 ppm)

Metabolites identified:

yes

Details on metabolites:

Following exposure to 500 ppm IPA nearly all of the radiolabel present as volatile compounds in the exhaled breath was accounted for by acetone. This was not the case following exposure to 5000 ppm IPA where an average of approximately 80% of the radiolabeled volatile compounds in the breath was identified as acetone with the balance being accounted for by IPA. A third radiolabeled metabolite (accounting for less than 5% of the total dose) was found when the urine was analyzed by HPLC; this urinary metabolite was identified as isopropyl glucuronic acid.

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
No bioaccumulation potential based on study results for Propan-2-ol (Isopropyl alcohol).
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of IPETC/ O-isopropyl ethylthiocarbamate . Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of IPETC/ O-isopropyl ethylthiocarbamate .

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Justification for type of information:

Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of IPETC/ O-isopropyl ethylthiocarbamate. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of IPETC/O-isopropyl ethylthiocarbamate .

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[2-14C]isopropanol

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, NC)
- Age at study initiation: 7 to 9 weeks old
- Weight at study initiation: 98 to 225 g
- Fasting period before study: not reported
- Housing: Housed in specially designed, polycarbonate restrainers
- Individual metabolism cages: Animals were housed in restrainers.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C (72 ± 3°F)
- Humidity (%): 50 ± 20%
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

intravenous

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

Single bolus injection

Remarks:

Doses / Concentrations:
300 ppm (actual concentration for the excretion and tissue distribution study was averaged to be 307 mg/kg bw for both males and females; actual concentration for the pharmacokinetic study was averaged to be 306 and 318 mg/kg bw for males and females, respectively).

No. of animals per sex per dose / concentration:

4 animals/sex

Control animals:

no

Statistics:

Statistical analysis was not performed.

Details on absorption:

Results from the pharmacokinetic study:
The concentration of radioactivity in blood was highest in the first blood sample drawn. This was expected since the dose was delivered as a bolus into the central circulatory compartment. The concentration of radiolabel in blood declined rapidly dropping more than 10-fold in 18 h. The time-courses of elimination of radiolabel from the blood of male rats and female rats were very similar, lacking any indication of sex-dependent elimination of radiolabel from the central compartment. IPA itself disappeared from the blood much more rapidly than did total radioactivity. IPA concentration in the blood decreased 10-fold in the 6 h following the intravenous (IV) bolus. This very rapid disappearance results from a combination of direct exhalation of IPA and metabolism of IPA to acetone. The concentration of acetone is seen to increase following the iv bolus, peaking 2 to 4 h following the dose. The temporal relationship of the fall of IPA concentration to the rise and fall of acetone concentration is typical of a precursor-product relationship.

Details on distribution in tissues:

Results from the excretion and tissue distribution study:
Only a small fraction of the original dose remained in the tissues of animals 168 h following IV bolus administration of 300 mg/kg bw IPA. Of significance was the observation that relative to the blood, IPA or its radiolabeled metabolites remained most concentrated in the adipose tissue. This is not particularly surprising in view of the nature of the compounds involved, that is, acetone and IPA. Even though they are water soluble these compounds, especially acetone, are good solvents with reasonably good lipid solubility. The lipid tissue represents a depot that IPA or acetone could partition into passively. Since the dose was administered intravenously the very large concentration gradient that existed immediately following the dose would facilitate the partitioning of these compounds into lipid tissue by simple mass action.
Also radiolabel was found to be elevated in the ovarian tissue of the female animals. Care was taken during the necropsy procedure to remove adherent adipose tissue so that this observation is almost certainly due to residual radiolabel being present in the ovarian tissue. No observations of adverse tissue conditions were made at the time of sacrifice or during the necropsy procedure.

Details on excretion:

Results from the excretion and tissue distribution study:
After IV administration of radiolabeled IPA the major route of elimination of radiolabel is the expired breath both for male rats and for female rats. There was essentially no difference in the exhalation of radiolabel as volatile organics between male rats and female rats during the 72 h period following IV dosing. Both sexes exhaled 55% of the dose during that period. The exhalation of significant quantities of radiolabel was expected since (1) the dose was delivered directly into the central circulatory compartment and (2) the volatility of IPA is such that excretion via the lung would begin almost instantaneously. In addition, the primary metabolite of IPA is acetone, a highly volatile organic that would very readily equilibrate into the alveolar air space from the blood. Excretion of radiolabel as CO2 in the exhaled breath was also a significant, if quantitatively smaller, route of excretion of radiolabel following IV dosing. Male and female rats excreted essentially the same amount of radiolabeled CO2 during the course of the experiment. The fact that radiolabeled CO2 is observed indicates that repetitive oxidative steps are occurring since the radiolabel is on the secondary carbon of IPA. Urine was a relatively minor route for the elimination of the dose. On average males and females excreted less than 5% of the administered radiolabel in the urine.

Overall excretion was very rapid, with nearly 90% of the dose being eliminated during the 24 h period following dosing. During the ensuing six days only miniscule fractions of the original dose were recovered on a daily basis.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 1.2 h (males) (blood) and 1.3 hr (females) (blood); pharmacokinetic study

Test no.:

#1

Toxicokinetic parameters:

Cmax: 364 μg-eq/g (males) at 15 min (blood) and 329 μg/eq/g (females) at 30 min (blood); pharmacokinetic study

Metabolites identified:

yes

Details on metabolites:

Results from the excretion and tissue distribution study:
Approximately 80% of the radiolabel recovered as radioactive volatile compounds in the breath from both male and female rats during the 24 h period following dosing was accounted for by exhaled acetone.

Since elimination of radiolabel in the breath as volatile organic compounds accounted for an average of 55% of the dose, this observation means that approximately 44% of the dose was eliminated in the exhaled breath as acetone. In the same way, an average of 17.5% of the dose was trapped and identified as IPA after it was exhaled in the breath. These observations are consistent with the conclusion that the bulk (>50%) of the intravenously administered dose of IPA is rapidly converted to acetone, most of which is exhaled in the expired breath.

Three radiolabeled compounds were found to be present in the urine collected during the 24 h interval following dosing. These compounds were acetone, which accounted for about 16% of the radiolabel present, IPA which accounted for less than 10%, and an unidentified compound which accounted for more than 75% of the radiolabel present in the urine.

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
No bioaccumulation potential based on study results for Propan-2-ol (Isopropyl alcohol).
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of IPETC/O-isopropyl ethylthiocarbamate. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of IPETC/ O-isopropyl ethylthiocarbamate .

Reference 5

Endpoint:

basic toxicokinetics in vivo

Data waiving:

other justification

Justification for data waiving:

other:

Reference 6

Endpoint:

dermal absorption, other

Remarks:

QSAR method for chemicals properties assessment.

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: US EPA accepted QSAR method for chemicals properties assessment.

Qualifier:

no guideline required

Principles of method if other than guideline:

Using the DERMWIN v2.01 QSAR model

GLP compliance:

no

Remarks:

not applicable to QSAR models

Radiolabelling:

no

Species:

other: QSAR model,

Strain:

other: QSAR model,

Sex:

not specified

Type of coverage:

other: QSAR model

Vehicle:

other: QSAR model

Duration of exposure:

not applicable to QSAR models

Doses:

not applicable to QSAR models

No. of animals per group:

not applicable to QSAR models

Control animals:

no

Details on study design:

not applicable to QSAR models

Details on in vitro test system (if applicable):

not applicable to QSAR models

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

A QSAR model predicts that the permeability of IPETC to human skin is quite low. The permeability coefficient was determined to be 7.62e-003 mg/cm2, which is around 1% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)=0.0375 cm/hr

A QSAR model predicts that the permeability of IPETC to human skin is quite low. The permeability coefficient was determined to be 7.62e-003 mg/cm2, which is around 1% of the skin penetration rate.

Predicted dermally absorbed coefficient was determined to be Kp (est)=0.0375 cm/hr

Conclusions:

A QSAR model predicts that the permeability of IPETC to human skin is quite low. The permeability coefficient was determined to be 7.62e-003 mg/cm2, which is around 1% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)=0.0375 cm/hr

Executive summary:

A QSAR model predicts that the permeability of IPETC to human skin is quite low. The permeability coefficient was determined to be 7.62e-003 mg/cm2, which is around 1% of the skin penetration rate.

Predicted dermally absorbed coefficient was determined to be Kp (est)=0.0375 cm/hr

Reference 7

Endpoint:

dermal absorption in vivo

Type of information:

other: published data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Dithiocarbamates are related compounds to Thionocarbamate.

Qualifier:

according to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Deviations:

yes

Remarks:

Recovery was not in the required range. Volatile 14C-compounds were not collected.

GLP compliance:

yes

Radiolabelling:

yes

Remarks:

(14C)-Ziram

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

- Source: Charles River Laboratories, Wilmington, Massachusetts, US
- Weight: 237-267 g (Individual data of control group not reported)

Type of coverage:

open

Vehicle:

water

Duration of exposure:

0.5, 1, 2, 4, 10 and 24 h

Doses:

1.2, 9.9, 57.1% (w/v)

No. of animals per group:

4 per timepoint

Control animals:

yes

Signs and symptoms of toxicity:

no effects

Dermal irritation:

not examined

Absorption in different matrices:

see Table 6_2-1

Total recovery:

see Table 6_2-1

Dose:

0.086 mg/cm²

Parameter:

percentage

Absorption:

28.5 %

Remarks on result:

other: 24 h

Dose:

0.95 mg/cm²

Parameter:

percentage

Absorption:

30.7 %

Remarks on result:

other: 24 h

Dose:

7.25 mg/cm²

Parameter:

percentage

Absorption:

4.89 %

Remarks on result:

other: 24 h

Table A6_2-1:     Mean recovery of radioactivity from male rats following a single dermal application of (^14C)-ziram
Parameter /Tissue	1.07 mg/rat						11.9 mg/rat						90.6 mg/rat
	[%] of administered dose
	0.5 h	1 h	2 h	4 h	10 h	24 h	0.5 h	1 h	2 h	4 h	10 h	24 h	0.5 h	1 h	2 h	4 h	10 h	24 h
Skin rinse	75.22	85.35	78.90	74.64	70.07	70.53	72.39	69.03	67.03	60.71	72.33	68.79	101.96	99.79	99.73	97.20	100.26	93.49
Skin cell cover	0.06	0.08	0.12	0.12	0.26	0.60	0.02	0.04	0.05	0.06	0.14	0.16	0.04	0.06	0.18	0.26	0.15	0.35
Skin enclosure	0.10	0.14	0.33	0.20	0.07	0.35	0.42	0.17	0.31	0.17	0.09	0.43	1.02	1.44	1.02	0.22	1.03	1.26
Total nonabsorbed dose	75.38	85.57	79.35	74.96	70.40	71.48	72.83	69.24	67.39	60.94	72.56	69.38	103.02	101.29	100.93	97.68	101.44	95.10
Urine	ND	ND	0.01^a	0.02	0.06^a	0.16	ND	ND	0.01	0.01	0.02	0.05	ND	ND	ND	0.01	0.01	0.01
Faeces	ND	ND/NS	ND	ND/NS	ND	0.01	ND/NS	ND/NS	ND/NS	ND/NS	ND/NS	0.01^a	ND/NS	0.01^c	ND/NS	ND/NS	ND/NS	ND
Cage wash	ND	ND	ND	ND	ND	0.02^b	ND	ND	0.01^c	ND	ND	ND	ND	ND	ND	ND	ND	ND
Cage wipe	ND	ND	0.01^a	0.01	0.01	0.01	ND	0.01^c	0.01^c	0.01^b	0.01	0.01	0.01^c	0.01^b	ND	0.01^b	ND	0.01^b
Total excreted	ND	ND	0.01	0.02	0.06	0.18	ND	0.01	0.01	0.01	0.02	0.05	0.01	0.01	ND	0.01	0.01	0.01
Carcass	ND	ND	ND	ND	0.08	0.14	ND	ND	0.01	ND	ND	0.03	ND	ND	ND	ND	ND	ND
Skin	5.63	3.18	4.57	5.05	7.88	3.79	3.04	3.48	5.67	9.93	8.86	4.46	0.56	0.93	1.11	1.48	1.44	1.52
Total absorbed dose	5.63	3.18	4.57	5.07	8.02	4.11	3.04	3.48	5.68	9.93	8.88	4.54	0.56	0.93	1.11	1.48	1.44	1.52
Total recovery	81.01	88.75	83.92	80.03	78.42	75.59	75.87	72.72	73.07	70.87	81.44	73.92	103.58	102.22	102.04	99.16	102.88	96.62
NS    Not sampled ND   Not detectable ^a      Mean of three animals ^b      Mean of two animals ^c      Mean of one animal

 

Table A6_2-2:     Concentations of radioactivity in blood from male rats following a single dermal application of (^14C)-ziram
Dose level	µg ziram/g
	0.5 h	1 h	2 h	4 h	10 h	24 h
1.07 mg	0.002	ND	ND	ND	0.002	0.006 .006
11.9 mg	ND	ND	ND	ND	ND	ND
90.6 mg	ND	ND	ND	ND	ND	ND
ND    Not detectable

 

Conclusions:

Dithiocarbamates are related compounds to Thionocarbamate.
Less than 0.3% of the administered radiolabel was retained in the carcass and was eliminated in the excreta within 24 h after exposure.
The mean amount absorbed (sum of radiolabel in urine, carcass, and skin at the test site) by 24 h was 29% of the administered dose in animals at 1.1 mg, 31% in those at 12 mg, and 5% for those at 91 mg, indicating non-linear dermal absorption.

Executive summary:

Less than 0.3% of the administered radiolabel was retained in the carcass and was eliminated in the excreta within 24 h after exposure. The mean amount absorbed (sum of radiolabel in urine, carcass, and skin at the test site) by 24 h was 29% of the administered dose in animals at 1.1 mg, 31% in those at 12 mg, and 5% for those at 91 mg, indicating non-linear dermal absorption.

Description of key information

IPETC/O-isopropyl ethylthiocarbamate has not bioaccumulation potential.
The chemical belongs to the thiocarbamate group. In general, thiocarbamates are absorbed via the skin, mucous membranes, respiratory and gastrointestinal tracts, with rapid elimination via expired air and urine. Thiocarbamates are also rapidly metabolised, producing either mercapturic acid compounds or compounds that enter the carbon metabolic pool.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

1

Additional information

IPETC/ O-isopropyl ethylthiocarbamate has not bioaccumulation potential.

The chemical belongs to the thiocarbamate group. In general, thiocarbamates are absorbed via the skin, mucous membranes, respiratory and gastrointestinal tracts, with rapid elimination via expired air and urine. Thiocarbamates are also rapidly metabolised, producing either mercapturic acid compounds or compounds that enter the carbon metabolic pool.

 

As a general rule, thiocarbamates can be absorbed by theorganism via the skin, mucous membranes, and the respiratory andgastrointestinal tracts.  They are eliminated quite rapidly,mainly via expired air and urine.

 

Two  major  pathways  exist  for  the  metabolism  ofthiocarbamates in mammals.  One is via sulfoxidation  andconjugation with glutathione. The conjugation product is thencleaved to a cysteine derivative, which is metabolized to amercapturic acidcompound. The second route is oxidation of thesulfur to a sulfoxide, which is then oxidized to a sulfone, orhydroxylation to compounds that enter the carbon metabolic pool.

 

In plants, thiocarbamates are rapidly metabolized in typicaloxidation reactions, e.g., thiol sulfur oxidation to the corres-ponding sulfoxides, reactive intermediates that are capable of reacting with sulfhydryl groups (as in glutathione, cysteine)to form conjugates. Onhydrolysis, mercaptans, carbon dioxide,and alkylamines may be formed.

 

While thiocarbamates and their metabolic products can befound in certain organs, such as liver and kidneys, accumulationdoes not take place because of their rapid metabolism.

 

Therefore testing for Basic toxicokinetics does not need to be performed.

References

World Health Orgnization Geneva, 1988,THIOCARBAMATE PESTICIDES - A GENERAL INTRODUCTION