Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Remarks:
citation in the IPCS "Concise International Chemical Assessment Document" 49
Objective of study:
absorption
Qualifier:
no guideline available
Principles of method if other than guideline:
oral application of Thiourea with subsequent analysis of Thiourea content in urine and feces
GLP compliance:
no
Radiolabelling:
yes
Species:
other: human, rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: unspecified
Vehicle:
not specified
Duration and frequency of treatment / exposure:
single exposure
Remarks:
Doses / Concentrations:
a single oral dose of 28,57 mg Thiourea/kg bw (human)
5 mg administered intravenously (rat)
No. of animals per sex per dose / concentration:
no data
Details on excretion:
A singel oral dose of 28,57 mg thiourea/kg bw in humans was completely eliminated within 48h in urine; a peak concentration was measured within 30 min.
In rats administered 5 mg intravenously, 30% of thiourea was recovered from the carcasses after 3h, and only traces after 25h.
No thiourea was excreted in the stools
Conclusions:
Interpretation of results: no bioaccumulation potential based on study results
Thiourea is rapidly absorbed form the GI tract and completely eliminated in the urine.
Executive summary:

A singel oral dose of 28,57 mg thiourea/kg bw in humans was completely eliminated within 48h in urine; a peak concentration was measured within 30 min. In rats administered 5 mg intravenously, 30% of thiourea was recovered from the carcasses after 3h, and only traces after 25h. No thiourea was excreted in the stools.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Remarks:
citated in the IPCS "Concise International Chemical Assessment Document" 49
Objective of study:
toxicokinetics
Qualifier:
no guideline available
Principles of method if other than guideline:
Intraperitoneal application of 100 mg/kg Thiourea with subsequent determination of half-time in plasma.
GLP compliance:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
intraperitoneal
Vehicle:
not specified
Duration and frequency of treatment / exposure:
single i.p. application
Remarks:
Doses / Concentrations:
100 mg/kg
Key result
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 3,3h
Conclusions:
After intraperitoneal injection of 100 mg/kg Thiourea in rats the half-time in plasma was 3,3 h.
Executive summary:

Rats were given Thiourea (100 mg/kg bw) intraperitoneally, the half-time in plasma was calculated to be 3,3 h.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Remarks:
cited in IARC monography volume 79 (2001)
Objective of study:
distribution
Qualifier:
no guideline available
Principles of method if other than guideline:
Intraperitoneal injection of 14C-Thiourea in male rats; subsequent determination of radioactivity in homogenized organs
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14C
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Route of administration:
intraperitoneal
Vehicle:
not specified
Duration and frequency of treatment / exposure:
single i.p. injection
Remarks:
Doses / Concentrations:
no data
No. of animals per sex per dose / concentration:
no data
Details on study design:
Radioactivity was measured in the supernatant fraction of lung, liver and kidney
Type:
distribution
Results:
distributed to tested organs (liver, kidney, lung)
Details on distribution in tissues:
Radioactivity from 14C thiourea has been shown to bind selectively to liver, kidney, and lung in elevated radioactivity half-lives in these tissues compared to that of plasma. Binding of 14C to tissue protein parallels tissue retention of radioactivity.

After intraperitoneal administration of 14C-labelled thiourea the radioactivity was located preferentially in the lungs, less in the kidneys and less still in the liver. In the lung most of the radioactivity was bound to a low molecular weight protein in the 100000 × g supernatant.

Conclusions:
low bioaccumulation potential based on study results
When intaperitoneal injected in male SD rats, C14-thiourea binds to liver, kidney and lung proteins with elevated radioactivity half-lives in these tissues compared to that of plasma.
Executive summary:

14C-Thiourea was injected intraperitoneally in male rats with a subsequent determination of radioactivity in homogenized organs (liver, kidney, lung). Radioactivity from 14C-thiourea has been shown to bind selectively to liver, kidney, and lung in elevated radioactivity half-lives in these tissues compared to that of plasma. Binding of 14C to tissue protein parallels tissue retention of radioactivity. The highest proportion of radioactivity both in terms of absolute counts and disintegration per min per 100ug protein was observed in lung tissue.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Remarks:
citated in the IPCS "Concise International Chemical Assessment Document" 49
Objective of study:
distribution
Qualifier:
no guideline available
Principles of method if other than guideline:
Intravenous injection of radiolabeled C14-Thiourea in pregnant mice with subsequent analysis of the distribution pattern by whole-body autoradiography at 5, 20, 60, 240 min and 1 and 4 days.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
C14
Species:
mouse
Strain:
not specified
Sex:
female
Route of administration:
intravenous
Vehicle:
not specified
Duration and frequency of treatment / exposure:
single application
Remarks:
Doses / Concentrations:
no data
No. of animals per sex per dose / concentration:
no data
Control animals:
not specified
Type:
distribution
Results:
radioactivity began to accumulate in the thyroid gland of mother and fetuses after 5 min
Details on distribution in tissues:
Radioactivity began to accumulate in the thyroid gland of mother and fetuses after 5 min and remained higher in in this tissue than in any other organ durign the enitre 4-day observation period. Increased levels of radioactivity were also found in the walls of the large blood vessel, the cortex of the adrenal glands, the mammary glands, liver, lungs, and kidneys.
Key result
Test no.:
#1
Transfer type:
blood/placenta barrier
Observation:
distinct transfer
Remarks:
In fetuses a very high uptake of radioactivity was found in the thyroid while the concentration in the other fetal tissues as well as the placenta did not exceed that of the blood of mother.
Conclusions:
Interpretation of results: bioaccumulation potential cannot be judged based on study results
Thiourea rapidly accumulates in the thyroid gland of mother and fetuses
Executive summary:

Intravenous injection of radio labeled C14-thiourea in pregnant mice with subsequent analysis of the distribution pattern by whole-body autoradiography at 5, 20, 60, 240 min and 1 and 4 days. Radioactivity began to accumulate in the thyroid gland of mother and fetusses after 5 min and remained higher in in this tissue than in any other organ during the enitre 4-day observation period. Increased levels of radioactivity were also found in the walls of the large blood vessel, the cortex of the adrenal glands, the mammary glands, liver, lungs, and kidneys.

In foetuses a very high uptake of radioactivity was found in the thyroid while the concentration in the other foetal tissues as well as the placenta did not exceed that of the blood of mother.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Objective of study:
metabolism
Qualifier:
no guideline followed
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
no data
Route of administration:
other: no data
Vehicle:
not specified
Details on exposure:
no data
Duration and frequency of treatment / exposure:
no data
Remarks:
Doses / Concentrations:
no data
No. of animals per sex per dose / concentration:
no data
Control animals:
not specified
Positive control reference chemical:
no data
Details on study design:
no data
Details on dosing and sampling:
no data
Statistics:
no data
Preliminary studies:
no data
Details on absorption:
no data
Details on distribution in tissues:
no data
Details on excretion:
no data
Metabolites identified:
not specified
Details on metabolites:
no data
Bioaccessibility (or Bioavailability) testing results:
no data

It was shown in vitro and in vivo that both cyanamide and thiourea are inhibitors of thyroid peroxidase. Doses of thiourea which completely inhibit in vivo protein-bound iodine formation have no irreversible effect on thyroid peroxidase, as measured by guaiacol peroxidation after removal of the thyroids. The data suggest that the primary in vivo and in vitro mode of action of thiourea is the reversible Ioxid-trapping mechanism. The anomalous inhibition of guaiacol peroxidation seen in the presence of thiourea plus iodide derives from the formation of formamide disulfide, followed by its nonenzymic decomposition to cyanamide.

Conclusions:
Results of in vitro and in vivo studies showed that thiourea is an inhibitor of thyroid peroxidase.
Executive summary:

The result of the study suggest that the primary in vivo and in vitro mode of action of thiourea is the reversible Ioxid-trapping mechanism. The anomalous inhibition of guaiacol peroxidation seen in the presence of thiourea plus iodide derives from the formation of formamide disulfide, followed by its nonenzymic decomposition to cyanamide.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Objective of study:
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
Thiourea, phenylthiourea, and methimazole were perfused into rat liver.
GLP compliance:
not specified
Radiolabelling:
not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
no data
Route of administration:
other: perfusion
Vehicle:
not specified
Details on exposure:
no data
Duration and frequency of treatment / exposure:
no data
Remarks:
Doses / Concentrations:
no data
No. of animals per sex per dose / concentration:
no data
Control animals:
not specified
Positive control reference chemical:
no data
Details on study design:
no data
Details on dosing and sampling:
no data
Statistics:
no data
Preliminary studies:
no data
Details on absorption:
no data
Details on distribution in tissues:
no data
Details on excretion:
Rapid cellular oxidation of GSH leads to biliary efflux of the disulfide.
Metabolites identified:
not specified
Details on metabolites:
no data
Bioaccessibility (or Bioavailability) testing results:
no data

Thiourea, phenylthiourea, and methimazole perfused into rat liver stimulated the biliary efflux of GSSG without affecting the excretion of GSH into either the bile or the caval perfusate. The thiocarbamide moiety appears essential, since perfusion with urea, phenylurea, or N-methylimidazole did not stimulate GSSG release. Hydrogen peroxide is also not an obligatory intermediate, since thiocarbamide-induced GSSG efflux was undiminished in livers from selenium-deficient animals. The response was also not affected by N-benzylimidazole, a potent cytochrome P-450 inhibitor, which suggests that this monooxygenase is not involved. However, the results are consistent with a model based on S-oxygenation of thiocarbamides to formamadine sulfenates catalyzed exclusively by the flavin-containing monooxygenase. The resulting sulfenate is reduced by GSH, yielding GSSG and the parent thiocarbamide. Rapid cellular oxidation of GSH by this mechanism leads to biliary efflux of the disulfide.

Conclusions:
Interpretation of results: bioaccumulation potential cannot be judged based on study results
Thiourea can form S-oxygenated products such as the reactive electrophiles formamidine sulfenic acid and formamidine sulfinic acid.
Executive summary:

Thiourea, phenylthiourea, and methimazole were perfused into rat liver and stimulated the biliary efflux of GSSG without affecting the excretion of GSH into either the bile or the caval perfusate.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Objective of study:
metabolism
Qualifier:
no guideline followed
GLP compliance:
not specified
Metabolites identified:
yes
Details on metabolites:
Thiourea reacts directly with hydrogen peroxide, forming formamidine sulfinic acid, NH2(NH)CSO2H, at neutral pH. Reaction of thiourea with iodine yields formamidine disulfide, NH2(NH)CSSC(NH)NH2.

Thiourea reacts directly with hydrogen peroxide, forming formamidine sulfinic acid, NH2(NH)CSO2H, at neutral pH. Reaction of thiourea with iodine yields formamidine disulfide, NH2(NH)CSSC(NH)NH2. The mechanisms of action may be summarized as follows: in addition to reductive activation which leads to breaking of disulfide bonds in protein, oxidation in the presence of iodine or with the fiavoprotein-dependent aminoxidase is of importance. Thus at least three mechanisms which depend on metabolism may contribute to toxicity:


- denaturation of functionally important proteins by breaking of disulfide bonds, forming thiosulfenic acids,


- membrane damage as a result of reduction in the GSH level in the lung, and


- metabolism to toxic sulfinic and sulfonic acids.

Conclusions:
at least three mechanisms which depend on metabolism may contribute to toxicity:
- denaturation of functionally important proteins by breaking of disulfide bonds, forming thiosulfenic acids,
- membrane damage as a result of reduction in the GSH level in the lung, and
- metabolism to toxic sulfinic and sulfonic acids.
Executive summary:

at least three mechanisms which depend on metabolism may contribute to toxicity:

- denaturation of functionally important proteins by breaking of disulfide bonds, forming thiosulfenic acids,

- membrane damage as a result of reduction in the GSH level in the lung, and

- metabolism to toxic sulfinic and sulfonic acids.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Objective of study:
metabolism
Qualifier:
no guideline followed
Metabolites identified:
yes
Details on metabolites:
Thiourea is oxidized by the thyroid gland peroxidase forming cyanamide and elementary sulfur.

In the presence of iodine or iodide and hydrogen peroxide, thiourea is oxidized by the thyroid gland peroxidase to formamidine disulfide, NH2(NH)CSSC(NH)NH2. Presumably, a thio-iodine complex is formed as an unstable intermediate [Davidson 1979]. Formamidine disulfide is also unstable: at pH values above 3.0 it decomposes forming cyanamide, elementary sulfur and thiourea. In vitro, cyanamide inhibits the peroxidation of iodide and the iodination of tyrosine. This explains the thyroid depressant action of thiourea. Autoradiographic studies of the distribution of 35S-labelled thiourea revealed a highly preferential and prolonged storage of the radioactivity in the thyroid gland [Schulman 1950]. Together with the main product, sulfate, protein-bound sulfur was detected [Maloof 1957].

Conclusions:
Thiourea is oxidized by the thyroid gland peroxidase forming cyanamide and elementary sulfur. In vitro, cyanamide inhibits the peroxidation of iodide and the iodination of tyrosine. This explains the thyroid depressant action of thiourea.
Executive summary:

Thiourea is oxidized by the thyroid gland peroxidase forming cyanamide and elementary sulfur. In vitro, cyanamide inhibits the peroxidation of iodide and the iodination of tyrosine. This explains the thyroid depressant action of thiourea.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Objective of study:
distribution
Qualifier:
no guideline available
Principles of method if other than guideline:
Measurement of the radioactivity in fluids and tissues, paper chromatographic analysis of the chemical state of the S35, and histologic localization of the S35 by radioautography.
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
S35
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
other: no data
Type:
distribution
Results:
Rapid passage of thiourea from the mother to the fetus occurred. The fetal serum concentration was lower than that of the maternal serum.

The metabolism of thiourea S35 by the developing fetal rat was studied by measurement of the radioactivity in fluids and tissues, paper chromatographic analysis of the chemical state of the S35, and histologic localization of the S35 by radioautography. Rapid passage of the thiourea from the mother to the fetus occurred. In older embryos, at 12 and 24 hr after the administration of thiourea the amniotic fluid concentration was higher than that in the maternal serum. The fetal serum concentration was lower than that of the maternal serum. The fetal thyroid to fetal serum concentration ratio began increasing on the 17th day, and by the 20th day it was 9.3 as compared with 24 for the mother. The time of appearance of the concentrating ability for thiourea S35 coincides with that for I131. The S35 was predominantly present as thiourea in the serum, amniotic fluid and urine, but some protein-bound material was also found in liver tissues, serum and amniotic fluid. Both fetal and maternal thyroid tissue had increased amounts of S3S as either sulfate or thiosulfate. The radioautographs showed concentration of grains over thyroid cells and colloid at 3 hr, but after 12 and 24 hr most of the activity was over the colloid. Some concentration of S36 was observed in fetal tracheal cartilage and in the tubules of the maternal kidney

Conclusions:
Rapid passage of thiourea from the mother to the fetus occurred. The fetal serum concentration was lower than that of the maternal serum.
Executive summary:

Rapid passage of thiourea from the mother to the fetus occurred. The fetal serum concentration was lower than that of the maternal serum.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Qualifier:
no guideline followed
Principles of method if other than guideline:
The mechanisms underlying enhanced cell proliferation in thyroid proliferative lesions of rats simultaneously treated with large amounts of vitamin A (VA) and thiourea (TU) were investigated.
GLP compliance:
not specified
Radiolabelling:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
no details are available
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
initial subcutaneous treatment of male Fischer 344 rats with NBHPA (N-bis(2-hydroxypropyl)nitrosamine ) at 2800 mg/kg bw;
administration of 0.2% Thiourea in the drinking-water for 10 weeks
Duration and frequency of treatment / exposure:
10 weeks; daily with drinking water
Remarks:
Doses / Concentrations:
0.2 %
No. of animals per sex per dose / concentration:
no data
Control animals:
yes, concurrent vehicle
Positive control reference chemical:
no data
Details on study design:
Male F344 animals were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection). Starting 1 week later, groups received water containing 0.2% TU (TU group), diet containing 0.1% vitamin A (VA group), both 0.2% TU and 0.1% vitamin A (TU + VA group) or tap water/basal diet without supplement (control group) for 10 weeks.
Details on dosing and sampling:
no data
Statistics:
no data
Details on absorption:
no
Details on distribution in tissues:
no
Details on excretion:
no
Metabolites identified:
not specified
Details on metabolites:
no
Bioaccessibility (or Bioavailability) testing results:
no

The serum levels of triiodothyronine (T3) and thyroxine (T4) were decreased and the thyroid stimulating hormone (TSH) levels were elevated in the TU and TU + VA groups, with the degree of change being significantly greater in the combined treatment group. The induction of P450 isoenzymes by TU was not enhanced by VA supplementation, but uridine diphosphate glucuronosyltransferase (UDP-GT) activity in the liver was significantly increased in the TU + VA group compared to the TU group. Thyroid weights were increased in both the TU and TU + VA groups, this being more pronounced with VA supplementation. Thyroid follicular cell hyperplasias and neoplasias were induced to similar extents in both TU treated groups, but their cell proliferation appeared to be increased by the VA supplementation.

Conclusions:
Thiourea inhibits the thyroid hormone synthesis.
Executive summary:

The results of the study suggest that enhanced cell proliferation is due to increased TSH stimulation, resulting from the decrease in serum T3/T4 levels brought about by induction of liver UDP-GT activity with the combined action of thiourea and vitamin A as well as inhibition of thyroid hormone synthesis in the thyroid by Thiourea.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Objective of study:
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
no details on method are available
GLP compliance:
not specified
Radiolabelling:
not specified
Species:
other: no data
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
no data
Route of administration:
other: no data
Vehicle:
not specified
Details on exposure:
no data
Duration and frequency of treatment / exposure:
no data
Remarks:
Doses / Concentrations:
no data
No. of animals per sex per dose / concentration:
no data
Control animals:
not specified
Positive control reference chemical:
no data
Details on study design:
no data
Details on dosing and sampling:
no data
Statistics:
no data
Preliminary studies:
no data
Details on absorption:
no data
Details on distribution in tissues:
no data
Details on excretion:
no data
Metabolites identified:
yes
Details on metabolites:
formamidine sulfenic acid and formamidine sulfinic acid

In liver microsomes, it has been shown that flavin-containing monooxygenase (FMO) catalyses the S-oxygenation of thiourea to the reactive electrophilic formamidine sulfenic acid and formamidine sulfinic acid.

Conclusions:
In liver microsomes, it has been shown that flavin-containing monooxygenase (FMO) catalyses the S-oxygenation of thiourea to the reactive electrophilic formamidine sulfenic acid and formamidine sulfinic acid.
Executive summary:

In liver microsomes, it has been shown that flavin-containing monooxygenase (FMO) catalyses the S-oxygenation of thiourea to the reactive electrophilic formamidine sulfenic acid and formamidine sulfinic acid.

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
November 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
reliabel with respect to excretion of thiourea in urine; not adequate to quantify dermal absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
The absorption of thiourea was estimated by determination of the amount of unchanged Thiourea excreted in the urine.
GLP compliance:
no
Radiolabelling:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 3.2 kg
- Fasting period before study: the night before treatment the animal had free access to tap water and standard laborytory diet. At the day of the experiment the rabbit was kept in the restraining box for the next 24 h under deprivation of water and feed.
- Housing: restraining box
- Individual metabolism cages: no
- Diet (e.g. ad libitum): see above
- Water (e.g. ad libitum): see above
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Type of coverage:
occlusive
Vehicle:
water
Duration of exposure:
24 h
Doses:
- Nominal doses: 25 % (w/v) solution of Thiourea corresponding to 2 g Thiourea/kg body weight
- Dose volume: 26 mL
No. of animals per group:
1
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: Thiourea was disolved in demineralized water in a concentration of 25 %(w/v)
- Method of storage: no data

APPLICATION OF DOSE: 26 ml of the 25 % (w/v) thiourea solution were injected through the polyethylene foil onto the cellulose sheet; the adminsitered volume corresponded to a dose of 2g thiourea/kg body weight

VEHICLE
- Amount(s) applied (volume or weight with unit): 26 mL
- Concentration (if solution): 25 % (w/v)
- Lot/batch no. (if required): no data
- Purity: demineralized water

TEST SITE
- Preparation of test site: Part of the trunk of the animal was freed from hair by the day before the start of the experiment using electric clippers
- Area of exposure: trunk of rabbit
- % coverage: 20 % of total body surface
- Type of cover / wrap if used: cellulose sheet and polyethylene foil
- Time intervals for shavings or clipplings: the hair was removed once, the day before application of the test substance

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: no

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: no
- Washing procedures and type of cleansing agent: no
- Time after start of exposure: no

SAMPLE COLLECTION
- Collection of blood: no
- Collection of urine and faeces: the bladder was emptied by means of a catheter
- Collection of expired air: no
- Terminal procedure: no
- Analysis of organs: no

SAMPLE PREPARATION
- Storage procedure: samples which could not be analysed within one hour were stored in a refigerator and analysed within 18 h after catheterization
- Preparation details: The urine samples were analysed either diluted (4 x with demineralized water) or undiluted.

ANALYSIS
- Method type(s) for identification: Technicon AutoAnalyzer technique of J.A. Gerfast (Anal.Biochem. 15 (1969)358); using Grote's reagent
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Key result
Dose:
2g/kg bw
Parameter:
percentage
Absorption:
3.76 %
Remarks on result:
other: 24 h
Remarks:
treatment with aqueous solution of thiourea; absorption extrapolated from 3,76 % excretion in urine
Conversion factor human vs. animal skin:
no data

Table 1: urinary excretion of dermally applied thiourea by a female rabbit






























































Period



Volume of catheterized urine



Amount of thiourea excreted per time interval



Amount in % of administered dose (6.5 g)



Rate of urinary excretion of unchanged thiourea



0-2 h



26 ml



1 mg



0.02 %



0.4 mg/h



2-4 h



 18 ml



10 mg



0.15 %



5 mg/h



4-6 h



9 ml



16 mg



0.25 %



8 mg/h



6-8 h



8 ml



27 mg



0.41 %



13 mg/h



8-14 h



50



95 mg



1.46 %



16 mg/h



14-24 h



96 ml



96 mg



1.48 %



10 mg/h



Total 0-24 h



207 ml



245 mg



3.77 %



 



 

Conclusions:
3,76 % of the dermally administered dose of Thiourea was excreted in the urine after 24h.
Executive summary:

In a study on percutaneous absorption of Thiourea one female rabbit (New Zealand White) was used. A 25% (w/v) solution Thiourea, corresponding to 2 g Thiourea/kg body weight was applied to the trunk of the rabbit. The urine was analysed regarding its Thiourea content. It was shown that 3.76 % of the dermally administered Thiourea was excreted unchanged in the urine within 24 h. This represents the minimum amount of urea percutanously absorbed by the rabbit.

There are no data on possible accumulation of Thiourea in the body. Furthermore the study was only conducted with one animal.

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
February 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
reliabel with respect to excretion of thiourea in urine; not adequate to quantify dermal absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
The absorption of thiourea was estimated by determination of the amount of unchanged thiourea excreted in the urine.
GLP compliance:
no
Radiolabelling:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: adults
- Weight at study initiation: about 3 kg
- Fasting period before study: free access to tap water and standard laboratory diet the night before the treatment; at the day of the treatment the animals were kept for 24 h under deprivation of water and feed
- Housing:restraining box
- Individual metabolism cages: no
- Diet (e.g. ad libitum): see above (fasting period before study)
- Water (e.g. ad libitum): see above (fasting period before study)
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Type of coverage:
occlusive
Vehicle:
other: one experiment was conducted with thiourea (unchanged), the other was conducted with a thiourea solution in water
Duration of exposure:
24 h
Doses:
Experiment with thiourea powder: 2 g thiourea/kg body weight (corresponded to 5.94 g thiourea)
Experiment with thiourea solution: 25 ml of a luke warm2.5% solution of thiourea in demineralized water (corresponded to a dose of 0.2 g thiourea/kg body weight)
No. of animals per group:
1 animal was treated with thiourea powder, 1 animal was treated with thiourea solution
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: the thiourea solution was prepared with demineralized water (2.5%(w/v) thiourea)
- Method of storage: no data

APPLICATION OF DOSE:
Experiment with thiourea powder: A shaved area of a rabbit was covered with a piece of transpaerent adhesive tape with the adhesive side on which 5.94 g thiourea were evenly spread attached to the skin.
Experiment with thiourea solution: A shaved area of the other rabbit was covered with a thin layer of cellulose sheet and wrapped in polyethylene foil shortly before the application of the test compound. 26 ml of luke warm 2.5% (w/v) solution of thiourea in deminearlized water was injected through the polyethylene foil onto the cellulose sheet; the administered volume corresponded with a dose of 0.2 g thiourea/kg body weight.


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Amount(s) applied (volume or weight with unit): 26 ml
- Concentration (if solution): 2.5% (w/v)

TEST SITE
- Preparation of test site: not reported
- Area of exposure: not reported
- % coverage: not reported
- Type of cover / wrap if used:
Experiment with thiourea powder: transparent adhesive tape; cotton bandage
Experiment with thiourea solution: cellulose sheet; polyethylene foil
- Time intervals for shavings or clipplings: the the animals were shaved once

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: no

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: no
- Washing procedures and type of cleansing agent: no
- Time after start of exposure: no

SAMPLE COLLECTION
- Collection of blood: no
- Collection of urine and faeces: the bladder was emptied by means of a catheter
- Collection of expired air: no
- Terminal procedure: no
- Analysis of organs: no

SAMPLE PREPARATION
- Storage procedure: samples which could not be analysed within one hour were stored in a refigerator and analysed within 18 h after catheterization
- Preparation details: The urine samples were analysed either diluted (4 x with demineralized water) or undiluted.

ANALYSIS
- Method type(s) for identification: Technicon AutoAnalyzer technique of J.A. Gerfast (Anal.Biochem. 15 (1969)358); using Grote's reagent
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Dose:
2 g/kg bw
Parameter:
percentage
Absorption:
0.1 %
Remarks on result:
other: 24 h
Remarks:
treatment with dry Thiourea powder; absorption extrapolated from 0.1 % excretion in urine
Key result
Dose:
0.2 g/kg bw
Parameter:
percentage
Absorption:
3 - < 4 %
Remarks on result:
other: 24 h
Remarks:
treatment with aqueous solution of Thiourea; absorption extrapolated from 3-4 % excretion in urine
Conversion factor human vs. animal skin:
not determined

In the present study it could be shown that water facilitates the percutaneous absorption of thiourea. The concentration of Thiourea in the urine were close to the detection limit.

Table 1: Urinary excretion of dermally applied thiourea by female rabbits

Period [h]

Thiourea applied as a dry powder

Thiourea administered as an aqueous solution

Volume of catheterized urine [ml]

Amount of thiourea excreted per time interval [mg]

Amount in % of administered dose (5.94 g)

Volume of catheterized urine [ml]

Amount of thiourea excreted per time interval [mg]

Amount in % of administered dose (0.65 g)

0-2

0.0

0.0

0

1.7

0.1

0.01

2-4

22.4

1.0

0.017

9.5

0.4

0.06

4-6

13.9

0.4

0.007

11.7

0.5

0.08

6-8

5.8

0.4

0.007

7.0

1.0

0.15

8-14

30.8

1.5

0.025

28.8

5.9

0.91

14-24

31.4

2.4

0.040

55.2

11.3

1.74

Total

0-24

104.3

5.7

0.096

113.9

19.2

2.95
Conclusions:
3-4 % of dermally applied Thiourea, administered in an aqueous solution at a dose level of 0.2 g/kg bw, is excreted with the urine after 24 h. In contrast only 0.1 % of the administered dose is excreted in urine if dry Thiourea is applied at a concentration of 2g/kg bw.
Executive summary:

Two females New Zealand White rabbits were treated with Thiourea. One animal was threated with dry thiourea powder at a dose level of 2 g/kg bw (total dose 5 .94 g), the other with an aqueous solution of thiourea at a dose level of 0.2 g thiourea/kg bw (total dose 0.65 g). The application of the powderous form of Thiourea resulted in a excretion of 5.7 mg in 24 h which corresponds to 0.1 % of administered dose. The administration of 0.2 g thiourea in solution resulted in an excretion of 19.2 mg in 24 h which corresponds to 3% of administered dose.

3% represents the minimum amount of urea percutanously absorbed by the rabbit.

There are no data on possible accumulation of Thiourea in the body. Furthermore the study was only conducted with one animal.

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1970
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Original reference in Russian; German translation is available.
Qualifier:
equivalent or similar to guideline
Guideline:
other: no guideline reported
Principles of method if other than guideline:
A 3% Thiourea solution was applied to the skin of rats at doses of 50, 125, 250 and 500 mg/kg. To determine long term effects, 10 mg/kg thiourea were applied daily for 8 month. The oxygen consumption, the hemoglobin content, the weight and functionality of the thyroid gland and pathomorphological changes were recorded.
The basis of the study was a report that workers that got in contact with wash waters containing 20-30 mg thiourea dioxide per 100 ml wash water did not establish a distinct skin reaction. This should be proven in a animal study.
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 100-120 g
Type of coverage:
open
Vehicle:
water
Duration of exposure:
Two experiments are described differing in the exposure time and doses applied:
1.single application; 72 h
2. daily application during 8 month
Doses:
Two experiments are described differing in the exposure time and doses applied:
1. Doses applied: 500, 250, 125, 50, 25 mg/kg
2. 10 mg/kg was applied.
No. of animals per group:
Two experiments are described differing in the exposure time and doses applied:
1. 6 animals per dose and 6 control animals
2. 12 animals per dose and 12 control animals
Control animals:
yes
Signs and symptoms of toxicity:
yes
Dermal irritation:
no effects
Remarks on result:
other: Thiourea and its dioxide are considered to have a resoptive effect. This effect is not described in detail.
Conversion factor human vs. animal skin:
no data

At doses of 500 mg/kg body weight the oxygen consumption decreased and the hemoglobin content increased. At doses of 250 and 125 mg/kg the oxygen consumption changed. Examination of the thyroid gland showed structural changes of the structural gland (decay of the thyroidic parenchym). At a dosis of 50 mg/kg no change in oxygen consumption and structural changes of the thyroid gland.

No weight change was detected during the 8 month obervation period. The changes observed in the thyroid gland that were provoked by thiourea dioxide were stronger than those of thiourea. Necrosis in the parenchym of the thyroid gland could be observed after treatment with thiourea dioxide and thiourea. The effects of thiourea dioxide are stronger than those observed after application of thiourea.

Conclusions:
Thiourea and its dioxide are considered to penetrate easily through the skin.
Executive summary:

Thiourea and its dioxide were applied to the skin of 6 rats each at concentrations of 25, 50, 125, 250 and 500 mg/kg body weight. The animals were observed for 72 h. To determine probable long term effects thiourea and its dioxide were applied to 12 rats in a concentration of 10 mg/kg for 8 month.

The reactions observed consisted of decrease in oxygen consumption and an increase in hemoglobin content. Thiourea did not induce skin irritation. Effects of the thyroid gland comprising of necrotic effects in the parenchym and a hypothyroidism are described for thiourea and more pronounced in thiourea dioxide. Thiourea and its dioxide are considered to penetrate easily through the skin.

Description of key information

Several pre-GLP/pre-OECD publications are available for the evaluating the toxicokinetics of Thiourea. In humans and animals, Thiourea is rapidly absorbed from the gastrointestinal tract (Williams, 1947). Three studies on dermal absorption show that Thiourea penetrates through the skin (Kosova, 1970; TNO 1979&1980). Slanina et al. (1973) examined the distribution of thiourea in mice (mother and fetuses); Hollinger examined the distribution in lung, liver and kidney.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
4

Additional information

Thiourea is rapidly absorbed from the gastrointestinal tract and excreted in the urine in humans and rats. A single oral dose of 28.57 mg/kg bw of Thiourea was almost completely eliminated from the blood within 48h in humans (Williams, 1947). In rats a recovery in the carcasses of 30% was reported 3h after intravenous injection of 5 mg thiourea - after 25h only traces were detected (Williams, 1947). The plasma half-time was determined with 3.3 h (Giri, 1972).

Hollinger (1974) reported distribution of Thiourea to lung, liver and kidney, with the highest proportion measured in lung tissue. Slanina (1973) reported accumulation of 14C-Thiourea in the thyroid gland of mother and fetusses in mice, showing that thiourea readily passes the blood-placenta barrier. Kosova (1970) applied thiourea to the skin of rats; it was considered to penetrate "easily". The amount was not quantified but estimated by systemic effects. 3,76 % of the amount dermal administered to rabbits was excreted in the urine after 24h (Leegwater, 1979). Vignole (1958) demonstrated that 50 -80% of orally or subcutaneous administered Thiourea is excreted unchanged in the urine by the rabbit within 3 days. According to Leegwater (1979, 1980) administration of aqueous solution facilitates the percutaneous absorption. The amount of Thiourea excreted in urine was between 3 and 4 % when administered as aqueous solution and only 0.1% when administered as dry powder.

Thiourea inhibits the thyroid hormone synthesis (Takegawa, 1997). Results of in vitro and in vivo studies showed that Thiourea is an inhibitor of thyroid peroxidase (1979). Thiourea is oxidized by the thyroid gland peroxidase forming cyanamide and elementary sulfur. In vitro, cyanamide inhibits the peroxidation of iodide and the iodination of tyrosine. This explains the thyroid depressant action of Thiourea. Autoradiographic studies of the distribution of 35S-labelled thiourea revealed a highly preferential and prolonged storage of the radioactivity in the thyroid gland [Schulman 1950]. Together with the main product, sulfate, protein-bound sulfur was detected [Maloof 1957]. The biochemical mechanisms of action of Thiourea can be summarized as follows: in addition to reductive activation which leads to breaking of disulfide bonds in protein, oxidation in the presence of iodine or with the flavoprotein-dependent aminoxidase is of importance. At least three mechanisms which depend on metabolism may contribute to toxicity – a) denaturation of functionally important proteins by breaking of disulfide bonds, forming thiosulfenic acids; b) membrane damage as a result of reduction in the GSH level in the lung, and c) metabolism to toxic sulfinic and sulfonic acids (MAK 1990).