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EC number: 200-543-5
CAS number: 62-56-6
It should be noted that the European Commission Staff Working Document
on the implementation of the "Community Strategy for Endocrine
Disrupters" did not identify thiourea as an endocrine disrupting
chemical from a review of a range of substances suspected of interfering
with the hormone systems of humans and wildlife (COM (1999) 706), (COM
(2001) 262) and (SEC (2004) 1372). The review below presents a short
discussion of each paper reviewed by type of organism (e.g. fish,
mollusc, etc.) and in chronological order.
1. Potential Effects on Fish
Mackay (1973) reported exposing Hypseleotris galii (the freshwater
tropical fish, firetail gudgeon) to 25 mg/l and 200 mg/l of thiourea
over a period of three weeks. The author concluded that at the higher
dose, thiourea caused thyroid hypertrophy, inhibited vitellogenesis, and
caused atresia of yolky oocytes. However, the author considered the
antigonadal effects to be part of a generalised non-physiological toxic
effect at the 200 mg/l concentration, although further description of
toxic effects is not provided. Exposure at the lower thiourea
concentration was considered to have caused thyroid hypertrophy without
McBride and van Overbeeke (1975) studied the effects of thiourea to
sexually maturing and gonadectomised Oncorhynchus nerka (sockeye salmon)
over a 7-14 week period. Fish were exposed to 0.03 and 0.06%
(corresponding to 300 and 600 mg/l) thiourea in water resulting in no
effects on spermatogenesis or the development of secondary sexual
characteristics (SSC) such as testes, skin colouration, hooked snouts
and large premaxillary teeth. Effects of thiourea on the pituitary gland
were clearest in the gonadectomised fish causing degranulation of
thyrotrophs. The authors concluded that similar, though indirect effects
were seen in several cell types in the pituitary gland of sexually
maturing fish. However, potential effects on sexually maturing fish are
complex and the authors report conflicting studies in papers published
between 1968 and 1973, although no information is provided on the study
designs (e.g., duration, thiourea concentration). In their review of
previous research, the authors decide that definite conclusions cannot
be drawn from the previously published studies, although there appears
to be some evidence of thiourea effects on degranulation of
thyrotropths, correlated with thyroid hypertrophy and, at least in some
species, effects on gonadotrophs. This study is considered to be
reliable with restriction (Klimisch 2e).
In a study on the freshwater tropical fish Channa punctatus (green or
spotted snakehead fish, or spotted murrel), Saxena and Mani (1979)
studied the effects of thiourea on sexual maturation in fish. The fish
were exposed to 0.033% (corresponding to 330 mg/l) thiourea in water for
a total of 145 days with specimens collected at 30, 60, 90, 120 and 145
days. Ovarian weights were significantly lower (P<0.01) in treated fish
from 90 days and thereafter, including ruptured tunica albuginea (white
covering) and the release of some oocytes into the body cavity, suggest
a direct effect of thiourea on the ovaries. However, previous studies,
including McBride and van Overbeeke (1975), consider the effect of
thiourea to be an indirect one. The authors conclude that further
research is required to investigate whether inhibitory effects of
thiourea are through the pituitary-thyroid axis or due to its direct
toxic action on gonadotrophs or gonads.
Extrathyroidal effects of low concentrations of thiourea on Salmo
gairdneri (rainbow trout) were reported by Eales (1981) and assigned
Klimisch 2e rating in this review. Immature fish were exposed to 0.0015%
(corresponding to 15 mg/l) thiourea for 67 days with the aim of
investigating whether thiourea inhibits the thyroid exclusively or
whether thiourea exerts confounding extrathyroidal effects. The results
showed that thiourea had no effect on body weight or depression of
circulating levels of T4 (thyroxine) or tri-iodothyronine (T3), T4
degradation rate, or T4 deiodination rate indicating no significant T4
influence on thyroidal hormone output. However, thiourea caused a small
but significant increase in haematocrit and a decrease in distribution
spaces for iodide and T4, indicating direct sensitivity of
extrathyroidal processes to thiourea. The author concludes that the
thiourea concentration of 15 mg/l may be close to the threshold for
influencing the thyroid, based on the lowered (but not significantly)
thyroid radioiodide uptake. Eales (1981) goes on to state that
extrathyroidal effects may have occurred in earlier published studies,
but misinterpreted as thyroid inhibition exclusively, although the
extent to which results could be mis-represented remains unknown.
Misra and Pandy (1985) exposed the tropical freshwater fish Mystus
vittatus (catfish) to 0.03% (or 300 mg/l) thiourea over a four week
period. The study conclusions indicate a significant suppression of
steriodogenesis in the testes of M. vittatus resulting in small changes
to secondary sexual characteristics such as a reduction in genital
papilla and caudal thickening in the male fish.
Madsen (1989) exposed yearling Salmo gairdneri (rainbow trout) to 3,000
and 5,000 mg/l (or 3 and 5 g/l) thiourea to assess potential effects on
osmoregulatory function following exposure to thiourea over a 14-day
period (Klimisch 2e rating). The conclusions state that the exposure
resulted in depression of gill Na+/K+-ATPase activity in seawater at the
higher thiourea concentration or delayed adaptive increase in ATPase
activity at the lower thiourea concentration. Plasma Na+ and Cl- levels
decreased in freshwater fish and increased in seawater-acclimated fish
when exposed to thiourea. These results indicate an impairment of the
osmoregulatory capacity of fish by thiourea exposure. Although
circulating levels of T4 (thyroxine) tended to offset this effect, the
authors stated that the hormone probably acts through a different
mechanism associated with thiourea toxicity in extrathyroidal sites.
This study, and similar studies, demonstrated the importance of
simultaneously investigating thyroid histology and thyroid hormone
concentrations when working with supposed goitrogens, such as thiourea.
Tagawa and Hirano (1991) assessed the effect of thyroid hormone
deficiency in eggs on the early development of Oryzias latipes (medaka).
To achieve thyroid hormone deficiency in eggs, spawning female fish were
exposed to 0, 0.001, 0.003, 0.01 and 0.03% (or 0, 10, 30, 100 and 300
mg/l) thiourea for 1-2 months. Several regimes were assessed during the
study; (i) changes in thyroid hormone concentrations in the eggs were
examined until hatching, (ii) the optimum conditions of thiourea
exposure of mother fish to obtain thyroid hormone-deficient eggs, and
(iii) hatchability, survival, and growth rate were compared between
normal and thyroid hormone-deficient eggs and larvae. The results showed
no differences in hatchability, time of hatching and survival or body
weight, length, condition factor or survival rate with and without food
between control and thyroid hormone-deficient eggs.
Studies that were reviewed but considered to be invalid for use in this
assessment include the following papers; Pfeiffer et al., (1985)
reported the effects of a range of hormones and other substances on
alarm substance cells and mucous cells in the epidermis of Phoxinus
phoxinus (European minnow). Fish were injected three times per week with
Thiourea concentrations ranging from 0.25, 2.5 and 25 mg for 10-42 days
(typically 4 weeks). Thiourea had a reducing effect on alarm substance
cells, but, unexpectedly, the size and number of mucous cells increased.
These effects are contradictory as an increase in alarm cells is
expected to stimulate mucous cells. It should be noted that a
dose-response relationship is not reported and nor are any statistical
analyses. This study is considered to be a Klimisch 3 due to the method
of thiourea exposure (injection), limited methodological information and
lack of interpretation of the contradictory results.
Exposure to 30 mg/l thiourea resulted in skin pigmentation changes in
Paralichthys olivaceus (flounder) larvae during metamorphosis, although
the consequences of these changes are unknown (Sugiyama and Yano, 1989).
Only the abstract was reviewed (Klimisch 4a).
In summary, the fish studies reviewed reported test concentrations of
thiourea within a broad range of 0.25 to 5,000 mg/l. Several studies
reported changes to secondary sexual characteristics at concentrations
of 300 mg/l or more, such as McBride & van Overbeeke (1975), Saxena
(1975) and Misra & Pandy (1985), although Tagawa & Hirano (1991)
reported no effects on hatchability, survival or body weight of young
medaka following 300 mg/l thiourea exposure to the mother medaka.
General toxicity (non-physiological response) was considered to be
responsible for effects seen at 200 mg/l in the Mackay (1973) study.
Thyroid hypertrophy, inhibited vitellogenesis, and atresia of yolky
oocytes in the firetail gudgeon were observed by Mackay (1973) at 25
mg/l exposure, which may be considered to be extrathyroidal effects by
later authors, such as Eales (1981) at 15 mg/l. Importantly, Eales
(1981) considered 15 mg/l to be a threshold for influencing the thyroid.
Little weight is given to the Sugiyama and Yano (1989) and Pfeiffer et
al., (1985) studies, due to the reliability of the studies and the lack
of evidence for dose-response related data (Pfeiffer study), though
potential effects on skin pigmentation and alarm cells are reported,
respectively. It would appear from the literature reviewed that a
threshold for influencing the thyroid may be approximately 15 mg/l
(Eales, 1981), however, changes to reproductive organs and secondary
sexual characteristics, growth or survival appear to occur at 300 mg/l
exposure or more.
In a study by Takigami et al., (2002) the potential effects of thiourea
(and methimazole) were assessed on survival, growth, and metamorphosis
(i.e., limb development and tail-length resorption) of the Xenopus
laevis (South African clawed frog) were investigated using
static-renewal tests. In the frog embryo teratogenesis assay, Xenopus
(FETAX) mortality and malformation were not observed for the two
chemicals at the highest concentration exposed (100 mg/l), which
suggests that FETAX is not an appropriate screening method for thyroid
action. Two bioassays for evaluating limb development and tail
regression were simplified to a specific assay for thyroid hormone
activity. Thiourea did not induce mal-development of the limbs, although
at concentrations > 100 mg/l thiourea resulted in a decreased rate of
Rana tigerina (Indian bull frog) were injected with human chorionic
gonadotropin (hCG) or hCG with 25 µg of thiourea in 0.1ml of distilled
water (equivalent to 25 mg/l) on alternate days for 30 days. Kurian and
Saidapur (1985) concluded that thiourea affects spermatogenesis so that
stages III (secondary spermatocytes) to V (sperm bundles attached to
Sertoli cells) fail to develop despite hCG stimulation.
In summary, under REACH Regulations, amphibians are not considered to be
a standard test organism. These studies are provided as supporting
information to the data for aquatic organisms and show that effects on
reproductive endpoints (e.g., spermatogenesis) can be seen at thiourea
concentrations of 25 mg/l or greater. These two studies suggest
amphibians are similar in sensitivity to fish.
A study on the inhibition of nitrification in the activated sludge
process of sewage disposal was reported by Tomlinson et al., (1966)
using a laboratory scale activated sludge unit. Thiourea was shown to be
a powerful inhibitor of nitrification in sewage sludge (0.076 mg/l
inhibiting oxidation by 75%), however, acclimatisation quickly occurs in
the microorganisms and nitrification continues in the activated sludge.
It was concluded that short-term effects of thiourea may be
unrepresentative of activated sludge plants operating under steady state
conditions as microorganisms become adapted with some microorganisms
actually decomposing thiourea.
In a short publication by Pandey et al., (1975), 750 mg/l of thiourea
was reported to prevent growth in Helminthosporium sativum (fungi) and
1,000 mg/l was stated to be fatal. The authors considered that gradual
retardation in the growth of fungal mycelia with increasing
concentrations of thiourea may be due to its possible effects on the
fungal metabolism and enzyme system.
Kubota and Asami (1985) investigated the source of nitrous acid
volatilisation from upland soils and applied a 100 and 200 mg/l thiourea
solution, plus nutrient solution, to two air-dried upland soils. After
20 days of incubation, the amounts of thiourea-N were 5 or 10% of the
total-N volatilised in the Taki and Matsuzawa soils, respectively. In
both soils, thiourea-N concentrations of 200 mg/l almost completely
supressed the oxidation of ammonium-N to nitrite-N and nitrate-N.
Zacherl and Amberger (1990) studied the effect of 100 mg/l thiourea on
soil microorganisms by measuring growth inhibition and respiration of
N-fixing bacteria. Only minor growth inhibition of Azotobacter
chroococcum occurred; no effects were seen on Rhizobium leguminosarum.
It was concluded that thiourea did not have a toxic effect on N-fixing
bacteria in pure culture.
In summary, microorganisms also appear to be similar in sensitivity to
thiourea as fish and amphibians. Potential effects from laboratory
studies range from 100 mg/l to 1,000 mg/l. The study by Tomlinson et
al., (1966) showed thiourea to be a nitrification inhibitor but under
real world conditions, microorganisms are likely to be acclimated to
thiourea and some microbes will break down thiourea during sewage
The European Commission Staff Working Document on the implementation of
the "Community Strategy for Endocrine Disrupters" did not identify
thiourea as an endocrine disrupting chemical from a review of a range of
substances suspected of interfering with the hormone systems of humans
and wildlife (COM (1999) 706), (COM (2001) 262) and (SEC (2004) 1372).
In the review of published papers relating to fish, amphibian and
microbial studies it can be concluded that thiourea can display
endocrine active properties that can result in changes in reproductive
organs but the mode of action is complex and varied, the reversibility
of these changes and the influence on future generations is unproven. If
a precautionary approach is taken, the fish study by Eales (1981)
considered a threshold for influencing the thyroid to be 15 mg/l. When
these studies are compared with traditional ecotoxicity REACH endpoints,
then aquatic invertebrates appear to be the most sensitive organisms
with a NOEC/EC10 value of 0.1 mg/l (Boje and Rudolph, 1985). Therefore
it can be concluded that, based on the ecotoxicity information in the
thiourea dossier, the most sensitive key value of 0.1 mg/l will be
protective of long-term effects on aquatic organisms and potential
effects on the endocrine system of aquatic organisms.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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