Trabajo de toxicología

TOXICO: Ditiocarbamatos

Base de datos: Sistema Integrado de Información de Riesgo (IRIS)

Maneb: Toxicidad aguda. DL50/CL50 oral (ratas): >5000 mg/kg; inhalación (ratas): >3,8
mg/L;dérmico (ratas): 2000 mg/Kg, >5000 mg/kg; dérmico (conejos): >5000
mg/kg. Clasificación:U. No peligro agudo (OMS); nd (EPA). Acción tóxica y
síntomas: síndrome tóxico por ditiocarbamato. Toxicidad tópica: capacidad irritativa:
ocular positiva (corrosiva); dérmicapositiva (leve); capacidad alergénica: positiva.
Toxicidad crónica y a largo plazo: neurotoxicidad: nivel 2
(colinérgica); teratogenicidad:requiere más estudio; mutagenicidad: requiere más
estudio; carcinogenicidad: 3. No clasificable (IARC); B2. Probable carcinógeno humano
(EPA); disrupción endocrina: categoría 1; otros efectos
reproductivos: nd; genotoxicidad: positiva (aberraciones
cromosómicas); Parkinson: positivo; otros efectos crónicos: puede afectar la glándula
tiroides, el riñón y corazón, causa dermatitis. El producto de degradación y metabolito de
maneb es ETU, que es oncogénico, teratogénico, mutagénico y bociogénico. Frases de
riesgo UE: R20: Nocivo por inhalación. R36: Irrita los ojos. R43: Posibilidad de
sensibilización en contacto con la piel. R63: Posible riesgo durante el embarazo de
efectos adversos para el feto.
Límites de exposición: ADI: 0,03 mg/kg; TLV-TWA: nd; BLV: nd. Límites en agua de
consumo: nd (Centroamérica), 85 µg/L (ES); 0,1 µg/L (Unión Europea); GV nd, HV nd
(Australia); % TDI nd, GV nd (OMS).
Metiram: Toxicidad aguda. DL50/CL50 oral (ratas): >5000 mg/kg; inhalación (ratas): >2,71
mg/L;dérmico (ratas): >2000 mg/kg; dérmico (conejos): nd. Clasificación: U. No peligro
agudo (OMS); nd (EPA). Acción tóxica y síntomas: síndrome tóxico por
ditiocarbamato. Toxicidad tópica: capacidad irritativa: ocular positiva
(moderada); dérmica positiva (moderada);capacidad alergénica: nd.
Toxicidad crónica y a largo plazo: neurotoxicidad: nd; teratogenicidad: requiere más
estudio; mutagenicidad: positiva; carcinogenicidad: nd (IARC); B2. Probable carcinógeno
humano (EPA); disrupción endocrina: categoría 2; otros efectos
reproductivos: nd;genotoxicidad: nd; Parkinson: nd; otros efectos crónicos: efectos
tiroideos y similares a los producidos por el mancozeb. Frases de riesgo UE: nd.
Límites de exposición: ADI: 0,03 mg/kg; TLV-TWA: nd; BLV: nd. Límites en agua de
consumo: nd (Centroamérica); 0,1 µg/L (Unión Europea); GV nd, HV nd (Australia); % TDI
nd, GV nd (OMS).
Tiram: Toxicidad aguda. DL50/CL50 oral (ratas): 2600 mg/kg; inhalación (ratas): 4,42
mg/L;dérmico (ratas): nd; dérmico (conejos): >2000 mg/kg. Clasificación: III. Ligeramente
peligroso (OMS); III. Ligeramente tóxico (EPA). Acción tóxica y síntomas: síndrome tóxico
por ditiocarbamato. Toxicidad tópica: capacidad irritativa: ocular positiva
(moderada);dérmica positiva (leve); capacidad alergénica: positiva (leve).
Toxicidad crónica y a largo plazo: neurotoxicidad: nivel 2
(colinérgica); teratogenicidad:positiva; mutagenicidad: no es clara; carcinogenicidad: 3. No
clasificable (IARC); no probable (EPA); disrupción endocrina: categoría 1; otros efectos
reproductivos: nd;genotoxicidad: positiva (aberraciones
cromosómicas); Parkinson: nd; otros efectos crónicos: en personas sensibles desarrolla
dermatitis de contacto. Es irritante del tracto respiratorio. Interacciona con el alcohol,
provocando enfermedad sistémica (efecto antabus). El metabolito etilentiourea (ETU) es
carcinógeno. Frases de riesgo UE: R20/22: Nocivo por inhalación y por ingestión. R36/38:
Irrita los ojos y la piel. R43: Posibilidad de sensibilización en contacto con la piel. R48/22:
Nocivo, riesgo de efectos graves para la salud en caso de exposición prolongada por
ingestión.
Límites de exposición: ADI: 0,01 mg/kg; TLV-TWA: nd; BLV: nd. Límites en agua de
consumo: nd (Centroamérica); 0,1 µg/L (Unión Europea); GV nd, HV 3 µg/L (Australia); %
TDI nd, GV nd (OMS).
Base de datos: banco de datos de sustancias peligrosas (HSDB)
Environmental Levels and Human Exposure

Information on the environmental impact of dithiocarbamates with respect to

persistence and bioaccumulation in the different species and food chains is limited. On
the basis of the available information, it is likely that most of these compounds are
rapidly degraded in the presence of oxygen, moisture, etc., to form a number of
compounds, some of which, e.g., ETU and propylenethiourea (PTU), are toxicologically
important.

When certain crops, such as spinach, carrots, and potatoes, are treated with EBDCs,
high levels of ETU can be found after cooking. In general, however, the ETU levels are
below 0.1 mg/kg product.

Human exposure to EBDCs was calculated for the population of the USA on the basis
of estimated consumption of dietary residues of ETU in treated crops. Upper limit
(worst case) and lower limit (lowest case) estimates of exposure to ETU were 3.65
µg/kg and 0.24 µg/kg body weight per day, respectively.

An estimate made for the Canadian population on the basis of results of available
market-basket surveys would be around 1 µg/kg body weight per day.

1.5. Kinetics and Metabolism

As a general rule, dithiocarbamates can be absorbed by the organism via the skin,
mucous membranes, and the respiratory and gastrointestinal tracts. Whereas
dithiocarbamates are absorbed rapidly from the gastrointestinal tract, metal-
complexed alkylene bisdithiocarbamates are absorbed poorly both from the
gastrointestinal tract and through the skin.

Dialkyldithiocarbamates and EBDCs are metabolized via different mechanisms.

The metabolism of the former is straightforward, dialkylthiocarbamic acid being
formed as a free acid or as S-glucuronide conjugate. Other metabolic products include
carbon disulfide, formaldehyde, sulfate, and dialkyl amine.
 The metabolic decomposition of EBDCs in mammals is complex and results in the
formation of carbon disulfide, EDA, a few ethylene bisthiuram disulfides, hydrogen
sulfide, ethylene bisthiocyanate, and ETU. The latter is further broken down to moieties
that are incorporated into compounds such as oxalic acid, glycine, urea, and lactose.
Dithiocarbamates and their metabolic products are found in certain organs, such as the
liver, kidneys, and, especially, the thyroid gland, but accumulation of these
compounds does not take place because of their rapid metabolism.

After treating plants with dithiocarbamates, a large number of metabolites are found,
including ETU, EU, imidazole derivatives, diisothiocyanates, diamines, disulfides, and
other metabolites, that are still unknown.

1.6. Effects on Organisms in the Environment

Soil microorganisms are capable of metabolizing dithio- carbamates. From the

limited information available, it seems that the breakdown products can affect enzyme
activities,
respiration, and nitrification at dose levels of the order of 10 mg/kg dry soil or more.

Dithiocarbamates have an LC 50 of less than 1 mg/litre for invertebrates (Daphnia) and

between 1 and 4 mg/litre for algae (Chlorella). The acute toxicity of dithiocarbamates
for fish is rather high. In general, the acute LC 50 of dialkyldithio- carbamates for fish is
less than 1 mg/litre, and that of EBDCs is in the range 1 - 8 mg/litre water. The sac fry
and early fry stages of the rainbow trout have a higher sensitivity than other early life
stages, and embryotoxic and teratogenic effects are induced by certain
dithiocarbamates. However, bioaccumulation is low (bioconcentration factor < 100). The
toxicity of ETU and EU for fish, Daphnia, Chlorella, and two bacteria species is very
low, of the order of g/litre.

Several dithiocarbamates were shown to intervene with testicular development and

function and to cause nerve fibre degeneration in domestic fowl.

Information on the influence of dithiocarbamates on honey

bees is lacking.

1.7. Effects on Experimental Animals and In Vitro Test Systems

The acute oral and dermal toxicities of the different dithiocarbamates are generally
low. Most compounds have a low volatility, and only limited information concerning
inhalation toxicity is available. Local irritation of the respiratory tract occurs when
dithiocarbamates are inhaled as dust, which can also induce eye and dermal irritation.
Some dithiocarbamates are sensitizing agents. ETU also has a low acute oral toxicity.

Many short- and long-term toxicity studies have been carried out on different
dithiocarbamates. In rats, some dithio-carbamates tested at high dose levels induced
dose-dependent adverse effects on the reproduction and endocrine structures and
functions, thus reducing reproductive capacity. Some dithio- carbamates also showed
effects on reproduction in birds.
 In teratogenicity studies on mice and rats, dithiocarbamates induced an increase in
resorption sites and somatic and skeletal malformations (cleft palate, hydrocephaly, and
other abnorm-alities). The dose levels needed to produce these effects were usually
higher than 200 mg/kg body weight in rats, and above 100 mg/kg body weight in mice.

In general, the results of mutagenicity studies with dithiocarbamates have been

negative.

From the available long-term carcinogenicity studies on mice and rats, there is no clear
indication of a carcinogenic effect. Some of the dithiocarbamates have shown a
goitrogenic effect at high dose levels.

There is evidence that certain dithiocarbamates may be converted in vivo to N-

nitroso derivatives, which are considered to be both mutagenic and carcinogenic.
However, the levels of nitroso compounds that can be expected to result from the dietary
intake of dithiocarbamate pesticide residues are negligible compared with those of the
nitroso precursors, which occur naturally in food and drinking-water.

In rats, high levels of dithiocarbamates produce an increase in thyroid weight, a

reduction in colloid in follicles, hyper-plasia, and nodular goitre. These distinct
morphological
changes are in agreement with an increase in thyroid-stimulating hormone (TSH).
Hypophyseal stimulation of the thyroid is the consequence of a decreased blood level
of thyroxin, the synthesis of which is inhibited by dithiocarbamates. The thyroid
hyperplasia induced by dithiocarbamates is largely reversible on cessation of exposure.

Another intriguing phenomenon is the induction of alcohol intolerance by most of

the alkyldithiocarbamates. This phenomenon has been studied in rats and produced in
man. It has even led to the use of disulfiram in the treatment of chronic alcoholism.

At dose levels above 50 mg/kg body weight, dithiocarbamates produce neurotoxic

effects in rats and rabbits, characterized by ataxia and paralysis of the hind legs, and
demyelination and degeneration of peripheral nerves. In birds, paralysis and muscular
and peripheral nerve atrophy have also been observed.

Dithiocarbamates have been reported to cause a redistri- bution of heavy metals,

e.g., lead and cadmium, in organs such as the brain. Furthermore, because of their
chelating properties, these dithiocarbamates may have an effect on the function of
enzymes containing metals, such as zinc and copper.

1.8. Effects on Man

Regular contact with dithiocarbamates can cause functional changes in the nervous
and hepatobiliary systems. Skin contact with dithiocarbamates may induce contact
dermatitis, and some of these compounds will induce sensitization. Alcohol intolerance
can be induced by certain dithiocarbamates.

There are indications that the mean incidence of chromosomal aberrations in

lymphocytes is increased in workers exposed to certain dithiocarbamates.
Epidemiological studies on workers exposed to dithiocarbamates or ETU did not show
any increase in the incidence of thyroid tumours. However, only a relatively
small number of workers was involved.