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Evaluation of Health Hazards by exposure to Triazines and Degradation Products

4 Animal toxicity

4.1 Single dose toxicity

4.1.1 Inhalation

The reported inhalation LC50-value for rats exposed to atrazine was greater than 5800 mg/m3 (2 studies reported) (Studies quoted in EC 1996a, US-EPA 2002a).

The reported inhalation LC50-value for rats exposed to simazine was greater than 5600 mg/m3 (2 studies reported) (Studies quoted in EC 1996b).

The reported inhalation LC50-value for rats exposed to terbutylazine was greater than 5300 mg/m3 (1 study reported) (Study quoted in US-EPA 1995, WHO 1998b).

4.1.2 Oral intake

The reported oral LD50-values for atrazine ranged from 670 to 3100 mg/kg for rats (6 studies reported) and from 1750 to 4000 mg/kg for mice (2 studies reported). Weanling male rats had a higher LD50-value than older male rats. (Studies quoted in ATSDR 2001, IARC 1999, EC 1996a, US-EPA 2002a, WHO 1996a).

The reported oral LD50-values for simazine was greater than 5000 mg/kg for rats, mice and rabbits (unknown number of studies) (Studies quoted in WHO 1996b).

The reported oral LD50-values for terbutylazine was 1000->2000 mg/kg for rats (2 studies reported), 7700 mg/kg for mice (1 study reported), and >3000 mg/kg for hamsters (1 study reported) (Studies quoted in NRA 2001, US-EPA 1995, WHO 1998b).

The reported oral LD50-values for cyanazine ranged from 150 to 840 mg/kg for rats (4 studies reported). In these studies, the percentage of active ingredient in the tested products was not clearly identified. Studies with technical cyanazine in rats, mice, and rabbits showed LD50-values of 180, 380, and 140 mg/kg, respectively (1 study reported). (Studies quoted in WHO 1998a).

The reported oral LD50-value for desethyl atrazine (DEA) was 670 mg/kg for female rats and 1890 mg/kg for male rats (1 study reported) (Kuhn 1991c – quoted from EC 1996a).

The reported oral LD50-value for desisopropyl atrazine (DIA) was 810 mg/kg for female rats and 2290 mg/kg for male rats (1 study reported) (Kuhn 1991d – quoted from EC 1996a).

The reported oral LD50-value for desethyldesisopropyl atrazine (DACT) ranged from 2360 to 5460 mg/kg for rats (3 studies reported) (Studies quoted in EC 1996a).

The reported oral LD50-value for hydroxyatrazine was greater than 5050 mg/kg for rats (1 study reported) (Kuhn 1991e – quoted from EC 1996a).

The reported oral LD50-value for hydroxysimazine was greater than 5000 mg/kg for rats (1 study reported) (Pels Rijcken 1994b – quoted from EC 1996b).

4.1.3 Dermal contact

The dermal LD50-value for rats and rabbits exposed to atrazine was >2000 mg/kg (3 studies reported) and 7500 mg/kg (1 study reported), respectively (Studies quoted in ATSDR 2001, IARC 1999, EC 1996a, US-EPA 2002a, WHO 1996a).

The dermal LD50-value for rats and rabbits exposed to simazine was >2000 mg/kg (3 studies reported) (Studies quoted in EC 1996b).

The dermal LD50-value for rats and rabbits exposed to terbutylazine was >2000 mg/kg (1 study reported) and >4000 mg/kg (1 study reported), respectively (Studies quoted in NRA 2001, US-EPA 1995, WHO 1998b).

4.2 Irritation

4.2.1 Skin irritation

Atrazine was none to moderately irritating to the rabbit skin (Studies quoted from EC 1996a, US-EPA 2002a, WHO 1996a).

Simazine was none to slightly irritating to the rabbit skin (Studies quoted from EC 1996b).

Terbutylazine was slightly irritating to the rabbit skin (Hazleton France 1990 – quoted from US-EPA 1995).

Cyanazine caused slight skin irritation at 2000 mg in rabbits (Shell Chemical Co. 1979 – quoted from WHO 1998a).

Desethyldesisopropyl atrazine (DACT) caused slight skin irritation in rabbits (Cannelongo 1979 – quoted from EC 1996a).

4.2.2 Eye irritation

Atrazine was not (appreciable) irritating to the rabbit eye (Studies quoted from EC 1996a, US-EPA 2002a, WHO 1996a).

Simazine was not (appreciable) irritating to the rabbit eye (Studies quoted from EC 1996b).

Terbutylazine was minimal to moderately irritating to the rabbit eye (Hazleton France 1990, Ciba-Geigy 1989 – quoted from US-EPA 1995).

Cyanazine caused mild eye irritation at 100 mg in rabbits (Shell Chemical Co. 1979 – quoted from WHO 1998a).

Desethyldesisopropyl atrazine (DACT) caused eye irritation in rabbits (Metha 1979 – quoted from EC 1996a).

4.3 Sensitisation

Atrazine caused dermal sensitisation in the guinea pig maximization test of Magnusson and Kligman and in the optimisation test (Maurer 1983, Schoch 1985 – quoted from EC 1996a) but not in another maximization test where results were poorly presented (Wandrag 1994c – quoted from EC 1996a).

Simazine caused dermal sensitisation (a weak 10% response) in one well-performed guinea pig maximization test of Magnusson and Kligman (Marty 1995 – quoted from EC 1996b) but not in several other tests including a well-performed Buehler test (Several studies quoted in EC 1996b).

Terbutylazine was not a sensitiser in the guinea pig maximization test (Hazleton France 1991 – quoted from US-EPA 1995).

A skin sensitisation test in guinea pigs with cyanazine was negative (Walker et al. 1974, Shell Chemical Co. 1979 – quoted from WHO 1998a).

4.4 Repeated dose toxicity

4.4.1 Inhalation

No data were found on repeated dose toxicity with inhalation of triazines.

4.4.2 Oral intake

See Table 4 for repeated dose toxicity animal studies with oral exposure to triazines.

For atrazine, Table 4 contains data from 8 studies with rats (5 with Sprague-Dawley rats, and 2 with Fischer rats), 1 study with mice, 1 study with dogs, and 1 study with pigs. In almost all studies decreased body weight and/or food consumption was observed. Several studies focused on the ability of atrazine to cause neuroendocrine effects. It was shown in rats that atrazine attenuated the luteinizing hormone surge, disrupted the oestrous cycle, increased the serum level of oestrogen and prolactin, increased the relative pituitary weights, and "thickened" mammary glands. In pigs, a disruption of the oestrous cycle was also observed but the serum level of oestrogen was decreased. See Table 10 for the lowest NOAELs/LOAELs for some of these effects as well as for other neuroendocrine effects that will be described in subsequent chapters. In addition to the neuroendocrine effects, haematological changes were observed (anaemia, increased myeloid hyperplasia in the bone marrow, extramedullary haematopoiesis and haemosiderin pigment in the spleen) in rats, mice and dogs. The haematological changes seem to be more severe in the rats than in the other species tested. In 2-year studies, the Sprague-Dawley rat seems to be more sensitive to the hormonal as well as the haematological changes than the Fischer 344 rat in which these effects were absent at the doses tested. Generally at higher doses than the haematological changes, kidney toxicity was detected in some of the studies in the form of decreased kidney weight and histopathological changes in rats, mice and pigs. Cardiac toxicity was detected in dogs and pigs but not in rats. In the dog, the cardiac toxicity was quite severe with clinical signs, ECG alterations, and macroscopic and histopathological findings. See Table 12 for the lowest NOAELs/LOAELs for haematological, kidney, and cardiac toxicity. Other more sporadic changes were observed – see Table 4 for more details.

For simazine, Table 4 contains data from 4 studies with Sprague-Dawley rats, and 2 studies with dogs. In general decreased body weight gain was observed. It was shown in rats that simazine attenuated the luteinizing hormone surge, disrupted the oestrous cycle, decreased the serum level of oestrogen, increased the serum level of prolactin, decreased the ovarian and uterine weights, and caused cystic glandular hyperplasia of the mammary gland. The Sprague-Dawley rat seemed to be more sensitive to the hormonal changes than the Fischer 344 rat. See Table 10 for the lowest NOAEL/LOAEL for the attenuation of LH surge as well as for other neuroendocrine effects that will be described in subsequent chapters. In addition to the neuroendocrine effects, haematological changes were observed (anaemia) in rats and dogs. Generally at higher doses than the haematological changes, kidney toxicity was detected in some of the studies in the form of increased kidney weight and histopathological changes in rats. See Table 12 for the lowest NOAELs/LOAELs for the haematological changes and the kidney toxicity. Cardiac toxicity was not evident in either the rat or the dog. Other more sporadic changes were observed – see Table 4 for more details.

For terbutylazine, Table 4 contains data from 4 studies with rats, 2 studies with rabbits, 1 study with mice, and 1 study with dogs. In almost all studies decreased body weight and/or food consumption was observed. None of the studies focused on the ability of terbutylazine to cause neuroendocrine effects. However, in one of the rabbit studies it was shown that terbutylazine decreased the testes weight. See Table 10 for the lowest NOAEL/LOAEL for this effect as well as for other neuroendocrine effects that will be described in subsequent chapters. In addition to the neuroendocrine effects, haematological changes were observed (anaemia) in rats, rabbits and dogs. Cardiac toxicity was only observed in rabbits in the form of decreased heart weight. See Table 12 for the lowest NOAELs/LOAELs for haematological, and cardiac toxicity. Other more sporadic changes were observed – see Table 4 for more details.

For cyanazine, Table 4 contains data from 3 studies with rats, 2 studies with mice, and 3 studies with dogs. In almost all studies decreased body weight gain was observed. None of the studies focused on the ability of cyanazine to cause neuroendocrine effects. Haematological changes were observed (increased myeloid hyperplasia in the bone marrow, extramedullary haematopoiesis in the spleen) in rats. Kidney toxicity was detected in rats, mice and dogs in some of the studies in the form of alterations in kidney function tests and increased kidney weight. Cardiac toxicity was not evident in any of the studies. See Table 12 for the lowest NOAELs/LOAELs for haematological and kidney toxicity. Other more sporadic changes were observed – see Table 4 for more details.

For desethyl atrazine (DEA), Table 4 contains data from 1 study with rats, and 1 study with dogs. In both studies decreased body weight was observed. None of the studies focused on the ability of DEA to cause neuroendocrine effects. Haematological changes (anaemia) as well as cardiac (decreased heart weight, atrial fibrillation, inflammation and hyperplasia of the atrial wall) and kidney (tubular hyperplasia) toxicity were observed only in dogs. See Table 12 for the lowest NOAELs/LOAELs for haematological, kidney, and cardiac toxicity.

For desisopropyl atrazine (DIA), Table 4 contains data from 1 study with rats, and 1 study with dogs. In both studies decreased body weight gain and/or food consumption was observed. None of the studies focused on the ability of DIA to cause neuroendocrine effects. However, in the dog study it was shown that DIA decreased the testes and prostate weight and in the rat study hypertrophy of pituitary cells occurred. See Table 10 for the lowest NOAEL/LOAEL for the effect on the testes and prostate as well as for other neuroendocrine effects that will be described in subsequent chapters. Haematological changes (extramedullary haematopoiesis in the spleen and liver) as well as kidney toxicity (increased weight) were observed only in rats. Cardiac toxicity (decreased heart weight) only occurred in the dog. See Table 12 for the lowest NOAELs/LOAELs for haematological, kidney, and cardiac toxicity. Other more sporadic changes were observed – see Table 4 for more details.

For desethyldesisopropyl atrazine (DACT), Table 4 contains data from 2 studies with Sprague-Dawley rats, and 1 study with dogs. Decreased body weight gain was observed in both the rat and dog studies. The rat studies focused on the ability of DACT to cause neuroendocrine effects. It was shown that DACT attenuated the luteinizing hormone surge, and disrupted the oestrous cycle. See Table 10 for the lowest NOAELs/LOAELs for these effects as well as for other neuroendocrine effects that will be described in subsequent chapters. The primary treatment-related effect in dogs was impairment of heart function resulting in moribund sacrifice of several dogs. In addition to the cardiac effects, haematological changes (anaemia) as well as kidney toxicity (increased weight) were observed in dogs. See Table 12 for the lowest NOAELs/LOAELs for haematological, kidney, and cardiac toxicity. Other more sporadic changes were observed – see Table 4 for more details.

For hydroxyatrazine, Table 4 contains data from 2 studies with Sprague-Dawley rats, and 1 study with dogs. In all studies decreased body weight gain was observed. None of the studies focused on the ability of hydroxyatrazine to cause neuroendocrine effects. The most severe effect both in rats and dogs was kidney toxicity (changes in clinical signs, in haematology, clinical chemical, and urinalysis parameters, in kidney weight, and in macroscopy and histopathology). At a dose of 17 mg/kg bw/day excessive mortality predominantly caused by renal failure occurred in one of the rat studies. In addition to the kidney toxicity, haematological changes were observed (anaemia). Cardiac toxicity was not evident in any of the studies. See Table 12 for the lowest NOAELs/LOAELs for haematological, and kidney toxicity.

No studies have been found on the repeated dose toxicity with oral exposure of desethyl terbutylazine, hydroxysimazine, and hydroxyterbutylazine.

4.4.3 Dermal contact

See Table 5 for repeated dose toxicity animal studies with dermal contact to triazines.

Table 5 contains data from only four studies (one with atrazine, one with simazine, and two with terbutylazine) all performed in rabbits. In all studies decreased body weight gain and food consumption was observed. Haematological changes were observed (anaemia, increased relative spleen weight) in the study with atrazine but at much higher doses (1000 mg/kg bw/day) than in the studies with oral exposure. Kidney and cardiac toxicity was not evident in any of the studies. The exposed rabbits had slight to moderate irritation of the skin. Other more sporadic changes were observed – see Table 5 for more details.

4.5 Toxicity to reproduction

4.5.1 Inhalation

In one study reported as an abstract, no developmental toxicity was seen in rats exposed by inhalation to concentrations up to 317 mg/m3 of simazine on days 7-14 of gestation. (Dilley et al. 1977 – quoted from IARC 1999b).

4.5.2 Oral intake

Two studies have been performed with mixed exposure to the triazines.

In the first study reported in the form of two abstracts, pregnant Long-Evans rats (more than 8/group) were dosed on gestational day 15-19 with a mixture of atrazine and its metabolites in doses estimated to be 50-10000 times the adult exposure (presuming that adults are drinking water with a concentration of 25 g/l of chlorotriazines). This concentration was based on combined maximum atrazine and degradation product concentrations detected in ground and surface water. The rats were gavaged with 0, 0.044, 0.087, 0.44, 0.87, 4.4, and 8.7 mg/kg bw/day of a mixture of atrazine (25%), desethyl atrazine (DEA)(15%), desisopropyl atrazine (DIA) (5%), desethyldesisopropyl atrazine (DACT) (35%), and hydroxyatrazine (20%).

Only the male offspring were studied. On postnatal days 4, 21, or 120, the body weights of offspring of dosed rats were not significantly different from controls. Preputial separation (a marker of male puberty in the rat) was not statistically different from control according to Fenton et al. 2002, but according to Enoch et al. 2003 preputial separation was statistically delayed (not stated at what doses).

At post-natal day 120, the males exposed to 0.087, 0.87, and 8.7 mg/kg bw/day had significantly larger anterior pituitary gland weights than controls. The ventral prostate weight was significantly smaller in the 4.4 and 8.7 mg/kg bw/day groups when compared to controls while the lateral prostate, testes, and seminal vesicle weights were unaffected by treatment at post-natal day 120. A subset of exposed males exhibited a dose-dependent increase in the concentration of serum testosterone (significant at 0.044, 0.44, and 4.4 mg/kg bw/day) at post-natal day 120. The concentration of serum oestrone was significantly increased (not stated at what doses) while the concentrations of serum and pituitary prolactin, serum oestradiol, and thyroid stimulating hormone were unaffected by treatment at post-natal day 120. A dose-dependent increase in the incidence of lipomatous masses nested in epididymal fat pads was noted. Lateral prostate inflammation was observed in several of the dose groups. However, the incidence and severity remained to be quantified via histopathology and immunohistochemistry. (Fenton et al. 2002, Enoch et al. 2003).

In the second study, atrazine, simazine, and/or cyanazine were administered in two mixtures containing several other pesticides, fertilizers and other organic substances commonly found in groundwater in California or Iowa, USA, in a continuous breeding protocol to Swiss CD-1 mice, and in a developmental study to pregnant Sprague-Dawley rats on day 6-20 of gestation. The individual triazines were dosed at concentrations of about 0, 0.3-0.5, 3-5, and 30-50 g/l of drinking water (equivalent to about 0, 0.075-0.13, 0.75-1.3, and 7.5-13 g/kg bw/day).

In the mice study, no effects on reproductive performance of F0 or F1 individuals, spermatogenesis, epididymal sperm concentration, percentage of motile sperm, percentage of abnormal sperm or testicular tissues were found.

In the rat study, no evidence of developmental toxicity was observed. (Heindel et al. 1994 – quoted from BCERF 1998a,b, IARC 1999a).

See Table 6 for toxicity to reproduction animal studies with oral exposure to individual triazines.

For atrazine, 1 reproductive toxicity study in Charles River CD rats, 5 prenatal (4 in various strains of rats, 1 in rabbits) and 6 postnatal (in Wistar and Sprague-Dawley rats) developmental toxicity studies as well as a special study on neurobehavioral effects in pups are included in Table 6.

In many of the studies decreased body weight gain in parental animals as well as in pups was observed. Atrazine was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites in foetuses was observed both in Sprague-Dawley and Charles River CD rats as well as in rabbits. Mild neurobehavioral effects were observed in pups of Fischer 344 dams, which had been dosed with atrazine a month before mating. See Table 11 for the lowest NOAELs/LOAELs for some of these effects.

Several studies focused on the ability of atrazine to cause neuroendocrine effects. It was shown in prenatal studies in rats and rabbits that atrazine might cause pre- and postimplantation loss, and full litter resorption. Preimplantation loss was observed in Fischer 344 rats while the postimplantation loss was observed in Holtzman rats, Charles River CD rats, and rabbits. The Fischer 344 rats were more sensitive than the Sprague-Dawley and Long-Evans rats to full litter resorption in dams dosed on gestation days 6-10. No full litter resorption occurred when the rats were dosed on gestation days 11-15 suggesting that the full litter resorption is maternally mediated and consistent with loss of luteinizing hormone support of the corpora lutea. Holtzman, Sprague-Dawley, Long-Evans, and Fischer 344 dams participating in the prenatal studies all had a decreased serum level of luteinizing hormone. However, only Sprague-Dawley dams had an increased serum level of oestrogen. It was shown in postnatal studies in rats that atrazine decreased the serum testosterone level, and the ventral prostate, testes, and seminal vesicle weights. An in vitro experiment demonstrated that atrazine directly inhibited Leydig cell testosterone production. Atrazine also delayed the preputial separation of male rats and delayed the vaginal opening of female rats dosed postnatally indicating a delayed puberty of the rats. The Sprague-Dawley rat seems to be more sensitive to delayed vaginal opening than the Wistar rat. Atrazine suppressed suckling-induced prolactin release in dams at postnatal days 1-4 and 6-9. This suppression resulted in an increased incidence and severity of prostate inflammation in the male offspring. See Table 10 for the lowest NOAELs/LOAELs for some of these effects as well as for other neuroendocrine effects that have been described in precedent chapters.

Other more sporadic changes were observed – see Table 6 for more details.

For simazine, 2 reproductive toxicity study in rats, and 3 prenatal (2 in Sprague-Dawley rats, 1 in rabbits) developmental toxicity studies are included in Table 6. In most of the studies decreased body weight gain in parental animals as well as in pups was observed. Simazine was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites in foetuses was observed both in rats and rabbits. See Table 11 for the lowest NOAELs/LOAELs for these effects. In one of the prenatal studies in rats, hypoplasia of the lungs in association with malposition of the heart was observed in foetuses at a much higher dose than the other effects.

For terbutylazine, 1 reproductive toxicity study in Sprague-Dawley rats, and 3 prenatal (1 in rats, 2 in rabbits) developmental toxicity studies are included in Table 6. In most of the studies decreased body weight gain in parental animals as well as in pups was observed. Slightly higher number of infertile pairings occurred in the reproductive study. Terbutylazine was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites in foetuses was observed in rats but not in rabbits, which were exposed to lower doses than the rats. See Table 11 for the lowest NOAELs/LOAELs for these effects.

For cyanazine, 2 reproductive toxicity study in Long-Evans and Sprague-Dawley rats, and 4 prenatal (2 in Fischer 344 rats, 1 in Sprague-Dawley rats, 1 in rabbits) developmental toxicity studies are included in Table 6. In many of the studies decreased body weight gain in parental animals as well as in pups was observed. Cyanazine was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites in foetuses was observed in rabbits and in Fischer 344 rats (but not in Sprague-Dawley rats at a similar dose). Microphtalmia/anophtalmia, diaphragmatic hernia associated with liver protrusion, and dilated brain ventricles were also observed in foetuses of Fischer 344 rat and rabbit dams dosed with cyanazine at the next dose level. See Table 11 for the lowest NOAELs/LOAELs for these effects. It was shown in prenatal studies in rats and rabbits that cyanazine might cause postimplantation loss and delayed parturition. See Table 10 for the lowest NOAELs/LOAELs for these effects as well as for other neuroendocrine effects that have been described in precedent chapters. Other more sporadic changes were observed – see Table 6 for more details.

For desethyl atrazine (DEA), 2 prenatal (in Sprague-Dawley and Fischer 344 rats) and 1 postnatal (in Wistar rats) developmental toxicity studies are included in Table 6. In the prenatal studies decreased body weight gain in the dams was observed. DEA was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites and of fused sternebrae in foetuses was observed in the Sprague-Dawley rats. See Table 11 for the lowest NOAELs/LOAELs for these effects. It was shown in one of the prenatal studies in rats that DEA might cause delayed parturition and altered pregnancy maintenance. It was shown in the postnatal study in rats that DEA decreased the prostate, seminal vesicle, epididymal and anterior pituitary weights. DEA also delayed the preputial separation of male rats dosed postnatally. See Table 10 for the lowest NOAELs/LOAELs for most of these effects as well as for other neuroendocrine effects that have been described in precedent chapters.

For desisopropyl atrazine (DIA), 2 prenatal (in Sprague-Dawley and Fischer 344 rats) and 1 postnatal (in Wistar rats) developmental toxicity studies are included in Table 6. In the prenatal studies decreased body weight gain in the dams was observed. DIA was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites and of fused sternebrae in foetuses was observed in the Sprague-Dawley rats. See Table 11 for the lowest NOAELs/LOAELs for these effects. It was shown in one of the prenatal studies in rats that DIA might cause delayed parturition and altered pregnancy maintenance. It was shown in the postnatal study in rats that DIA decreased the serum testosterone level and the prostate, seminal vesicle, epididymal and anterior pituitary weights. DIA also delayed the preputial separation of male rats dosed postnatally. See Table 10 for the lowest NOAELs/LOAELs for most of these effects as well as for other neuroendocrine effects that have been described in precedent chapters.

For desethyldesisopropyl atrazine (DACT), 2 prenatal (in Sprague-Dawley and Fischer 344 rats) and 2 postnatal (in Wistar rats) developmental toxicity studies are included in Table 6. In the prenatal studies decreased body weight gain in the dams and foetuses was observed. DACT was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites and kidney toxicity in foetuses was observed in the Sprague-Dawley rats. See Table 11 for the lowest NOAELs/LOAELs for these effects. It was shown in the prenatal studies in rats that DACT might cause delayed parturition and altered pregnancy maintenance. It was shown in one of the postnatal studies in rats that DACT increased the serum oestrone level and decreased the ventral prostate, seminal vesicle, epididymal and anterior pituitary weights of the male offspring. DACT also delayed the preputial separation of male rats and delayed the vaginal opening of female rats dosed postnatally. See Table 10 for the lowest NOAELs/LOAELs for most of these effects as well as for other neuroendocrine effects that have been described in precedent chapters.

For hydroxyatrazine, 2 prenatal (in Sprague-Dawley and Fischer 344 rats) and 2 postnatal (in Wistar rats) developmental toxicity studies are included in Table 6. In the prenatal studies decreased body weight gain and/or food consumption in the dams and foetuses was observed. Hydroxyatrazine was not a developmental toxicant when administered in doses that were not maternally toxic in the prenatal studies. An increased incidence of incomplete ossification sites in foetuses and kidney toxicity in dams was observed in the Sprague-Dawley rats. See Table 11 for the lowest NOAELs/LOAELs for most of these effects. It was shown in the prenatal studies in rats that hydroxyatrazine might cause altered pregnancy maintenance. It was shown in the postnatal studies in rats that hydroxyatrazine delayed the preputial separation of male rats but not the vaginal opening of female rats. See Table 10 for the lowest NOAELs/LOAELs for these effects as well as for other neuroendocrine effects that have been described in precedent chapters.

No studies have been found on the reproductive toxicity of desethyl terbutylazine, hydroxysimazine, and hydroxyterbutylazine.

4.5.3 Dermal contact

No data were found.

4.5.4 Other routes

Atrazine administered intraperitoneally twice a week for a period of 60 days to adult male Fischer 344 rats at 0, 60, or 120 mg/kg bw/day affected the spermatogenesis (increased testicular sperm numbers, decreased epididymal sperm numbers, decreased epididymal sperm motility) at both doses. Histological changes of the rat testis and degenerative changes in Leydig and Sertoli cells were observed. (Kniewald et al. 2000).

4.6 Mutagenic and genotoxic effects

See Table 7 for mutagenic and genotoxic effects of triazines in vitro and Table 8 for mutagenic and genotoxic effects of triazines in vivo.

In general, atrazine was mutagenic in Drosophila, yeast and plant cells but was not mutagenic in bacteria. Atrazine tested negative for most genotoxic effects in mammalian cells in vitro and in vivo. However, positive results have been found in some but not all studies in vitro for chromosomal aberrations and DNA damage in human lymphocytes, and in vivo for DNA damage in rats and mice and for micronucleus formation in mice.

Simazine was mutagenic in Drosophila and plant cells but was not mutagenic in bacteria and yeast. Simazine tested negative for genotoxic effects in mammalian cells in vitro and in vivo.

Terbutylazine was not mutagenic in Ames test. Terbutylazine tested negative for genotoxic effects in mammalian cells in vitro and in vivo.

Cyanazine was not mutagenic in bacteria, yeast, and Drosophila. Cyanazine tested negative for most genotoxic effects in mammalian cells in vitro and in vivo. However, positive results have been found in some but not all studies in vitro for chromosomal aberrations in human lymphocytes and for repairable DNA damage in rat hepatocytes.

Desethyl atrazine (DEA), desisopropyl atrazine (DIA), desethyldesisopropyl atrazine (DACT), and hydroxyatrazine were not mutagenic in Ames test. They tested negative for genotoxic effects in mammalian cells in vitro (repairable DNA damage) and in vivo (micronucleus formation).

Hydroxysimazine was not mutagenic in Ames test.

No studies have been found on the mutagenic and genotoxic effects of desethyl terbutylazine, and hydroxyterbutylazine.

4.7 Carcinogenic effects

No data were found on carcinogenic effects following inhalation of or dermal contact with triazines.

See Table 9 for carcinogenic effects in animal studies with oral exposure to triazines.

For atrazine, Table 9 contains data from 5 studies with Sprague-Dawley rats, 2 studies with Fischer rats, and 1 study with mice. In general, atrazine caused an increased incidence and an earlier onset of mammary gland tumours (adenocarcinomas, fibroadenomas) in female Sprague-Dawley rats but not in Fischer 344 rats (in doses up to 38 mg/kg bw/day), CD-1 mice (in doses up to 483 mg/kg bw/day), or ovariectomised Sprague-Dawley rats (in doses up to 21 mg/kg bw/day). The lowest dose at which atrazine caused a statistically significant increase in mammary gland tumours in Sprague-Dawley rats was 3.1 mg/kg bw/day. The lowest dose at which atrazine caused an earlier onset of mammary gland tumours was 1.5 mg/kg bw/day. In one study in Sprague-Dawley rats an increased incidence of Leydig cell tumours were observed at a dose of 42 mg/kg bw/day. The incidence fell within historical control data and was attributed in part to the better survival of these animals. The NOAEL for carcinogenicity in Sprague-Dawley rats was 0.5 mg/kg bw/day.

Simazine caused a statistically significant increase in the incidence of and an earlier onset of mammary gland tumours (adenocarcinomas, fibroadenomas) in females in one study with Sprague-Dawley rats dosed at 5.3 mg/kg bw/day for 2 years. The incidence of pituitary gland carcinomas was also significantly increased but within historical control data at 46 mg/kg bw/day in females. A small increase in renal tubular tumours was observed in both sexes at 46 mg/kg bw/day based on which the European Commission has classified simazine for carcinogenicity. The NOAEL for carcinogenicity was 0.52 mg/kg bw/day.

Simazine was not carcinogenic in one study with mice dosed with up to 600 mg/kg bw/day for almost 2 years.

Terbutylazine caused a statistically significant increase in the incidence of mammary gland carcinomas and a decrease in mammary gland fibroadenomas in females in one study with rats (probably Sprague-Dawley) dosed at 53 mg/kg bw/day for 2 years. At the same dose level an increased incidence of Leydig cell tumours were observed mainly in the old rats. The NOAEL for carcinogenicity was 7.0 mg/kg bw/day.

Terbutylazine was not carcinogenic in one study with mice dosed with up to 89 mg/kg bw/day for 2 years.

Cyanazine caused a statistically significant increase in the incidence of and an earlier onset of mammary gland carcinomas in females in one study with Sprague-Dawley rats dosed at 1.4 mg/kg bw/day for 2 years. The NOAEL for carcinogenicity was 0.26 mg/kg bw/day.

Cyanazine was not carcinogenic in one study with mice dosed with up to 130 mg/kg bw/day for 2 years.

Desethyldesisopropyl atrazine (DACT) caused a statistically significant increase in the incidence of mammary gland tumours in females in one study with Sprague-Dawley rats dosed at 10 mg/kg bw/day for 1 year. The NOAEL for carcinogenicity was 3.5 mg/kg bw/day.

Hydroxyatrazine was not carcinogenic in one study with Sprague-Dawley rats dosed with up to 22 mg/kg bw/day for 2 years.

No studies have been found on the carcinogenicity of desethyl atrazine (DEA), desisopropyl atrazine (DIA), desethyl terbutylazine, hydroxysimazine, and hydroxyterbutylazine.

IARC have concluded that there is sufficient evidence in experimental animals for the carcinogenicity of atrazine and that there is limited evidence in experimental animals for the carcinogenicity of simazine.

However, IARC has made an overall conclusion that atrazine is not classifiable as to its carcinogenicity to humans. In making this conclusion, the IARC working group concluded that the mammary tumours associated with exposure to atrazine involve a non-DNA-reactive, hormonally mediated mechanism. In reaching this conclusion, the following evidence was considered:

  1. Atrazine produces mammary tumours (fibroadenomas, adenocarcinomas) only in intact female Sprague-Dawley rats (not in Fischer 344 rats, CD-1 mice or ovariectomised Sprague-Dawley rats) and does not increase the incidences of other tumour types.
  2. Atrazine affects neuroendocrine pathways of the hypothalamus to accelerate the onset of reproductive senescence in female Sprague-Dawley but not Fischer 344 rats.
  3. Atrazine does not have intrinsic estrogenic activity.
  4. There are critical interspecies differences in the hormonal changes associated with reproductive senescence.

Therefore, there is strong evidence that the mechanism by which atrazine increases the incidence of mammary gland tumours in Sprague-Dawley rats is not relevant to humans.

Nevertheless, US-EPA has also concluded that it is not unreasonable to expect that atrazine might cause adverse effects on hypothalamic-pituitary function in humans and that the same endocrine perturbations that induce tumours also appear to play a role in at least some reproductive developmental effects which may be relevant to humans.

 

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Version 1.0 October 2004, © Danish Environmental Protection Agency