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Evaluation of Health Hazards by exposure to Triazines and Degradation Products
8 References
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IARC (1999b). Simazine. In: IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans, Vol. 73, Lyon, 625-640.
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Mills PK and Yang R (2003). Prostate cancer risk in California farm workers. J Occup Environ Med 45, 249-258.
MM (2001). Bekendtgørelse om vandkvalitet og tilsyn med vandforsyningsanlæg. Miljø- og Energiministeriets bekendtgørelse nr. 871 af 21. september 2001.
MM (2002). The Statutory Order from the Ministry of the Environment no. 439 of June 3rd 2002, on the List of Chemical Substances.
MST (2003a). Miljømæssig vurdering af terbutylazine, Bilag 1.a.
MST (2003b). Oversigt over godkendte bekæmpelsesmidler. http://www.mst.dk/bekaemp/findbek.asp
NRA (2001). Public release summary on evaluation of the active terbutylazine in the product Swimcare T swimming pool algaecide. National registration authority for agricultural and
veterinary chemicals. Canberra, Australia. http://www.apvma.gov.au/publications/prster.pdf
Sanderson JT, Letcher RJ, Heneweer M, Giesy JP, and van der Berg M (2001). Effects of chloro-s-triazine herbicides and metabolites on aromatase activity in various human cell lines
and on vitellogenin production in male carp hepatocytes. Environ Health Perspectives 109, 1027-1031.
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Suárez S, Rubio A, Sueiro RA, and Garrida J (2003). Sister chromatid exchanges and micronuclei analysis in lymphocytes of men exposed to simazine through drinking water. Mutation
Research 537, 141-149.
Tennant AH, Peng B, and Kligerman AD (2001). Genotoxicity studies of three triazine herbicides: in vivo studies using the alkaline single cell gel (SCG) assay. Mutation Research 493,
1-10.
US-EPA (1995). Re-registration eligibility decision (RED) Terbutylazine. http://www.epa.gov/oppsrrd1/REDs/2645.pdf
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WHO (1996a). Atrazine. In: Guidelines for drinking-water quality. Second edition, Vol. 2. World Health Organization, Geneva, 608-614.
WHO (1996b). Simazine. In: Guidelines for drinking-water quality. Second edition, Vol. 2. World Health Organization, Geneva, 753-758.
WHO (1998a). Cyanazine. In: Guidelines for drinking-water quality. Second edition, Vol. 2. World Health Organization, Geneva, 165-175.
WHO (1998b). Terbutylazine. In: Guidelines for drinking-water quality. Second edition, Vol. 2. World Health Organization, Geneva, 245-253.
Table 4. Repeated dose toxicity animal studies with oral exposure to triazines.
Duration of study
Species (Strain)
No/sex/group
|
Dose levels |
Results |
NOAEL |
Reference |
| Atrazine |
91 weeks
Mice (CD-1)
60/sex/group
Carcinogenicity study
|
0, 10, 300, 1500, 3000 mg/kg of feed (equal to 0, 1.4, 38, 194, 386 mg/kg
bw/day for m and to 0, 1.6, 48, 246, 483 mg/kg bw/day for f)
technical atrazine (purity >96%)
|
38(m)/48(f) mg/kg bw/day and above: Decreased mean body weight (according
to EC 1996a)
194(m)/246(f) mg/kg bw/day and above: Decreased mean body
weight (according to IARC 1999a and US-EPA 2002a); decreased
red blood cell parameters in m; increased cardiac thrombi in f.
386(m)/483(f) mg/kg bw/day: Increased mortality in f; decreased
food consumption; decreased red blood cell parameters also in f;
decreased brain and kidney weight and percentages of neutrophiles
and lymphocytes in f; increased cardiac thrombi also in m.
See chapter 4.7.2 for carcinogenic effects.
|
1.4 (EC) - 38 (IARC, US-EPA) mg/kg bw/day |
Ciba-Geigy 1987 - quoted from IARC 1999a, EC 1996a, US-EPA 2002a |
4 weeks
Rats (Sprague-Dawley)
20 females/group
|
0, 2.5, 5, 40, 200 mg/kg bw/day by gavage
atrazine (purity not specified)
|
40 mg/kg bw/day and above: Significantly decreased adjusted peak LH surge. |
5 mg/kg bw/day |
Minnema 2001a – quoted from US-EPA 2002b |
90 days
Rats (Tif/RAIf, RII/1 x RII/2
hybrids (Sprague-Dawley
derived))
10/sex/group
|
0, 10, 50, 500 mg/kg of feed (equal to 0, 0.6, 3.3, 34 mg/kg bw/day for m
and to 0, 0.6, 3.4, 35 mg/kg bw/day for f)
technical atrazine (97% pure)
|
3.3 (m)/3.4(f) (according to EC 1996a) - 34(m)/35(f) (according to US-EPA
2002a) mg/kg bw/day: Decrease in mean body weights; haemosiderin pigment in the
spleen at an increased incidence and severity. |
0.6 (EC) - 3.3 (US-EPA) mg/kg bw/day |
Bachmann 1994 – quoted from EC 1996a, US-EPA 2002a |
3 months
Rats
|
0-75 mg/kg bw/day
technical atrazine (purity not
specified)
|
No differences from controls in running time to the goal (food) or number
of errors in behavioural maze studies. |
75 mg/kg bw/day |
Dési 1983 – quoted from ATSDR 2001. |
6 months
Rats (Sprague-Dawley)
90 females/group
|
0, 25, 50, 400 mg/kg of feed (equal to 0, 1.8, 3.7, 29 mg/kg bw/day)
technical atrazine (97% pure)
|
3.7 mg/kg bw/day and above: Oestrous cycle alterations and luteinizing hormone
surge attenuation.
29 mg/kg bw/day: Decrease in mean body weights and in food
consumption; increased relative pituitary weights; thickened
mammary glands.
|
1.8 mg/kg bw/day |
Corning Hazleton Inc. 1996 – quoted from US-EPA 2002a |
2 years
Rats (Sprague-Dawley)
70-90/sex/group
|
0, 10, 70, 500, 1000 mg/kg of feed (equal to 0, 0.4, 2.6, 20, 42 mg/kg bw/day
for m and to 0, 0.5, 3.5, 30, 65 mg/kg bw/day for f)
technical atrazine (96% pure)
|
20(m)/25(f) mg/kg bw/day and above: Decrease in mean body weights and in food
consumption; increased myeloid hyperplasia in the bone marrow of the femur and
sternum in f; splenic extra medullary haematopoiesis in f.
42(m)/65(f) mg/kg bw/day: Decreased survival for f but increased
survival for m; reduced red blood cell parameters in f; depressed
glucose levels during the first 12 months in f; decreased serum
triglyceride in m; histopathological changes in retina, liver, muscles,
bladder and kidney in f, and in muscle, prostate, kidney and
mammary gland in m.
See chapter 4.7.2 for carcinogenic effects.
|
2.6 mg/kg bw/day |
Ciba-Geigy 1986 - quoted from IARC 1999a, EC 1996a, US-EPA 2002a, WHO 1996a |
2 years (serial sacrifice at 1, 3, 9, 12, 15, 18 and 24 months)
Rats (Sprague-Dawley)
70/females/group
|
0, 70, 400 mg/kg of feed (equivalent to 0, 4.2, 26 mg/kg bw/day)
technical atrazine (97% pure)
|
4.2 mg/kg bw/day and above: Early onset of anovulation, increased serum oestradiol
and prolactin levels, and increased days in the oestrous phase of the oestrous
cycle.
26 mg/kg bw/day: Increased mortality; decreased body weights and
food consumption.
No significant dose-related alterations in serum progesterone and
corticosterone levels.
|
< 4.2 mg/kg bw/day |
Hazleton Washington Inc. 1991,1993, Ciba-Geigy 1995 – quoted from US-EPA
2002a |
2 years
Rats (Fischer 344)
60/sex/group
|
0, 10, 70, 200, 400 mg/kg of feed (equal to 0, 0.5, 3.4, 9.9, 20 mg/kg bw/day
for m and to 0, 0.6, 4.4, 13, 26 mg/kg bw/day for f)
technical atrazine (97% pure)
|
9.9(m)/13(f) mg/kg bw/day and above: Decreased body weight gain.
20(m)/26(f) mg/kg bw/day: Decreased food consumption in m.
See chapter 4.7.2 for carcinogenic effects.
|
3.4 mg/kg bw/day |
Hazleton Washington 1992 - quoted from IARC 1999a, US-EPA 2002a |
2 years (serial sacrifice at 1, 3, 9, 12, 15, 18 and 24 months)
Rats (Fischer 344)
70/females/group
|
0, 10, 70, 200, 400 mg/kg of feed (equal to 0, 0.68, 4.8, 14, 34 mg/kg bw/day)
technical atrazine (97% pure)
|
34 mg/kg bw/day: Decreased body weight gain.
No consistently significant dose-related alterations in serum
oestradiol, prolactin, progesterone and corticosterone levels.
No altering of the oestrous cycling.
|
14 mg/kg bw/day |
Hazleton Washington Inc. 1991,1993, Ciba-Geigy 1995 – quoted from US-EPA
2002a |
1 year
Dogs (beagle)
4-6/sex/group
|
0, 15, 150, 1000 mg/kg of feed (equal to 0, 0.5, 5, 34 mg/kg bw/day for m
and f)
technical atrazine (97% pure)
|
34 mg/kg bw/day: Decreased body weight gain and food consumption; ECG alterations,
clinical signs, macroscopic and histopathological findings referable to cardiac
toxicity; increased relative liver weights in m; changes in haematological values
and slight decreases in total serum protein and albumin in m. |
5 mg/kg bw/day |
Ciba-Geigy 1987 - quoted from ATSDR 2001, EC 1996a, US-EPA 2002a, WHO 1996a |
19 days
Pigs (landrace)
f
|
0, 1, 2 mg/kg bw/day
technical atrazine (99% pure)
|
1 mg/kg bw/day and above: Decreased oestradiol and increased progesterone
accompanied by an absence of oestrus onset; histopathological changes of the ovaries
2 mg/kg bw/day: Increased liver enzymes and histopathological
changes of the liver (chronic interstitial inflammation, lymphocyte and
eosinophil infiltration, and narrowing and irregular forms of bile
canaliculi), the kidneys (subacute glomerulitis, and degeneration and
desquamation of the proximal tubules), and the heart (degeneration
of a small number of myocardial fibres).
The effects on the liver, kidney and heart were not studied at 1
mg/kg bw/day.
|
<1 mg/kg bw/day |
Æuriæ et al. 1999, Gojmerac et al. 1995,1996,1999 – quoted
from ATSDR 2001 |
| Simazine |
14 days
Rats (Sprague-Dawley and
Fischer 344)
females
|
0, 100, 300 mg/kg bw/day
technical simazine (97% pure)
|
Treatment related effects included decreased body weights, increased oestrus
cycle duration, increased plasma corticosteroid levels, decreased oestradiol levels,
increased adrenal gland weights, and decreased ovarian and uterine weights.
The effects were more marked in Sprague-Dawley rats than in
Fischer 344 rats.
|
|
Eldridge et al. 1994 – quoted from EC 1996b |
4 weeks
Rats (Sprague-Dawley)
20 females/group
|
0, 2.5, 5, 40, 200 mg/kg bw/day by gavage
simazine (purity not specified)
|
40 mg/kg bw/day and above: Significantly decreased adjusted peak LH surge. |
5 mg/kg bw/day |
Minnema 2001a – quoted from US-EPA 2002b |
13 weeks
Rats (Sprague-Dawley)
10/sex/group
|
0, 200, 2000, 4000 mg/kg of feed (equivalent to 10, 100, 200 mg/kg bw/day)
simazine (98% pure)
|
10 mg/kg bw/day and above: Decreased body weight gain and food consumption;
slightly reduced erythrocyte parameters and leucocyte counts; reduced blood urea
nitrogen in f.
100 mg/kg bw/day and above: Increased relative liver and kidney
weight in f; increased incidence of renal calculi.
200 mg/kg bw/day: Increased relative liver and kidney weight in m;
increased incidence of renal transitional epithelial hyperplasia in m.
|
<10 mg/kg bw/day |
Ciba-Geigy 1985 - quoted from EC 1996b |
2 years
Rats (Sprague-Dawley)
80-90/sex/group
|
0, 10, 100, 1000 mg/kg of feed (equivalent to 0.5, 5, 50 mg/kg bw/day)
technical simazine (97% pure)
|
5 mg/kg bw/day and above: Decreased survival in f; decreased body weight gain;
changes in haematological parameters; increased serum level of prolactin in f.
50 mg/kg bw/day: Increased survival in m; increased relative liver
and kidney weight; reduced serum level of FSH and oestrogen, and
increased serum level of growth hormone in f; cystic glandular
hyperplasia of the mammary gland in f; ovarian atrophy and ovarian
Sertoli cell hyperplasia.
See chapter 4.7.2 for carcinogenic effects.
|
0.5 mg/kg bw/day |
Ciba-Geigy 1988,1990 - quoted from EC 1996b, IARC 1999b, WHO 1996b |
2 years
Dogs
2/sex/dose
|
0, 15, 150, 1500 mg/kg of feed (equivalent to 0.5, 5, 50 mg/kg bw/day)
simazine (purity not specified)
|
50 mg/kg bw/day: Transitory increase in aspartate aminotransferase in two
out of four animals. |
5 mg/kg bw/day |
Ciba-Geigy 1964 - quoted from WHO 1996b |
1(IARC)-2 (WHO) years (different studies?)
Dogs
4/sex/dose
|
0, 20, 100, 1250 mg/kg of feed (equivalent to 0.7, 3.3, 42 mg/kg bw/day)
simazine (purity not specified)
|
3.3 mg/kg bw/day and above: Reduced weight gain and reduced red blood cell
parameters in f.
42 mg/kg bw/day: Cachexia; reduced weight gain and reduced red
blood cell parameters also in m; increase in thrombocytes in m;
changes in relative organ weights not accompanied by histological
findings.
|
0.7 mg/kg bw/day |
Ciba-Geigy 1988 - quoted from IARC 1999b, WHO 1996b |
| Terbutylazine |
2 years
Mice (Tif/MAGF)
50/sex/group
|
0, 30, 150, 750 mg/kg of feed (equal to 0, 3.3, 17, 87 mg/kg bw/day for m
and to 0, 3.2, 17, 89 mg/kg bw/day for f)
technical terbutylazine (98% pure)
|
87(m)/89(f) mg/kg bw/day and above: Reduced body weight gain and food consumption.
Increased survival of treated males (statistically significant at 3.3 and
87 mg/kg bw/day).
See chapter 4.7.2 for carcinogenic effects.
|
17 mg/kg bw/day |
Ciba-Geiga 1982 – quoted from US-EPA 1995, WHO 1998b |
28 days
Rats (RAI)
m and f
|
0, 25, 75, 250, 750 mg/kg of feed (equal to 0, 2.4, 7.7, 27, 69 mg/kg bw/day
for m and to 0, 2.3, 8.1, 28, 63 mg/kg bw/day for f)
technical terbutylazine (99.8% pure)
|
2.4(m) mg/kg bw/day and above: Dose-related decreased body weight gain in
m; reduced relative thymic weight in m.
8.1(f) mg/kg bw/day and above: Dose-related decreased body
weights in f.
|
< 2.4 mg/kg bw/day |
Ciba-Geiga 1984 – quoted from US-EPA 1995 |
90 days
Rats
10/sex/group
|
0, 6, 30, 100, 300 mg/kg of feed (equivalent to 0.3, 1.5, 5, 15 mg/kg bw/day)
terbutylazine (purity not specified)
|
5 mg/kg bw/day and above: Reduced body weight gain.
15 mg/kg bw/day: Reversible changes in haematology and clinical
chemistry parameters. No macroscopic or histopathological changes.
|
1.5 mg/kg bw/day |
Ciba-Geiga ? – quoted from WHO 1998b |
2 years (followed by untreated diet for 8 (m) or 18 (f) weeks)
Rats (Tif/RAIf)
80/sex/group
|
0, 30, 150, 750 mg/kg of feed (equal to 0, 1.2, 7.0, 42 mg/kg bw/day for m
and to 0, 1.4, 7.8, 53 mg/kg bw/day for f)
technical terbutylazine (97% pure)
|
1.2(m)/1.4(f) mg/kg bw/day and above: Reduced body weight gain; reduced food
consumption in m.
7.0(m)/7.8(f) mg/kg bw/day and above: Reduced food consumption
also in f; effects on red blood cell and urinary parameters in f.
42(m)/53(f) mg/kg bw/day: Increased survival of m; effects on
urinary parameters also in m; Leydig cell nodular hyperplasia of the
testes; hepatic cysts, foam cells in lung alveoli.
Increased incidence of non-neoplastic lesions in the thyroid (dose not
stated).
See chapter 4.7.2 for carcinogenic effects.
|
< 1.2 mg/kg bw/day |
Ciba-Geigy 1983 – quoted from NRA 2001, US-EPA 1995, WHO 1998b |
98 weeks (followed by untreated diet for 20 (m) or 23 (f) weeks)
Rats (Tif/RAIf)
80/sex/group
|
0, 6, 30 mg/kg of feed (equal to 0, 0.4, 1.6 mg/kg bw/day for m and f)
technical terbutylazine (98% pure)
|
1.6 mg/kg bw/day: Reduced body weight gain and food consumption.
See chapter 4.7.2 for carcinogenic effects.
|
0.4 mg/kg bw/day |
Ciba-Geigy 1983 – quoted from US-EPA 1995, WHO 1998b |
28 days (5 days/week)
Rabbits (New Zealand white)
5/sex/group
|
0, 5, 50, 500 mg/kg bw/day
Because of high mortality, doses were
reduced to 0, 5, 20, 100 mg/kg
bw/day 3 days after the start of
treatment.
Terbutylazine (purity not specified)
|
5 mg/kg bw/day and above: Signs of systemic toxicity (sedation, dyspnoea,
diarrhoea, tremors); decreased food consumption; decreased liver weight (almost
reversible during 2 week recovery period).
50/20 mg/kg bw/day and above: Decreased heart, thymus, and
testes weights (almost reversible during 2 week recovery period).
500/100 mg/kg bw/day: High mortality and body weight loss;
decreased red blood cell parameters; atrophy of thymus, lymph
nodes and spleen; immature testes.
|
<5 mg/kg bw/day |
Ciba-Geiga 1984 – quoted from WHO 1998b |
28 days
Rabbits (New Zealand white)
5/sex/group
|
0, 0.05, 0,5, 5 mg/kg bw/day
terbutylazine (purity not specified)
|
No deaths and no significant indications of any target organ toxicity at any
of the tested doses. |
5 mg/kg bw/day |
Ciba-Geiga 1987 – quoted from WHO 1998b |
1 year
Dogs
m and f
|
0, 10, 50, 250, 500 mg/kg of feed (equal to 0, 0.4, 1.7, 8,15 mg/kg bw/day)
terbutylazine (purity not specified)
|
1.7 mg/kg bw/day and above: Reduced body weight gain and food consumption.
8 mg/kg bw/day and above: Slight reduction in some red blood cell
parameters in f.
|
0.4 mg/kg bw/day |
Ciba-Geiga ? – quoted from NRA 2001, WHO 1998b |
| Cyanazine |
13 weeks
Mice
m and f
|
0, 10, 50, 500, 1000, 1500 mg/kg of feed (equivalent to 0, 1.3, 6.5, 65, 130,
195 mg/kg bw/day)
cyanazine (purity not specified)
|
65 mg/kg bw/day and above: Reduced body weight gain; increased relative liver
weight |
6.5 mg/kg bw/day |
Shell Chemical Co. 1979 – quoted from WHO 1998a |
2 years
Mice
m and f
|
0, 10, 25, 250, 1000 mg/kg of feed (equivalent to 0, 1.3, 3.3, 33, 130 mg/kg
bw/day)
cyanazine (96% pure)
|
33 mg/kg bw/day and above: Reduced body weight gain; kidney toxicity; skin
ulcerations; parenchymal atrophy of the liver in f; slightly reduced survival
of f.
See chapter 4.7.2 for carcinogenic effects.
|
3.3 mg/kg bw/day |
Shell Chemical Co. 1981 – quoted from WHO 1998a |
4 weeks
Rats (CFE)
10/sex/group
|
0, 1, 10, 100 mg/kg of feed (equivalent to 0, 0.05, 0.5, 5 mg/kg bw/day)
cyanazine (75% or 97% pure)
|
0.05 mg/kg bw/day and above: The LOAEL was based on kidney function tests
(no further details reported), which seemed to be the focus of the study.
5 mg/kg bw/day: Reduction in body weight.
|
<0.05 mg/kg bw/day |
Shell Chemical Co. 1968 – quoted from WHO 1998a |
13 weeks
Rats
m and f
|
0, 1, 1.5, 3, 6, 12, 25, 50, 100 mg/kg of feed (equivalent to 0, 0.05, 0.075,
0.15, 0.30, 0.60, 1.3, 2.5, 5 mg/kg bw/day)
cyanazine (purity not specified)
|
0.075 mg/kg bw/day in m and 2.5 mg/kg bw/day in f and above: Reduced body
weight gain. |
0.05 mg/kg bw/day |
Shell Chemical Co. 1968 – quoted from WHO 1998a |
2 year
Rats (Sprague-Dawley)
50/sex/group
10/sex/group as satellite
groups sacrificed after 1 year
|
0, 1, 5, 25, 50 mg/kg of feed (equal to 0, 0.040, 0.20, 0.99, 2.1 mg/kg bw/day
for m and to 0, 0.053, 0.26, 1.4, 2.8 mg/kg bw/day for f)
cyanazine (96% pure)
|
0.99(m)/1.4(f) mg/kg bw/day and above: Increased incidence of hyperactivity
in m; decreased body weight gain.
2.1(m)/2.8(f) mg/kg bw/day: Extramedullary haematopoiesis of the
spleen in m; granulocytic hyperplasia of the bone marrow; sciatic
nerve demyelinization in f.
See chapter 4.7.2 for carcinogenic effects.
|
0.20 mg/kg bw/day |
E.I. duPont de Nemours and Co. 1990 – quoted from Bogdanffy et al. 2000,
WHO 1998a |
13 weeks
Dogs (beagle)
m and f
|
0, 1.5, 5, 15 mg/kg bw/day by gelatine capsules
cyanazine (purity not specified)
|
15 mg/kg bw/day: Reduced body weight gain; increased kidney and liver weight
in f; emesis in m within the first hour of dosing. |
5 mg/kg bw/day |
Shell Chemical Co. 1968, Walker et al. 1974 – quoted from WHO 1998a |
1 year
Dogs (beagle)
m and f
|
0, 10, 25, 100, 200 mg/kg of feed (equal to 0, 0.27, 0.68, 3.2, 6.1 mg/kg
bw/day for m and to 0, 0.28, 0.72, 3.0, 6.4 mg/kg bw/day for f)
cyanazine (98% pure)
|
3.2(m)/3.0(f) mg/kg bw/day and above: Decreased body weight gain; non-significant
elevation of platelet count; increased relative liver weight; slightly increased
relative kidney weight in f.
6.1(m)/6.4(f) mg/kg bw/day: Decreased serum levels of total protein,
albumin and calcium.
|
0.68 mg/kg bw/day |
E.I. duPont de Nemours and Co. 1986 – quoted from WHO 1998a |
2 year
Dogs (beagle)
|
0, 0.63, 1.3, 5 mg/kg bw/day by gelatine capsules
technical cyanazine (97% pure)
|
5 mg/kg bw/day: Reduced growth rate; emesis within the first hour of dosing;
reduced serum protein.
Inadequate histopathology and data reporting in the study.
|
1.3 mg/kg bw/day |
Shell Chemical Co. 1970 – quoted from WHO 1998a |
| Desethyl atrazine (DEA) |
13 weeks
Rats (Tif/RAIf
Sprague-Dawley)
10/sex/group
|
0, 10, 50, 500 mg/kg of feed (equal to 0, 0.68, 3.2, 35 mg/kg bw/day for m
and to 0, 0.72, 3.3, 38 mg/kg bw/day for f)
desethyl atrazine (purity not specified)
|
35(m)/38(f) mg/kg bw/day: Decreased body weight in f, and decreased food efficiency
in both sexes. |
3.2 mg/kg bw/day |
Ciba-Geiga 1991 – quoted from EC 1996a, US-EPA 2002a |
13 weeks
Dogs (Beagle)
4/sex/group
|
0, 15, 100, 1000 mg/kg of feed (equal to 0, 0.56, 3.7, 29 mg/kg bw/day for
m and to 0, 0.51, 3.9, 32 mg/kg bw/day for f)
desethyl atrazine (purity not specified)
|
29(m)/32(f) mg/kg bw/day: Decreased body weight gain; renal tubular hyperplasia;
decreased relative (to brain) heart weights; anaemia; atrial fibrillation, and
inflammation and hyperplasia of the atrial wall. |
3.7 mg/kg bw/day |
Ciba-Geiga 1992 – quoted from US-EPA 2002a |
| Desisopropyl atrazine (DIA) |
13 weeks
Rats (Tif/RAIf
Sprague-Dawley)
10/sex/group
|
0, 10, 50, 500 mg/kg of feed (equal to 0, 0.60, 3.2, 35 mg/kg bw/day for m
and to 0, 0.64, 3.3, 38 mg/kg bw/day for f)
desisopropyl atrazine (97% pure)
|
3.2(m)/3.3(f) mg/kg bw/day and above: Decreased body weight gain in m; extramedullary
haematopoiesis of the spleen in f.
35(m)/38(f) mg/kg bw/day: Decreased body weight gain in f;
increased relative liver weights and extramedullary haematopoiesis of
the liver in f; increased relative kidney, testes and brain weights in m;
minimal to moderate fatty changes of the adrenal cortex, and
hypertrophy of the thyroid follicular epithelium and pituitary cells in
m.
|
0.6 mg/kg bw/day |
Ciba-Geiga 1992 – quoted from EC 1996a, US-EPA 2002a |
14 weeks
Dogs (Beagle)
4/sex/group
|
0, 15, 100, 500, 1000 mg/kg of feed (equal to 0, 0.6, 3.8, 19, 33 mg/kg bw/day
for m and to 0, 0.6, 3.8, 18, 33 mg/kg bw/day for f)
technical desisopropyl atrazine (purity
not specified)
|
19(m)/18(f) mg/kg bw/day and above: Decreased body weight gain and food consumption
in f; decreased relative (to brain) heart, testes and prostate gland weights in
m.
33 mg/kg bw/day: Decreased body weight gain and food
consumption in m.
|
3.8 mg/kg bw/day |
Ciba-Geiga 1992 – quoted from US-EPA 2002a |
| Desethyldesisopropyl atrazine (DACT) |
4 weeks
Rats (Sprague-Dawley)
20 females/group
|
0, 2.5, 5, 40, 200 mg/kg bw/day by gavage
desethyldesisopropyl atrazine (purity
not specified)
|
40 mg/kg bw/day and above: Significantly decreased adjusted peak LH surge. |
5 mg/kg bw/day |
Minnema 2001a – quoted from US-EPA 2002b |
13 weeks
Rats (Sprague-Dawley)
15/sex/group
|
0, 10, 100, 250, 500 mg/kg of feed (equal to 0, 0.7, 6.7, 17, 34 mg/kg bw/day
for m and to 0, 0.7, 7.6, 19, 40 mg/kg bw/day for f)
desethyldesisopropyl atrazine (98%
pure)
|
7.6 mg/kg bw/day and above: Altered oestrous cyclicity.
19 mg/kg bw/day and above: Decreased body weight gain in f; slight
perturbations of serum calcium, total protein, and globulin; increased
testes weight.
34 mg/kg bw/day: Decreased body weight gain in m; high urinary
volume and increased relative kidney weights; histological renal
inflammatory changes in 3 f; increased spleen weight and decreased
relative thymus weight.
No apparent effects on serum levels of oestradiol, progesterone,
prolactin, and corticosterone.
No biologically significant effects on haematology.
|
0.7 mg/kg bw/day |
Ciba-Geiga 1991 – quoted from EC 1996a, US-EPA 2002a |
13 or 52 weeks
Dogs
m and f
|
0, 5, 100, 1500/750 (after 6 weeks) mg/kg of feed (equal to 0, 0.19, 3.6,
24 mg/kg bw/day for m and to 0, 0.20, 3.4, 33 mg/kg bw/day for f)
desethyldesisopropyl atrazine (purity
not specified)
|
24(m)/33(f) mg/kg bw/day: Moribund sacrifice of 5 m and 2 f because of impairment
of heart function (primary treatment-related effect); secondary treatment-related
effects in liver, testes, thymus, bone marrow, and pericardium, thoracic and abdominal
cavities; decreased body weight gain; increased spleen, liver, and kidney weights;
anaemia; changes in some clinical chemical parameters. |
3.4 mg/kg bw/day |
Ciba-Geiga 1990 – quoted from US-EPA 2002a |
| Hydroxyatrazine |
13 weeks
Rats (Sprague-Dawley)
15/sex/group
|
0, 10, 100, 300, 600 mg/kg of feed (equal to 0, 0.64, 6.3, 19, 37 mg/kg bw/day
for m and to 0, 0.75, 7.4, 23, 46 mg/kg bw/day for f)
hydroxyatrazine (97% pure)
|
19(m)/23(f) mg/kg bw/day and above: Increased urine volume in m; toxic nephrosis.
37(m)/46(f) mg/kg bw/day: Decreased body weight gain; depressed
red blood cell parameters; increased serum blood urea nitrogen,
creatinine, sodium, and chloride; increased urine volume in f;
increased relative kidney weights; tubule crystals in the kidneys.
|
6.3 mg/kg bw/day |
Ciba-Geiga 1989 – quoted from US-EPA 2002a |
2 years
Rats (Crl:CD(SD)BR)
70-80/sex/group
|
0, 10, 25, 200, 400 mg/kg of feed (equal to 0, 0.39, 0.96, 7.8, 17 mg/kg bw/day
for m and to 0, 0.48, 1.2, 9.4, 22 mg/kg bw/day for f)
technical hydroxyatrazine (97% pure)
|
0.96(m)/1.2(f) mg/kg bw/day and above: Transient dose-related increase in
-glutamyl transferase in f, in m this finding was confined to the top dose.
7.8(m)/9.4(f) mg/kg bw/day and above: Gross and histopathological
effects in the kidneys.
17(m)/22(f) mg/kg bw/day: Excessive, treatment-related mortality
predominantly caused by severe renal failure; clinical signs of renal
failure; decreased body weight gains and food consumption; changes
in haematology parameters, in clinical chemical parameters, in
urinalysis parameters, and in organ weights indicating kidney toxicity.
See chapter 4.7.2 for carcinogenic effects.
|
0.48 (EC) - 0.96 (US-EPA) mg/kg bw/day |
Ciba-Geiga 1995 – quoted from EC 1996a, US-EPA 2002a |
13 weeks
Dogs (Beagle)
4/sex/group
|
0, 15, 150, 1500, 6000 mg/kg of feed (equivalent to 0.5, 5, 50, 200 mg/kg
bw/day)
hydroxyatrazine (97% pure)
|
50 mg/kg bw/day and above: Increased urine volume; gross and histopathological
effects in the kidneys.
200 mg/kg bw/day: Decreased body weight gain; depressed red
blood cell parameters (without statistical significance).
|
5 mg/kg bw/day |
Chau et al. 1990 – quoted from EC 1996a |
Table 5. Repeated dose toxicity animal studies with dermal contact to triazines.
Duration of study
Species (Strain)
No/sex/group
|
Dose levels |
Results |
NOAEL |
Reference |
| Atrazine |
25 days (6 hrs/day)
Rabbits (New
Zealand white)
5/sex/group
|
0, 10, 100, 1000 mg/kg bw/day
technical atrazine (98%
pure)
|
100 mg/kg bw/day: Transient body weight decreases in females (according to
EC 1996a).
1000 mg/kg bw/day: Reduced body weight gain and food consumption;
increased relative spleen and liver weight; reduced red blood cell parameters and
increased cholesterol and triglyceride levels in f; reduced total protein and
chloride levels in m.
Dermal findings: Limited to slight acanthosis at all dose levels; minimal to
moderate acanthosis and focal subacute inflammation in the treated skin in 3
females at the high dose.
|
10 (EC) -100 (US-EPA) mg/kg bw/day for systemic toxicity |
Huber 1989 – quoted from EC 1996a, US-EPA 2002a |
| Simazine |
Three weeks (5 days/week, 6 hrs/day)
Rabbits (New
Zealand white)
10/sex/group
|
0, 10, 100, 1000 mg/kg bw/day
technical simazine (98%
pure)
|
100 mg/kg bw/day: Reduced body weight gain in m.
1000 mg/kg bw/day: Reduced body weight gain also in f.
Dermal findings: A localised ulcerative dermatitis in 3 animals, and transient very
slight erythema and/or oedema in 2 animals at the two highest doses.
|
10 mg/kg bw/day for systemic toxicity |
Bier 1980 – quoted from EC 1996b |
| Terbutylazine |
28 days (6 hrs/day)
Rabbits (New
Zealand white)
5/sex/group
|
0, 0.05, 0.5, 500 mg/kg bw/day (moistened with distilled water)
technical terbutylazine
(97% pure)
|
500 mg/kg bw/day: Reduced body weight gain and food consumption; mortality
occurred in one female preceded by cachexia, hypothermia and muscle wasting. |
0.5 mg/kg bw/day |
Ciba-Geiga 1987 – quoted from US-EPA 1995 |
28 days (6 hrs/day, 5days/week)
Rabbits (New
Zealand white)
5-10/sex/group
|
0, 5, 50, 500 mg/kg bw/day (in aqueous vehicle)
technical terbutylazine
(99.8% pure)
|
5 mg/kg bw/day and above: Dose-related clinical signs (dyspnoea, piloerection,
sedation, curved body posture, tremors, ataxia); dermal irritation.
500 mg/kg bw/day: Reduced body weight gain and food consumption.
|
< 5 mg/kg bw/day |
Ciba-Geiga 1984 – quoted from US-EPA 1995 |
Table 6. Toxicity to reproduction animal studies with oral exposure to triazines.
Click here to see the Table.
Table 7. Mutagenic and genotoxic effects of triazines in vitro.
| Species (test system) |
End point |
With activation |
Without activation |
Reference |
| Atrazine |
| Prokaryotic organisms: |
| Salmonella typhimurium (Ames test) |
Reverse mutation |
- (1/12 of the Ames tests were + for TA100) |
- |
Several studies 1972-1997 – quoted from ATSDR 2001, IARC 1999a
Ciba-Geigy 1986 – quoted from US-EPA
2002a
|
Salmonella typhimurium
Escherichia coli
|
Forward mutation |
- |
- |
Adler 1980 – quoted from ATSDR 2001, IARC 1999a |
| Bacteriophage |
Reverse mutation
Forward mutation
|
Not tested |
- |
Andersen et al. 1972 – quoted from ATSDR 2001, IARC 1999a |
| Escherichia coli PQ37 |
SOS repair |
- |
- |
Ruiz and Marzin 1997 – quoted from ATSDR 2001, IARC 1999a |
| Eukaryotic organisms: |
| Saccharomyces cerevisiae |
Reverse mutation
Forward mutation
Gene conversion
Mitotic recombination
|
Not tested
Not tested
-/+
Not tested
|
-/(+)
-/+
-/+
-
|
Several studies 1976-1992 – quoted from ATSDR 2001, IARC 1999a |
| Aspergillus nidulans |
Forward mutation
Gene conversion
Mitotic recombination
Aneuploidy
|
+
Not tested
+/-
+
|
-
-
-
-
|
Several studies 1979-1988 – quoted from ATSDR 2001, IARC 1999a |
| Schizosaccharomyces pombe |
Reverse mutation |
+ |
+ |
Mathias 1987 – quoted from ATSDR 2001, IARC 1999a |
| Neurospora crassa |
Aneuploidy |
Not tested |
+ |
Griffiths 1979 – quoted from IARC 1999a |
Hordeum vulgare
Zea mays
Nicotiana tabacum
|
Mutation |
Not tested |
+/-
+
-
|
Several studies 1966-1989 – quoted from IARC 1999a |
| Tradescantia paludosa |
Micronucleus formation |
+ |
- |
Ma et al. 1984, Mohammed and Ma 1999 – quoted from ATSDR 2001, IARC
1999a |
Hordeum vulgare
Zea mays
Vicia faba
Sorghum sp.
Nigella damascena
|
Chromosomal aberrations |
Not tested |
+/-
-
+/-
+/-
+/-
|
Several studies 1967-1987 – quoted from IARC 1999a |
| Mammalian cells: |
| Chinese hamster lung V79 (HPRT gene mutation assay) |
Forward mutation |
- |
- |
Adler 1980 – quoted from IARC 1999a |
| Chinese hamster ovary (chromosome damage assay) |
Chromosomal aberrations |
- |
- |
Adler 1980, Ishidate 1988 – quoted from IARC 1999a |
| Human lymphocytes |
Chromosomal aberrations |
Not tested |
+ |
Meisner et al. 1992, 1993 – quoted from ATSDR 2001, IARC 1999a |
| Human lymphocytes |
Chromosomal aberrations |
Not tested |
- |
Kligerman et al. 2000b |
| Human lymphocytes |
DNA damage |
- |
+ |
Ribas et al. 1995 – quoted from ATSDR 2001, IARC 1999a |
| Human lymphocytes |
DNA repair exclusive of unscheduled DNA synthesis |
Not tested |
- |
Surrallés et al. 1995 - quoted from IARC 1999a |
| Human EUE (unscheduled DNA synthesis) |
Repairable DNA damage |
- |
- |
Adler 1980 – quoted from IARC 1999a |
| Rat primary hepatocytes (unscheduled DNA synthesis) |
Repairable DNA damage |
- |
Not applicable |
? 1984, Ciba-Geigy 1992 – quoted from US-EPA 2002a |
| Human lymphocytes |
Sister chromatid exchange |
Not tested |
- |
Kligerman et al. 2000b |
| Human lymphocytes |
Sister chromatid exchange |
- |
- |
Ghiazza et al. 1984, Dunkelberg et al. 1994 – quoted from ATSDR 2001,
IARC 1999a |
| Simazine |
| Prokaryotic organisms: |
Salmonella typhimurium (Ames test)
Escherichia coli WP2 uvr
Serratia marcescens
|
Reverse mutation |
- |
- |
Several studies 1973-1988 – quoted from IARC 1999b |
| Escherichia coli |
Forward mutation |
Not tested |
- |
Fahrig 1974 – quoted from IARC 1999b |
Salmonella typhimurium
Bacillus subtilis
|
Differential toxicity |
Not tested |
- |
US-EPA 1984, Kuroda et al. 1992 – quoted from IARC 1999b |
| Escherichia coli PQ37 |
SOS repair |
- |
Not tested |
Mersch-Sundermann et al. 1988 – quoted from IARC 1999b |
| Eukaryotic organisms: |
| Saccharomyces cerevisiae |
Reverse mutation
Gene conversion
Mitotic recombination
Homozygosis by
recombination
|
- |
- |
Several studies 1974-1987 – quoted from IARC 1999b |
| Neurospora crassa |
Aneuploidy |
Not tested |
- |
Griffiths 1979 – quoted from IARC 1999b |
| Hordeum vulgare |
Mutation |
Not tested |
+/- |
Wuu and Grant 1966, Stroev 1968a – quoted from IARC 1999b |
| Rizobium meliloti |
Mutation |
Not tested |
- |
Kaszubiak 1968 – quoted from IARC 1999b |
Zea mays
Fragaria ananassa
|
Mutation |
Not tested |
+ |
Several studies 1982-1990 – quoted from IARC 1999b |
| Tradescantia paludosa |
Micronucleus formation |
Not tested |
- |
Ma et al. 1984 – quoted from IARC 1999b |
Hordeum vulgare
Vicia faba
Allium cepa
Crepis capillaris
|
Chromosomal aberrations |
Not tested |
+/(+)
+/(+)
+
+
|
Several studies 1966-1984 – quoted from IARC 1999b |
| Mammalian cells: |
| Mouse lymphoma L5158Y (TK gene mutation assay) |
Forward mutation |
- |
(+) |
US-EPA 1984 – quoted from IARC 1999b |
| Chinese hamster ovary (chromosome damage assay) |
Chromosomal aberrations |
Not tested |
- |
Biradar and Rayburn 1995 – quoted from IARC 1999b |
| Human lymphocytes |
Chromosomal aberrations |
Not tested |
- |
Kligerman et al. 2000b |
| Human lung WI 38 fibroblasts (unscheduled DNA synthesis) |
Repairable DNA damage |
- |
- |
US-EPA 1984 – quoted from IARC 1999b |
Chinese hamster ovary
Chinese hamster lung V79
|
Sister chromatid exchange |
Not tested |
- |
US-EPA 1984, Kuroda et al. 1992 – quoted from IARC 1999b |
| Human lymphocytes |
Sister chromatid exchange |
Not tested |
- |
Kligerman et al. 2000b |
| Human lymphocytes |
Sister chromatid exchange |
- |
(+)/- |
Ghiazza et al. 1984, Dunkelberg et al. 1994 – quoted from IARC 1999b |
| Terbutylazine |
| Prokaryotic organisms: |
| Salmonella typhimurium (Ames test) |
Reverse mutation |
- |
- |
Ciba-Geigy 1977, 1987 – quoted from US-EPA 1995, WHO 1998b |
| Mammalian cells: |
| Mouse lymphoma (TK gene mutation assay) |
Forward mutation |
- |
- |
Ciba-Geigy 1983 – quoted from US-EPA 1995, WHO 1998b |
| Chinese hamster V79 (gene mutation assay) |
Forward mutation |
- |
- |
Ciba-Geiga ? – quoted from WHO 1998b |
Chinese hamster
Human lymphocytes
(chromosome damage assay)
|
Chromosomal aberrations |
- |
- |
Ciba-Geiga ? – quoted from WHO 1998b |
| Human fibroblasts (unscheduled DNA synthesis) |
Repairable DNA damage |
- (not stated whether with or without activation) |
Ciba-Geigy 1984 – quoted from US-EPA 1995, WHO 1998b |
| Rat hepatocytes (unscheduled DNA synthesis) |
Repairable DNA damage |
- |
Not applicable |
Ciba-Geigy 1984, 1989 – quoted from US-EPA 1995, WHO 1998b |
| Cyanazine |
| Prokaryotic organisms: |
| Salmonella typhimurium (Ames test) |
Reverse mutation |
- |
- |
Several studies 1979-1993 – quoted from Bogdanffy et al. 2000, WHO 1998a |
| Salmonella typhimurium (Ames test) |
Reverse mutation |
- with rodent metabolic activation
+ with a plant-derived
activation system
|
Plewa et al. 1984 – quoted from WHO 1998a |
| Escherichia coli WP2 hcr |
Reverse mutation |
- |
Not tested |
Moriya et al. 1983 – quoted from Bogdanffy et al. 2000 |
| Serratia marcescens |
Reverse mutation |
Not tested |
- |
Dean et al. 1974 – quoted from Bogdanffy et al. 2000 |
| Escherichia coli PQ37 |
SOS repair |
+ (not stated whether with or without activation) |
Venkat et al. 1995 - quoted from Bogdanffy et al. 2000 |
| Escherichia coli |
SOS repair |
- (not stated whether with or without activation) |
Xu and Schurr 1990 - quoted from Bogdanffy et al. 2000 |
| Eukaryotic organisms: |
| Saccharomyces cerevisiae |
Reverse mutation |
- |
- |
Plewa et al. 1984 - quoted from Bogdanffy et al. 2000 |
| Mammalian cells: |
| Mouse lymphoma L5178Y (TK gene mutation assay) |
Forward mutation |
+ |
+ |
Shell 1986 – quoted from Bogdanffy et al. 2000, WHO 1998a |
| Chinese hamster ovary (HPRT gene mutation assay) |
Forward mutation |
- (not stated whether with or without activation) |
E.I. duPont de Nemours and Co. 1987 – quoted from Bogdanffy et al. 2000,
WHO 1998a |
| Chinese hamster ovary (flow cytometric analysis) |
Clastogenesis |
- (not stated whether with or without activation) |
Teats et al. 1998 – quoted from Bogdanffy et al. 2000 |
| Human lymphocytes |
Sister chromatid exchange |
Not tested |
- |
Kligerman et al. 2000b |
| Human lymphocytes |
Chromosomal aberrations |
Not tested |
- |
Kligerman et al. 2000b |
| Human lymphocytes (chromosome damage assay) |
Chromosomal aberrations |
- (not stated whether with or without activation) |
E.I. duPont de Nemours and Co. 1987 – quoted from Bogdanffy et al. 2000,
WHO 1998a |
| Human lymphocytes (chromosome damage assay) |
Chromosomal aberrations |
+ (not stated whether with or without activation) |
Roloff et al 1992 - quoted from Bogdanffy et al. 2000 |
| Rat primary hepatocytes (unscheduled DNA synthesis) |
Repairable DNA damage |
+ |
Not applicable |
E.I. duPont de Nemours and Co. 1987 – quoted from Bogdanffy et al. 2000,
WHO 1998a |
| Desethyl atrazine (DEA) |
Salmonella typhimurium (Ames test)
Escherichia coli
|
Reverse mutation |
- (not stated whether with or without activation) |
Ciba-Geiga 1989 – quoted from US-EPA 2002a |
| Rat primary hepatocytes (unscheduled DNA synthesis) |
Repairable DNA damage |
- |
Not applicable |
Ciba-Geiga 1991 – quoted from US-EPA 2002a |
| Desisopropyl atrazine (DIA) |
Salmonella typhimurium (Ames test)
Escherichia coli WP2 uvrA
|
Reverse mutation |
- (not stated whether with or without activation) |
Ciba-Geiga 1990 – quoted from US-EPA 2002a |
| Rat primary hepatocytes (unscheduled DNA synthesis) |
Repairable DNA damage |
- |
Not applicable |
Ciba-Geiga 1991 – quoted from US-EPA 2002a |
| Desethyldesisopropyl atrazine (DACT) |
| Salmonella typhimurium (Ames test) |
Reverse mutation |
- (not stated whether with or without activation) |
Ciba-Geiga 1987 – quoted from US-EPA 2002a |
| Human fibroblasts (unscheduled DNA synthesis) |
Repairable DNA damage |
- (unclear whether with or without activation) |
Ciba-Geiga 1987 – quoted from US-EPA 2002a |
| Hydroxyatrazine |
| Salmonella typhimurium (Ames test) |
Reverse mutation |
- (not stated whether with or without activation) |
Ciba-Geiga 1988 – quoted from US-EPA 2002a |
| Rat primary hepatocytes (unscheduled DNA synthesis) |
Repairable DNA damage |
- |
Not applicable |
Ciba-Geiga 1988 – quoted from US-EPA 2002a |
| Human fibroblasts (unscheduled DNA synthesis) |
Repairable DNA damage |
- (not stated whether with or without activation) |
Ciba-Geiga 1988 – quoted from US-EPA 2002a |
| Hydroxysimazine |
| Salmonella typhimurium (Ames test) Escherichia coli WP2 uvrA |
Reverse mutation |
- |
- |
Hertner 1994c – quoted from EC 1996b |
Table 8. Mutagenic and genotoxic effects of triazines in vivo.
| Species (test system) |
End point |
Results |
Reference |
| Atrazine |
| Mammalian cells: |
| Rat stomach, liver and kidney |
DNA strand breaks |
+ |
Pino et al. 1988 – quoted from ATSDR 2001, IARC 1999a |
| Rat lung |
DNA strand breaks |
- |
Pino et al. 1988 – quoted from ATSDR 2001, IARC 1999a |
| Mice leukocytes (alkaline single cell gel electrophoresis assay) |
DNA damage |
+ |
Tennant et al. 2001 |
| Mice (NMRI) bone marrow |
Micronucleus formation |
- (males)/+(females) |
Gebel et al. 1997 – quoted from ATSDR 2001, IARC 1999a |
| Mice bone marrow |
Micronucleus formation |
- |
Ciba-Geigy 1988 – quoted from US-EPA 2002a |
| Mice bone marrow |
Micronucleus formation |
- |
Kligerman et al. 2000a |
| Mice bone marrow |
Chromosome aberrations |
- |
Meisner et al. 1992 – quoted from ATSDR 2001, IARC 1999a |
| Mice (dominant lethal assay) |
Post-implantation mortality of embryos |
- |
Hertner 1993 – quoted from EC 1996a, US-EPA 2002a |
| Mice (dominant lethal assay) |
Post-implantation mortality of embryos |
(+) |
Adler 1980 – quoted from IARC 1999a |
| Mice |
Sperm morphology |
- |
Osterloh et al. 1983 – quoted from IARC 1999a |
| Non-mammalian cells: |
| Rana catesbeiana tadpoles |
DNA damage |
+ |
Clements et al. 1997 – quoted from IARC 1999a |
| Drosophila melanogaster |
Somatic mutation
Dominant lethal mutation
Aneuploidy
|
+ |
Several studies 1977-1993– quoted from ATSDR 2001, IARC 1999a |
| Drosophila melanogaster |
Sex-linked recessive lethal mutation |
+/- |
Several studies 1977-1993 – quoted from IARC 1999a |
| Simazine |
| Mammalian cells: |
| Mice leukocytes (alkaline single cell gel electrophoresis assay) |
DNA damage |
- |
Tennant et al. 2001 |
| Mice bone marrow and peripheral blood |
Micronucleus formation |
- |
US-EPA 1984 – quoted from IARC 1999b |
| Mice bone marrow |
Micronucleus formation |
- |
Kligerman et al. 2000a |
| Non-mammalian cells: |
| Drosophila melanogaster |
Somatic mutation
Dominant lethal mutation
|
+ |
Tripathy et al. 1995, Murnik and Nash 1977 – quoted from IARC 1999b
|
| Drosophila melanogaster |
Sex-linked recessive lethal mutation |
+/- |
Several studies 1969-1995 – quoted from IARC 1999b |
| Drosophila melanogaster |
Aneuploidy |
- |
Murnik and Nash 1977 – quoted from IARC 1999b |
| Terbutylazine |
| Chinese hamster |
Chromosomal aberrations |
- |
Ciba-Geigy ? – quoted from WHO 1998b |
| Mice bone marrow |
Micronucleus formation |
- |
Ciba-Geigy 1989 – quoted from US-EPA 1995, WHO 1998b |
| Cyanazine |
| Mammalian cells: |
| Rat hepatocytes |
DNA strand breaks |
- |
Grilli et al. 1991 - quoted from Bogdanffy et al. 2000 |
| Mice leukocytes (alkaline single cell gel electrophoresis assay) |
DNA damage |
(+) |
Tennant et al. 2001 |
| Mice bone marrow |
Micronucleus formation |
- |
Kligerman et al. 2000a |
| Mice bone marrow |
Chromosome aberrations |
- |
Dean 1974 - quoted from Bogdanffy et al. 2000 |
| Mice (dominant lethal assay) |
Post-implantation mortality of embryos |
- |
Dean 1974 - quoted from Bogdanffy et al. 2000 |
| Rat spermatocytes (unscheduled DNA synthesis) |
DNA damage in germ cells |
- |
E.I. duPont de Nemours and Co. 1987 – quoted from Bogdanffy et al. 2000,
WHO 1998a |
| Non-mammalian cells: |
| Drosophila melanogaster |
Dominant lethal mutation
Sex-linked recessive lethal
mutation
Non-disjunction
|
- |
Murnick and Nash 1977 - quoted from Bogdanffy et al. 2000 |
| Desethyl atrazine (DEA) |
| Mice (Tif:MAGF) polychromatic erythrocytes |
Micronucleus formation |
- |
Ciba-Geigy 1991 – quoted from US-EPA 2002a |
| Desisopropyl atrazine (DIA) |
| Mice (Tif:MAGF) polychromatic erythrocytes |
Micronucleus formation |
- |
Ciba-Geigy 1991 – quoted from US-EPA 2002a |
| Desethyldesisopropyl atrazine (DACT) |
| Mice (Tif:MAGF) polychromatic erythrocytes |
Micronucleus formation |
- |
Strasser 1988 – quoted from EC 1996a |
| Hydroxyatrazine |
| Mice |
Micronucleus formation |
- |
Ciba-Geigy 1988 – quoted from US-EPA 2002a |
Table 9. Carcinogenic effects in animal studies with oral exposure to triazines.
Duration of study
Species (Strain)
No/sex/group
|
Dose levels |
Tumours |
NOAEL |
Reference |
| Atrazine |
91 weeks
Mice (CD-1)
60/sex/group
|
0, 10, 300, 1500, 3000 mg/kg of feed (equal to 0, 1.4, 38, 194, 386 mg/kg
bw/day for m and to 0, 1.6, 48, 246, 483 mg/kg bw/day for f)
technical atrazine (purity > 96%)
|
Atrazine was not carcinogenic in mice.
See chapter 4.4.2 for non-neoplastic effects.
|
386 mg/kg bw/day |
Ciba-Geigy 1987 - quoted from IARC 1999a, US-EPA 2002a |
2 years
Rats (Sprague-Dawley)
70-90/sex/group
|
0, 10, 70, 500, 1000 mg/kg of feed (equal to 0, 0.4, 2.6, 20, 42 mg/kg bw/day
for m and to 0, 0.5, 3.5, 30, 65 mg/kg bw/day for f)
technical atrazine (96% pure)
|
At the three highest doses, a significant increase in the incidence of mammary
gland adenocarcinomas was seen in females (15/88, 16/69, 27/69, 27/70 and 43/89
in order of increasing dose). At the highest dose, the incidence of mammary gland
fibroadenomas in females was significantly increased (29/88, 29/69, 36/69, 39/70
and 45/89 in order of increasing dose).
In males, the incidence of Leydig cell tumours was significant increased at
the highest dose but fell within historical control data and was attributed in
part to the better survival of these animals.
See chapter 4.4.2 for non-neoplastic effects.
|
0.5 mg/kg bw/day |
Ciba-Geigy 1986 - quoted from IARC 1999a, EC 1996a, US-EPA 2002a, WHO 1996a |
2 years
Rats (Sprague-Dawley)
60/females/group
|
0, 70, 400 mg/kg of feed (equivalent to 0, 3.8, 23 mg/kg bw/day)
technical atrazine (97% pure)
|
The overall incidences of mammary gland tumours at the end of the study were
similar in the treated and control groups. However, a statistically significant
earlier onset of mammary gland tumours was observed in high dose animals. |
3.8 mg/kg bw/day |
Hazleton Washington Inc. 1992 – quoted from ATSDR 2001, IARC 1999a,
US-EPA 2002a |
Life-time
Rats (Sprague-Dawley)
49-54/females/group
|
0, 10, 100, 1000 mg/kg of feed (equivalent to 0.5, 5, 50 mg/kg bw/day)
technical atrazine (96% pure)
|
The incidences of mammary gland fibroadenomas were significantly increased
in low and high dose females (11/54, 20/52, 14/54 and 22/49 in order of increasing
dose), but there was no significant increase in the incidence of mammary gland
adenocarcinomas (11/54, 8/52, 12/54 and 13/49 in order of increasing dose). |
?? mg/kg bw/day |
Stevens et al. 1994 – quoted from IARC 1999a |
2 years
Rats (Sprague-Dawley)
29-40/females/group culled from the
F2 generation of a two-generation
study of reproductive toxicity
|
0, 10, 50, 500 mg/kg of feed (equivalent to 0.5, 2.5, 25 mg/kg bw/day)
technical atrazine (98% pure)
|
The incidences of mammary gland tumours were not increased. |
25 mg/kg bw/day |
Stevens et al. 1994 – quoted from IARC 1999a |
2 years
Rats (Sprague-Dawley)
160/females/group
Half of the females in each group
were ovariectomised at seven weeks
of age.
|
0, 25, 50, 70, 400 mg/kg of feed (equal to 0, 1.5, 3.1, 4.2, 24 mg/kg bw/day
for intact f and to 0, 1.2, 2.5, 3.5, 21 mg/kg bw/day for ovariectomised f)
technical atrazine (97% pure)
|
No mammary tumours were found in any group of treated, ovariectomised females.
However, the incidence of mammary gland fibroadenomas in the intact
females was significantly increased at the three highest doses after
adjustment for survival (16/80, 25/80, 33/78, 29/80 and 25/80 in order of
increasing dose), and the incidence of mammary gland carcinomas was
significantly increased in females dosed with 3.1 and 24 mg/kg bw/day
(12/80, 18/80, 20/78, 14/80 and 27/80 in order of increasing dose). An
earlier onset of mammary gland tumours was observed in all dosed animals.
|
<1.5 mg/kg bw/day |
Covance Laboratories 1998 – quoted from IARC 1999a, US-EPA 2002a |
2 years
Rats (Fischer 344)
60/sex/group
|
0, 10, 70, 200, 400 mg/kg of feed (equal to 0, 0.5, 3.4, 9.9, 20 mg/kg bw/day
for m and to 0, 0.6, 4.4, 13, 26 mg/kg bw/day for f)
technical atrazine (97% pure)
|
Atrazine was not carcinogenic in Fischer 344 rats.
See chapter 4.4.2 for non-neoplastic effects.
|
20 mg/kg bw/day |
Hazleton Washington 1992 - quoted from ATSDR 2001, IARC 1999a, US-EPA 2002a |
Life-time
Rats (Fischer 344)
50-56/sex/group
|
0, 500, 1000 mg/kg of feed (equivalent to 25, 50 mg/kg bw/day)
Because of toxicity, doses were
reduced to 0, 375, 750 mg/kg
of feed (equivalent to 19, 38
mg/kg bw/day) 8 weeks after
the start of treatment.
Technical atrazine (99% pure)
|
Atrazine was not carcinogenic in Fischer 344 rats.
An increased incidence of uterine adenocarcinomas and combined
leukaemia and lymphoma in females, and benign mammary gland tumours in
males at the highest dose was not significant when adjusted for increased
survival in the treated groups.
|
38 mg/kg bw/day |
Pinter et al. 1990, Thakur et al. 1998 – quoted from ATSDR 2001, IARC
1999a |
| Simazine |
95 weeks
Mice (Swiss CD-1)
60/sex/group
|
0, 40, 1000, 4000 mg/kg of feed (equivalent to 6, 150, 600 mg/kg bw/day)
technical simazine (purity not
specified)
|
Simazine was not carcinogenic in mice. |
600 mg/kg bw/day |
Ciba-Geigy 1988 - quoted from WHO 1996b |
2 years
Rats (Sprague-Dawley)
80-90/sex/group
|
0, 10, 100, 1000 mg/kg of feed (equal to 0.52, 5.3, 46 mg/kg bw/day in f)
technical simazine (97% pure)
|
An increased incidence and an earlier onset of mammary gland tumours were
observed in high-dose females according to IARC 1999b. According to EC 1996b,
US-EPA 2002b and WHO 1996b, there was an increase of mammary tumours also at mid-dose.
The incidences of fibroadenomas were 22/70, 27/70, 19/70, and 40/70 in
order of increasing dose. The incidences of adenocarcinomas were 14/70, 13/70,
19/70, and 35/70 in order of increasing dose. The incidence of pituitary gland
carcinoma (1/70, 3/70, 0/69, 6/70) was also significantly increased at the high
dose in females but fell within the historical control data.
According to WHO 1996b, the incidence of adenomas and carcinomas of
the liver in males increased. According to IARC 1999b, the male rats did
not show increased incidences of tumours.
According to EC 1996b, a small increase in renal tubular tumours (adenoma
and carcinoma) was observed based on which the European Commission
has classified simazine for carcinogenicity. Renal tubular adenomas were
only observed in high dose animals with an incidence of 2/80 in males and
2/80 in females. Renal tubular carcinomas were only observed in males with
incidences of 1/80, 0/80, 0/80, and 2/80 in order of increasing dose.
See chapter 4.4.2 for non-neoplastic effects and chapter 5 for classification.
|
0.52 mg/kg bw/day (EC 1996b, US-EPA, WHO)
5.3 mg/kg
bw/day
(IARC)
|
Ciba-Geigy 1988 - quoted from EC 1996b, IARC 1999b, US-EPA 2002b, WHO 1996b |
| Terbutylazine |
2 years
Mice (Tif/MAGF)
50/sex/group
|
0, 30, 150, 750 mg/kg of feed (equal to 0, 3.3, 17, 87 mg/kg bw/day for m
and to 0, 3.2, 17, 89 mg/kg bw/day for f)
technical terbutylazine (98%
pure)
|
Terbutylazine was not carcinogenic in mice.
See chapter 4.4.2 for non-neoplastic effects.
|
87 mg/kg bw/day |
Ciba-Geigy 1982– quoted from US-EPA 1995, WHO 1998b |
2 years (followed by untreated diet for 8 (m) or 18 (f) weeks)
Rats (Tif/RAIf)
80/sex/group
=Sprague-Dawley ??
|
0, 30, 150, 750 mg/kg of feed (equal to 0, 1.2, 7.0, 42 mg/kg bw/day for m
and to 0, 1.4, 7.8, 53 mg/kg bw/day for f)
technical terbutylazine (97%
pure)
|
An increased incidence of mammary gland carcinomas (18% vs. 5% in the controls)
and a decreased incidence of fibroadenomas of the mammary gland were observed
in high-dose females. The incidence of mammary gland tumours was within the historical
control range.
An increased incidence of Leydig cell tumours (13% vs. 4% in the controls)
was observed in high-dose males. Most of these tumours were observed in
old rats (after 2 years).
See chapter 4.4.2 for non-neoplastic effects.
|
7.0 mg/kg bw/day |
Ciba-Geigy 1983 – quoted from US-EPA 1995, WHO 1998b |
98 weeks (followed by untreated diet for 20 (m) or 23 (f) weeks)
Rats (Tif/RAIF)
80/sex/group
|
0, 6, 30 mg/kg of feed (equal to 0, 0.4, 1.6 mg/kg bw/day for m and f)
technical terbutylazine (98%
pure)
|
Terbutylazine was not carcinogenic at the doses tested.
See chapter 4.4.2 for non-neoplastic effects.
|
1.6 mg/kg bw/day |
Ciba-Geigy 1983 – quoted from US-EPA 1995, WHO 1998b |
| Cyanazine |
2 years
Mice
m and f
|
0, 10, 25, 250, 1000 mg/kg of feed (equivalent to 0, 1.3, 3.3, 33, 130 mg/kg
bw/day)
cyanazine (96% pure)
|
Cyanazine was not carcinogenic in mice.
See chapter 4.4.2 for non-neoplastic effects.
|
130 mg/kg bw/day |
Shell Chemical Co. 1981 – quoted from WHO 1998a |
2 year
Rats (Sprague-Dawley)
52/sex/group
10/sex/group as satellite groups
sacrificed after 1 year
|
0, 1, 5, 25, 50 mg/kg of feed (equal to 0, 0.040, 0.20, 0.99, 2.1 mg/kg bw/day
for m and to 0, 0.053, 0.26, 1.4, 2.8 mg/kg bw/day for f)
cyanazine (96% pure)
|
The incidence of palpable masses was significantly increased for females at
the highest dose and the median time to first observed mass was decreased compared
to controls.
Cyanazine caused statistically significant increases in malignant mammary
gland tumours (adenocarcinoma and carcinosarcoma) in females at the two
highest doses with incidences of 5/58 (8%), 7/61 (11%), 12/60 (20%),
20/62 (32%), and 15/62 (24%) in increasing order of dose. The incidences
of these tumours in dosed rats were outside the historical control data at the
two highest doses.
See chapter 4.4.2 for non-neoplastic effects.
|
0.26 mg/kg bw/day |
E.I. duPont de Nemours and Co. 1990 – quoted from BCERF 1998, Bogdanffy
et al. 2000, WHO 1998a |
| Desethyldesisopropyl atrazine (DACT) |
1 year
Rat (Sprague-Dawley)
f
|
0, 25, 50, 70, 200 mg/kg of feed (equivalent to 1.3, 2.5, 3.5, 10 mg/kg bw/day)
desethyldesisopropyl atrazine
(purity not specified)
|
Desethyldesisopropyl atrazine caused a statistically significant increase
in the incidence of mammary gland tumours at the highest dose tested. |
3.5 mg/kg bw/day |
Minnema 2002 – quoted from US-EPA 2002b |
| Hydroxyatrazine |
2 years
Rats (Crl:CD(Sprague-Dawley)BR)
70-80/sex/group
|
0, 10, 25, 200, 400 mg/kg of feed (equal to 0, 0.39, 0.96, 7.8, 17 mg/kg bw/day
for m and to 0, 0.48, 1.2, 9.4, 22 mg/kg bw/day for f)
technical hydroxyatrazine (97%
pure)
|
Hydroxyatrazine was not carcinogenic in Sprague-Dawley rats.
See chapter 4.4.2 for non-neoplastic effects.
|
17 mg/kg bw/day |
Ciba-Geiga 1995 – quoted from US-EPA 2002a |
Table 10. Lowest NOAELs/LOAELs (mg/kg bw/day) for selected neuroendocrine effects in rats (unless otherwise stated) following oral exposure to the triazines or their degradation
products.
Click here to see the Table.
Table 11. Lowest NOAELs/LOAELs (mg/kg bw/day) for selected reproductive and developmental effects other than neuroendocrine effects in rats (unless otherwise stated) following
oral exposure to the triazines or their degradation products.
| Chemical |
Decreased body weight and/or food consumption in parental animals |
Decreased fetal body weight and/or pup viability |
Increased incidence of incomplete ossification sites and/or fused sternebrae
in foetuses |
Microphtalmia/anophtalmia, diaphragmatic hernia associated with liver protrusion,
and dilated brain ventricles in foetuses |
| a) atrazine |
3.7/39 (rats)
5/75 (rabbits)
|
3.7/39? (rats)
5/75 (rabbits)
|
10/70 (rats)
5/75 (rabbits)
|
No effect up to 700 (rats)
No effect up to 75 (rabbits)
|
| b) simazine |
0.5/5 (rats)
5/75 (rabbits)
|
5/75 (rabbits) |
10/50 (rats)
5/75 (rabbits)
|
No effect up to 300 (rats)
No effect up to 75 (rabbits)
|
| c) terbutylazine |
0.3/3 (rats)
0.5/1.5 (rabbits)
|
3/15 |
5/30 (rats)
No effect up to 5 (rabbits)
|
No effect up to 30 (rats)
No effect up to 5 (rabbits)
|
| d) cyanazine |
1.4/4.1(rats)
1/2 (rabbits)
|
3.8/11 |
<5/5 (rats)
1/2 (rabbits)
|
10/25 (rats)
2/4 (rabbits)
|
| e) desethyl atrazine (DEA) |
5/25 |
- [3] |
25/100 |
No effect up to 100 |
| f) desisopropyl atrazine (DIA) |
5/25 |
- |
5/25 |
No effect up to 100 |
| g) desethyl terbutylazine |
- |
- |
- |
- |
| h) desethyldesisopropyl atrazine (DACT) |
2.5/25 |
25/75 |
2.5/25 |
No effect up to 150 |
| i) hydroxyatrazine |
25/125 |
25/125 |
25/125 |
No effect up to 125 |
| j) hydroxysimazine |
- |
- |
- |
- |
| k) hydroxyterbutylazine |
- |
- |
- |
- |
Table 12. Lowest NOAELs/LOAELs (mg/kg bw/day) for selected repeated dose toxicity effects other than neuroendocrine effects in rats (unless otherwise stated) following oral
exposure to the triazines or their degradation products.
| Chemical |
Decreased body weight and/or food consumption |
Haematological changes [4] |
Cardiac toxicity [5] |
Kidney toxicity [6] |
| a) atrazine |
1.4/38 (mice)
0.6/3.3 (rats)
5/34(dogs)
|
38/194 (mice)
0.6/3.3 (rats)
5/34(dogs)
|
No effect up to 65 (rats)
5/34(dogs)
<2/2 (pigs)
|
194/386 (mice)
25/65 (rats)
<2/2 (pigs)
|
| b) simazine |
0.5/5 (rats)
0.7/3.3 (dogs)
|
0.5/5 (rats)
0.7/3.3 (dogs)
|
No effect up to 200 |
5/50 |
| c) terbutylazine |
17/87 (mice)
0.4/1.2 (rats)
<5/5 (rabbits)
0.4/1.7 (dogs)
|
1.2/7.0 (rats)
20/100 (rabbits)
1.7/8 (dogs)
|
No effects up to 42 (rats)
5/20 (rabbits)
|
- [7] |
| d) cyanazine |
3.3/33 (mice)
0.05/0.075 (rats)
0.68/3.0 (dogs)
|
0.99/2.1 |
No effects up to 5 |
3.3/33 (mice)
<0.05/0.05 (rats)
0.68/3.0 (dogs)
|
| e) desethyl atrazine (DEA) |
3.2/35 (rats)
3.7/29 (dogs)
|
No effect up to 35 (rats)
3.7/29 (dogs)
|
No effect up to 35 (rats)
3.7/29 (dogs)
|
No effect up to 35 (rats)
3.7/29 (dogs)
|
| f) desisopropyl atrazine (DIA) |
0.6/3.2 (rats)
3.8/18 (dogs)
|
0.6/3.2 |
3.8/18 (dogs) |
3.2/35 |
| g) desethyl terbutylazine |
- |
- |
- |
- |
| h) desethyldesisopropyl atrazine (DACT) |
7.6/19 (rats)
3.4/24 (dogs)
|
3.4/24 (dogs) |
No effect up to 34 (rats)
3.4/24 (dogs)
|
19/34 (rats)
3.4/24 (dogs)
|
| i) hydroxyatrazine |
7.8/17 (rats)
50/200 (dogs)
|
19/37 (rats)
50/200 (dogs)
|
No effect up to 37 (rats)
No effect up to 200 (dogs)
|
0.96/7.8 (rats)
5/50 (dogs)
|
| j) hydroxysimazine |
- |
- |
- |
- |
| k) hydroxyterbutylazine |
- |
- |
- |
- |
Footnotes
[3] - = No data or not able to determine a NOAEL/LOAEL from available data
[4] Anaemia, increased myeloid hyperplasia in the bone marrow, extramedullary haematopoiesis in the liver and spleen, and/or haemosiderin pigment in the spleen
[5] Clinical signs, ECG alterations, heart weight changes, and macroscopic and/or histopathological findings
[6] Changes in clinical signs, in haematology, clinical chemical, and urinalysis parameters, in kidney weight, and/or in macroscopy and histopathology
[7] - = No data or not able to determine a NOAEL/LOAEL from available data
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