Based on Heinz bodies formation and increased hemosiderin in liver or spleen at dose levels of 675 mg/kg bw/day and above
The pronounced emetic response/resultant loss of test material after gavage precluded the administration of higher dose levels to the Beagle dog.
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Based on haemolysis in dogs fed propylene glycol at dose level 5000 mg/kg bw/day which were not present in animals given an equicaloric control diet. 
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Highest dose
highest dose tested
highest dose tested
highest dose tested
Even at the highest tested dose level of 625 ppm, corresponding to 25 mg/kg bw/day of ingested test material, no treatment-related effects could be evidenced.
slight increase in plasma alkaline phosphatase activity
histopathological changes of the liver
Hematology, clinical chemistry, urinalyses, and histopathological observations.
No effect on survival, body weight, Opthalmoscopic examination, Urinanalysis,  Organ weight, gross pathology and histopathology
no adverse neurotoxic effects observed
Increased cholesterol, phospholipid and triglyceride concentrations and elevated alkaline phosphatase activity. Increased liver weight and associated microscopic lesions.
The evaluated No Observed Effect Level of Ametryn Technical in Beagle dogs was 400 ppm in food which is equivalent to 7.81 mg/kg Bwt/day in males and 6.64 mg/kg Bwtl/ay in females.
Changes in the liver. Increased liver weight and hepatocytic hypertrophy. Reduced body weight gain, reduced food consumption Elevated phosphatase activities
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based on reduced body weight and food consumption and alteration in clinical blood parameters
based on reduced body weight and food consumption and alteration in clinical blood parameters
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(i.e., equivalent to > 23 mg a.i./kg bw/day)
Test-article related adverse effects were seen at higher doses. No adverse effects occurred at 200 ppm.
The NOAEL is 1.0 mg/kg bw/day  of the pure active subsatnce cyanamide. Haematological changes which correlated to histomorphological findings, macroscopic findings and histopathological changes at 5 mg/kg bw/day dose group.
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The administration of 500 mg/kg bw/day was tolerated by the male and female dogs without any changes that could be related to the test substance.
growth inhibition; gross pathology
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equivalent to 200 ppm; no (adverse) effects observed
equivalent to 2000 ppm; severe clinical signs (leading to sacrifice in one animal), several hematological and clinicochemical effects
Adverse effects were observed at the 2 higher dose levels (900 and 2470 ppm). No adverse effects on general health, growth, hematology parameters, clinical chemistry, and urinalysis at this dose level (300 ppm).
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The NOAEL was based on retarded body weight gain, reduced food consumption as well as evidence on testicular damage at the high dose level of 12 mg/kg bw/day.
This is the highest dosage level administered for the entire duration of the study and it corresponds to plasma levels of 3159-6346ug*h/ml.
There was no effect of treatment at this dose level.
There was no effect of treatment at this dose level.
There was no effect of treatment at this dose level.
There was no effect of treatment at this dose level.
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corresponds to the highest dose tested
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See information for LOAEL
(based on the onset of nephrotoxicity indicated by polyuria)
Liver weight and activities of PCoA and CAT
See information for LOAEL
increased mortality, reduced bodyweight gain, increased water consumption, urinary output and plasma urea nitrogen values, nephropathy, lesions in the stomach, changes in the epididymides (males) and testes (males).
Liver functional and morphological changes Altered clinical chemistry Tubular degeneration and a reduced number of spermatocytes in the testes Gall bladder calculi Reduced prostrate weight and increased mineralisation Slight depression in bone marrow
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There was an increase in the liver weights in the 1.0% group, however there were no pathological changes or other changes evident in monkeys fed up to 1.0% in the diet.
Decreased body weight gain at 2500 mg/kg bw/day
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decrease relative kidney weights in females, increase in hepatic catalase activity in males.
no liver effects
no adverse effects observed related to treatment
no treatment-related pathologies observed
histopathology: increased renal tubular regeneration
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Males and females given 1560 mg/kg bw/day showed a 10-25% reduction in body-weight gain.
reduced water consumption and body weight gain (280 mg/kg bw/day)
dose corresponds to 370 mg/kg bw/day; reduced body weight related to reduced water consumption; limited number of parameters tested (carcinogenicity study)
decrease in body weight
Survival, clinical signs, body weight gain, neoplastic histopathology
histopathology: chronic forestomach inflammation, hyperplasia, and papillomas
see 'Remark'
The LOAEL for carcinogenicity has been determined at 3000 ppm.
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At doses at and above 2000 ppm in female mice both neoplastic and non-neoplastic effects were identified.
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Based on non-neoplastic kidney effects at 6000 ppm.
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clinical signs; mortality; reduced body weight
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clinical sign (lethargy )
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Deaths were observed in the 4000 and 8000 mg/kg dose groups
NOAEL = 100 mg/kg bw ↓bwg from 3,100 ppm (males) and from 1600 ppm (females)
reduced body weight
mortality
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Decrease in serum cholesterol and phospholipids in males of the 5000 mg/L dose group.
effect on food consumption,body weight,organ weight were observed
based on histopathology
based on clinical signs and body-weight gain
attributable to microscopic kidney lessions
ppm values were converted to mg/kg bw/d by study authors based on actual chemical consumed and separately for females and males (converted from 6250 ppm)
ppm values were converted to mg/kg bw/d by study authors based on actual chemical consumed and separately for females and males (converted from 6250 ppm)
Reduced body weight. Corresponding to 2000 ppm.
Reduced body weight. Corresponding to 1000 ppm.
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Diffuse follicular cell (thyroid gland), hepatocellular cytomegaly (liver)
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Body weight, feed consumption, hematology, clinical chemistry, sperm analysis, histopathology
Body weight, feed consumption, hematology, clinical chemistry, vaginal cytology evaluation, histopathology
>=2500 ppm: increased relative and absolute liver and kidney weights
highest tested dose level
Mortality, clinical signs and histopathology
Decreased body weight gain (> 20%)
Decreased body weight gain
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clinical signs; mortality; body weight; haematology; gross pathology; organ weights.
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Effects observed in Body weight, Clinical signs, organ weight, hematology  and histopathology
(Basis for effect: hepatic toxicity) (LOAEL ~ 200 mg/kg bw/day in males, ~ 270 mg/kg bw/day in females)
Steroid hormone-related effect on male fertility in this dose group based on sperm investigations (Sperm motility in 50 mg/kg males was significantly lower).
Deaths were observed in the 10000 and 15000 mg/kg dose groups
see 'Remark'
water consumption; haematology
body weight; food consumption
(based on liver changes; this dose level was considered as NOAEL based on haematotoxicity when excepting the target organ liver)
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reduced body weight
reduced body weight, mortality
This NOAEL is considered as a worst case since reduction weight gain (considered as adverse effect)  at the highest dose was observed only during the two last weeks of treatment (week 101 and week 104). Expert judgment.
Maximum 13.9%  transient reduction in body weight at week 101  only, at the highest dose.Body weight gain decrease up to 21%  within the entire study. Reduction body weight gain higher to 10 % from week 49. Expert judgment.
No effect up to the highest dose level tested in males
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No effect on survival, gross pathology and histopathology
Hepatocyte labelling index: significantly elevated at 2000 mg/kg bw  (24,40 weeks). Thymidine kinase activity in liver: at 2000 mg/kg bw , increase at 2 weeks, decrease at 8 weeks; at 1000 mg/kg bw , increase at 2 and 40 weeks
No adverse effect on survival, body weight, hematology, gross pathology and histopathology
mortallity, body weight, relative organ weight, peroxysome proliferation
see 'Remark'
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small effect on food consumption
small effect on food consumption
based on reduced body weight and food consumption, altered haematological parameters and clinical signs
based on reduced body weight and food consumption, altered haematological parameters and clinical signs
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liver: increase of weights, histopathologal findings (at 65-week interim sacrifice only)
Significant increase of liver adenoma or carcinoma combined
see 'Remark'
see above remarks
see above remarks
see above remarks
Clinical signs; functional changes of the liver; testis and thymus weights increased in males
No mortality and no significant changes in body weight, body weight gain, gross pathology and histopathology in both sexes of mice exposed for 90 days to Eugenol containing diet f up to 6000 ppm (equivalent to 900 mg/kg bw/d). Expert judgment.
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slight but significant body weight gain reduction
slight but significant body weight gain reduction
(1500 ppm in the drinking water)
(1500 ppm in the drinking water)
clinical signs; mortality; body weight; haematology; gross pathology; organ weights.
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There was no effect of treatment at this dose level.
There was no effect of treatment at this dose level.
Decreased body weight gain. Recalculated to be approx. 200 mg/kg bw/day.
(i.e., 6.5 and 8.25 mg/kg bw/day for the males and females, respectively)
(i.e., 136 and 169 mg/kg bw/day for the males and females, respectively);  based on liver effects.
Based on centrilobular hypertrophy in adult males at 300 ppm
The EU RAR Update 2008 concluded that NOAEL is 300 ppm based on reduced body weight and effects on liver and kidney weight and histopathology at 3500 ppm
Based on reduced body weight spleen and testes weights and delay in acquisition of puberty in F1 males at 3500 ppm
Based on centrilobular hypertrophy in adult males at 300 ppm
The EU RAR Update 2008 concluded that NOAEL is 300 ppm based on reduced body weight and effects on liver and kidney weight and histopathology at 3500 ppm
Based on reduced body weight spleen and testes weights and delay in acquisition of puberty in F1 males at 3500 ppm
(based on dose-related changes in haematology parameters (decreased in erythrocyte count, hemoglobin, and hematocrit), increased liver weight, and depression in total cholesterol seen from 25 mg/kg bw/da upward)
no effects were observed after 13 w of exposure for males/female mice.
result from developmental toxicity evaluation; the effect level corresponds to 23 mg/kg (with a density of 0.919 g/mL at 25 °C)
Based on body weight reduction in rats and female mice and increased incidence of multinucleated hepatocellular giant cells in male mice
Based on cecal enlargement in male rats at 250 ppm.
Based on the presence of multinucleated giant hepatocytes in male mice at 5000 ppm.
overall effects NOAEL for rats (3300 ppm)
overall effects LOAEL for rats (6500 ppm)
No toxicologically relevant effect
overall effects
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Highest dose tested
Based on higher liver weights at 10 and 30 mg/kg, with hepatocellular hypertrophy and necrosis at 30 mg/kg.
The reproduction NOAEL was cited as being at least 30 mg/kg.
Based on lower pup body weight and increased postnatal loss at 10 and 30 mg/kg, and lower mean number of living pups at first litter check at 30 mg/kg.
Corresponding to 15000 ppm (highest dose tested).
Corresponding to 15000 ppm (highest dose tested).
No clinical signs, no alteration of liver cells, no change of body weight after 8 months of treatment
alterations in hepatic cell morphology after 4 months of treatment
Liver - hepatitis (hepatocellular necrosis), significant reduction in ALP, TP, ALB, TC and HDL
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liver weight and histopathology
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increased relative liver and kidney weights occurred and in male rats and a vacuolization in cells of the pars distalis in the pituitary glands were observed
↓bw from 70 mg/kg bw. Liver: ↑pp and nb mitoch from 70 mg/kg bw, ↑p.enz.act. from 7 mg/kg bw, no tumours. Testes: atrophy and inhibition of spermatogenesis from 7 mg/kg bw
body weight gain
No treatment related effect
no neoplastic effect
No non-neoplastic effects were observed, but the high-dose females (given 600 mg/kg bw/day) showed an increased incidence of mononuclear cell leukemia.
Mean body weights of high-dose rats of either sex were lower than those of the controls throughout the study.
reduced water consumption (200 mg/kg bw/day)
reduced body weight (450 mg/kg bw/day)
corresponding to 450 mg/kg bw/day; NOAEL because reduced body weight related to reduced water consumption; limited number of parameters tested (carcinogenicity study)
decrease in body weight
liver lesions
Based on the increased incidence of hyperplasia and adenomas (and one carcinoma) of the pancreatic acinar cells at 500 mg/kg bw/day.
Based on the increased incidences of hyperplasia and transitional epithelial papillomas in the urinary bladder at 1200 mg/kg bw/day.
Effects observed in Body weight, Survival rates, hematology and histopathology
Compound-related effects were observed at concentrations > 500 ppm
see 'Remark'
No NOAEL determined
see 'Remark'
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A statistically significant (and dose-dependent) increase in simple transitional cell hyperplasia and deposit of hemosiderin was observed at levels at and above 1500 ppm.
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Not statistically significant relative weight reductions in the thymus and pituitary.
body weight gain and food consumption decreased  Blood Ht  and plasma protein decrease.  Relative pituitary weight decrease (significant).
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No evidence of a significant decrease in testes weight was observed until Day 11 when differences were noted in the 500 and 1000 mg/kg/day groups
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body weight and nervous system depression
No toxicologically relevant effects were noted in the study
body weight, food consumption, organ weights, Leydig cell hyperplasia, haematology
kidney effects (tubular atrophy)
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mortality; clinical signs; reduced body weight
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corresponding to 2% test substance in the diet
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acute CNS effects indicated by clinical examination (tremors)
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minimal hepatocellular necrosis
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kidney lesions in females
reduced body weight
1) an increase in the amount of serious degenerative liver damage (nuclear pyknosis), 2) a clear and dose-dependent increase in the absolute and relative liver weight, and 3) an increase in the kidney weight (females only).
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- Nominal concentration = 300 ppm (mg/kg feed).
- Corresponds to 2000 ppm (mg/kg feed).  - Based on irreversible liver weight increases seen at this and higher doses that were also accompanied by irreversible microscopic changes in the liver.
Significantly longer estrous cycles
Body weight, feed consumption, sperm analysis
NOAEL = 320 mg/kg bw ↓bwg at 25,000 ppm. Testes: atrophy from 12,500 ppm
no effects
no effects
no effects
no effects
based on decrease in body-weight gain
based on clinical signs, mortality (males), haematological effect, and some evidence of histological changes (kidney, thymus).
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Periarteritis in both sexes.
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Decreased red blood cells and haemogobin; increased MCV and MCH; increased incidence of slight to moderate hyperplasia in the kidney and urinary bladder.
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See remarks:
See remarks:
organ weights; histopathology changes at 200 and 2000 ppm
mean test article intake (ranges: 13 to 6, 27 mg/kg bw/day during 13 weeks)
mean test article intake (range from 13 to 8, 26 mg/kg bw/day during 13 weeks)
Changes in body weight gain, food intake, blood and urine chemistry, organ weights, histopathology, peroxisome proliferation and electron microscopy at 2000 ppm
mean test article intake (range from  27 to 11 mg/kg bw/day during the 13 weeks)
mean test article intake (range from 26 to 15 mg/kg bw/day during the 13 weeks)
attributable to microscopic kidney lessions
ppm values were converted to mg/kg bw/d by study authors based on actual chemical consumed and separately for females and males (converted from 6250 ppm)
ppm values were converted to mg/kg bw/d by study authors based on actual chemical consumed and separately for females and males (converted from 6250 ppm)
Periarteritis (females) and nephrophathy (males).
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hyaline-droplet degeneration of the proximal convoluted tubules in the kidneys
liver weight
hyaline droplet degeneration of the proximal convoluted tubules in kidneys
decrease in body weight, increase in relative kidney weights and SGPT values
Diffuse follicular cell adenoma in all animals.
reduced water consumption at 1000 ppm (107 mg/kg bw/day in females and 83 mg/kg bw/day in males)
Neurotoxicity (360 or 308 mg/kg bw/day in females or males, respectively)
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Neglecting the effect on males at 50 ppm
based on reduced body weight and food consumption and alterations in clinical blood chemistry
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No adverse effects observed at this dose level
>= 7500 ppm: increased relative liver and kidney weights
Highest dose level tested
>=175 mg/kg bw/d: increased mortality, clinical signs includinglethargy, exessive salivation, tremor and occasional convulsions and comas, hepatotoxicity and nephrotoxicity
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histopathologic observations in kidneys
clinical signs; gross pathology; histopathology: periportal hepatocellular necrosis and fibrosis, bile duct hyperplasia, hepatocellular nodular hyperplasia
histopathology: hepatocellular basophilia, cellular and nuclear hypertrophy, nuclear hyperchromatism
histopathology: hepatocellular basophilia, cellular and nuclear hypertrophy, nuclear hyperchromatism
histopathology: hepatocellular basophilia, cellular and nuclear hypertrophy, nuclear hyperchromatism
no adverse effects
no adverse effects
decreased body weight gain, increased liver weights,
decreased body weight gain, increased liver weights
effects on food consumption,body weight
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Decreased body weight
Decreased body weight
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(1600 ppm in the drinking water)
(1600 ppm in the drinking water)
Hepatocellular cytomegaly at 150 mg/kg bw
liver: ↑relw from 100 mg/kg/day, ↑p.enz.act. from 25 mg/kg/day
hemolysis
overall effects
↓bwg (males). Liver: ↑absw, ↑relw, ↑pp, ↑pSER, mitoch changed. Kidney: ↑weight (females), ↑pp. Testes: ↓weight, atrophy. ↓CHO (males), ↓TG (males)
Corresponding to 12000 ppm (highest dose tested).
Corresponding to 12000 ppm (highest dose tested).
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Significantly reduced body weight.
liver: dose-related ↑absw from 182 mg/kg bw  following 2 or 4 weeks of treatment, ↑nb peroxisomes from 18 mg/kg bw, ↑p.enz.act. from 5 mg/kg bw
overall effect (650 ppm ~ 50 mg/kg bw/day)
small decrease in bodyweight gain, food consumption, food utilization, together with evidence of morphological changes in the liver and possibly kidneys (2000 ppm ~150 mg/kg bw/d)
Effects observed in Body weight, clinical chemicsry, hematology  and histopathology
(Basis for effect: hepatic and renal toxicities)  (LOAEL ~ 75 mg/kg bw/day in males, ~ 80 mg/kg bw/day in females)
Steroid hormone-related effect on male fertility in the next higher dose group based on sperm investigations (The numbers of sperm per mg cauda epididymis were significantly decreased).
Based on the mortality of the rats in the two highest dose groups and the absence of adverse effects in the other test groups.
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No effect on body weight, food intake and reproductive performances
Deaths were observed in the 1250 (only males), 5000, 10000 and 15000 mg/kg dose groups
increase in liver relative weight
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LOAEL = 143-154 mg/kg bw ↓bw from 1.0%. liver: ↑absw and relw from 0.2%, no histological findings. testes: ↓absw and ↑relw  from 1.0%, atrophy
estimated dose ca. 750 mg/kg bw/d (neglecting 31% substance loss within 1 week due to evaporation)
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slight increase in relative liver weights
no adverse effects
decreased body weights, increased absolute and relative liver weights, decreased absolute and rel. testis weights, atrophy of testicular tubules and spermatogenic arrest and epididymis, hypospermia
decreased body weights, increased absolute and relative liver weights
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at this concentration animals did not die, for the next higher dose mortality has been detected
approx 37.5 mg/kg bw/day (corrected: 23.5 mg/kg bw/day): based on methemoglobinemia and decreased body weight gain in males and females
reduced body weight
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Reduced body weight up to 15% from weeks 51 to 102 of treatment and a decreased of body weight gain of 10% within the 104 weeks were measured in high dose female group . Expert judgment.
No effect up to the highest dose level tested in males
growth inhibition; gross pathology
Effect level expressed as the acid
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corresponding to 800 ppm
corresponding to 4000 ppm; based on structural alterations in the urinary bladder
corresponding to 4000 ppm
corresponding to 10,000 ppm; based on renal mineralisation, renal cystic tubular dilatation, renal infarct
Effect level expressed as the acid
No effect on survival, body weight, organ weigh, gross pathology and histopathology
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decreases in body weight and increases in thyroid-to-body weight ratios after 12 months, nodular hyperplasia at dose levels of 125 ppm and higher; carcinomas were found at dose levels of 250 and 500 ppm.
Effect on body weight, hematology, clinical chemistry and histopathology
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Behavior, growth rate, feed intake, diet efficiency, mortality, hematology, clinical chemistry, urinalyses, gross and histopathological observations
increase in palmitoyl Co A activity at 105 mg/kg
corresponding to 11 mg/kg per day in males and 12 mg/kg per day in females
see 'Remark'
see 'Remark'
see 'Remark'
corresponding to the highest dose tested (equivalent to 2% test substance in the diet)
Testicular atrophy and reduced epididymal spermatozoa concentration at 25000 ppm (1660 mg/kg bw/day)
No adverse effects observed at this dose level
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The NOAEL in mg/kg bw/d was calculated from actual amount of substance consumed/day based on body weight at end of study.
(Basis for effects: hemathology, liver and kidney weight and liver cells hyperthrophy)
(Basis for effect: No treatment-related adverse effects observed at the highest dose, 20 mg/kg bw/day)
decreased iron pigment of the ameloblasts at maturation stage in the incisors in both sexes, increased relative kidney weight in males, and increased absolute and relative liver weights in females of the 25 mg/kg group
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kidney effects
see 'Remark'
see 'Remark'
No adverse effect observed on mortality, clinical signs, body weight, Gross pathology, hematology, histopathology
decreases in body-weight gain
clinical signs; mortality; body weight; food consumption; ophthalmoscopic examination; haematology; clinical chemistry; gross pathology; organ weights; histopathology.
Increased relative liver weight in males with no accompanying microscopic changes. Reduced serum urea in females. Macroscopically enlarged caecum in males. These changes were not of toxicological significance.
↓bw at 1,000 mg/kg/day for 9 months. liver: ↑w from 50 mg/kg/day, ↑pp, ↑pSER, ↑p.enz.act., mitoch changed (males).
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LOAEL = 24 mg/kg/day ↓bw at 2.5%. Liver: ↑absw from 0.5%, ↑relw from 0.02%, ↑p.enz.act. from 0.1%. Testes: ↓absw and relw and atrophy at 2.5%
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highest dose tested
Decrease in hematocrit in females
Decrease of the serum T3 and T4, Increase of serum TSH.
ultrastructural alterations, nerves and capillaries were affected
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Alterations in renal proximal tubule epithelial cells
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no mortality nor clinical effects were observed
overall effects (clinical signs; body weight; water consumption; haematology; clinical chemistry; urinalysis; gross pathology; organ weights; histopathology)
corresponding to a nominal concentration of 10,000 ppm (mg/kg feed)
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body weight gain, urinalysis (proteinuria, urobilinogen, pH), kidney weight, histological changes in caecum
relative liver weight, increased extramedullary hematopoiesis and overall splenic effects
no treatment related effects observed
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Effects on thyroid and liver were observed in both sexes.
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Effects limited to clinical signs; doubtful reporting
salivation (non-adverse)
based on histopathological changes in the liver at 1000 mg/kg bw/day
increase of relative liver weight from 300 mg/kg bw/day onwards
increased liver weights, changes in hematology, adverse effects on testis (e.g. sperm retention and degeneration of step 19 spermatids)
increase in liver weights
Relative high kidney weights in males and low cholinesterase in females at 40 mg/kg/d. However these effects were not considered as adverse by the authors in the absence of any histopathological changes in the 40 mg/kg bw dose group.
see 'Remark'
see 'Remark'
Steroid hormone-related effects, i.e. slight alteration of hematological parameters (erythrocytes, hemoglobin) and indications of beginning uterus atrophy in this dose group.
No effect on uterine wet weight
overall effects
A number of adverse effects (see below) were reported at higher dose levels (1000 and 4000 ppm). No test-substance specific effects were noted at this concentration (250 ppm).
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Overall mortality: 85-96%. ↓bw at 300-400 mg/kg bw . Liver and kidney weight increased at 300-400 mg/kg bw after 3-6 months but not after 12-24 months. No histological findings
Mortality: all pups in three youngest age groups at 2,000 mg/kg/day groups. ↓bw in two highest dose groups. Liver: ↑absw and relw  from 100 mg/kg/day, ↑pp, ↑p.enz.act. ↓TG, ↓CHO
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overall effects: reduced appetite
overall effects: micropathology
overall effects: micropathology
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lower weight gain and increased blood urea concentrations observed at 3300mg/kg/day level
decreased serum testosterone levels; increased reactive oxygen species formation, impaired insulin signal transduction and glucose uptake in skeletal muscle
equivalent to 1.7 mg/kg bw/d in males and 1.9 mg/kg bw/d in females
= 8 mg/kg bw/d/ thyroid toxicity
50 ppm = 5 mg/kg approximately
=10 mg/kg bw/d. Increase of thyroid weight in rats exposed during 60 and 120 days to ETU.
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Based on all results observed. Males more sensitive than females.
LOAEL of thiourea is lower than 300 mg/kg diet, which is equivalent to 30 mg/kg bw/d
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body weight gain and elevated alkaline phosphatase values in plasma in male animals
overall effects
tentative salivation, increased relative liver weight accompanied by centrilobular hypertrophy
General effects
tentative salivation, increased liver weight
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Body weight, organ weight and gross pathology of sperms.
apathy, prone position, slight to severe atactic gait, flat footed gait, partly stradding
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Decreased bodyweight gain in females at the next higher dose.
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Slightly lower bodyweight, corresponding to lower food consumption, in first 13 weeks
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Adverse effects on red blood cells, splenic congestion.
Relative organ weight changes: kidney, liver, heart.
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Reduced terminal body weight
body weight reduction, increased severity of CPN, significant increase of renal tubuli adenoma
Significant increase of mononuclear leukaemia
no biologically relevant adverse effects
Increase of the thyroid weight and decrease of T4 blood levels
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-decreased body weight gain and food intake; hematology and clinical chemistry changes; organ weight changes seen at 500 ppm and 2000 ppm dose groups
see 'Remark'
see 'Remark'
see 'Remark'
see 'Remark'
The NOAEL (1.5 mg/kg bw/day pure active substance cyanamide, equivalent to 30 ppm in the diet) is based on the histopathological findings in the thyroid at 4.5 mg/kg bw/day cyanamide (equivalent to 90 ppm in the diet) in males and females.
hepatic injury
No adverse effects on the general health, growth, hematological and clinical parameters at the low-dose (250 ppm) group.  Adverse effects reported in mid-dose (750 ppm) and high-dose (2250 ppm) groups.
See above remarks
See above remarks
See above remarks
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liver weight/enzyme induction
No significant changes were noted
Histopathological effects seen in kidneys of male animals.
No dose dependent adverse alterations observed.
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see 'Remark'
6% lower final body weight observed in female rats administered 12500 ppm eugenol (equivalent to 1250 mg/kg body weight) compared to control females. Expert judgment.
overall effects haematology - leukopenia  (reduced WBC and lymphocyte count, reduced MCHC) only
overall effects clinical chemistry - increased serum creatinine only
overall effects  histopathology
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No significant differences were observed in the growth rate, food efficiency, organ weights, blood urea nitrogen values or histopathology.
The daily dose was calculated to be 151.0 mg/kg for males and 174.2 mg/kg for females.
equivalent to 20 ppm; no effects observed
equivalent to 100 ppm; reversible effects (reduced alkaline phosphatase activity, changed liver and kidney weight, fine vascular degeneration in the liver) were considered as not adverse
see 'Remark'
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increase in glucose-6-phosphatase
Decrease in relative body weights, atrophy of mammary gland
regenerative anaemia, effects on liver (hypertrophy), uterus (epithelial metaplasia) and ovaries (relative weights)
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increased incidence of thyroid changes in the form of a decreased colloid density in the thyroid follicles are not regarded as relevant for humans.
increased relative liver and kidney weights occurred and in male rats and a vacuolization in cells of the pars distalis in the pituitary glands were observed
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effects :- Blood - methemoglobinemia-carboxyhemoglobin Blood - changes in spleen Blood - changes in other cell count (unspecified)
No toxicologically significant effects in males or females, although some changes in hematological and blood biochemical parameters and a marginal increase in histiocytosis and mastocytosis were observed at this dose level.
Treatment related effect on body weight gain, food consumption, changes at clinical pathology and histiocytosis and mastocytosis in mesenteric lymph nodes.
30 ppm were calculated to be approximately 2.08 mg/kg body weight/day
100 ppm are calculated to be 7.32 mg/kg body weight /day
corresponding to 8% test substance in the diet
body weight; food consumption; haematology; clinical chemistry; organ weights; histopathology
body weight; food consumption; haematology; clinical chemistry; organ weights; histopathology
There was no effect of treatment at this dose level.
There was no effect of treatment at this dose level.
Findings were limited to slight decreases in body weight gains, increased absolute/relative liver weights, a slight increased incidence of small testes and an increase in the severity of tubular atrophy.
Findings were limited to the occurrence of necrosis and of single cell necrosis in the liver.
Lack of adverse effects on in-life parameters and clinical and anatomic pathology parameters.
oral administration of m-DIPB to male Crl:CD(SD) rats at dosage levels of 75, 150, and 300 mg/kg/day for up to 91 or 92 days resulted in adverse microscopic changes in the stomach (leading to erosion and/or ulcer).
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At 1000 mg/kg bw/day increased relative liver (m/f) and kidney weight (m) was observed.   In addition, histopathology revealed increased eosinophilic and hyaline droplets in the kidney (m/f).  Increased follicle atresia in the ovary (f) were found.
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Based on reduced body weight, increased kidney effects and renal tubular effects at 300 mg/kg/day
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see 'Remark'
No significant effects were seen in the F1 generation.
decreased body weight gain. Recalculated to be approx. 630 mg/kg bw/d.
Recalculated to be app. 2000mg/kg
see 'Remark'
corresponding to 71 mg/kg bw/day; effects at 300 mg/kg bw/day
corresponding to 300 mg/kg bw/day; decreased body weight/body weight gain, decreased food consumption, increased organ to body weight ratios secondary to reduced water consumption (flavour aversion to phenol).
highest dose tested
lower body weight gain, ataxia, and foot splay at 40 mg/kg/day
increased mortality, reduced pup body weight/litter at 40 mg/kg/day (maternal dose)
highest dose tested
highest dose tested
lower body weight gain, ataxia, and foot splay at 40 mg/kg/day
increased mortality, reduced pup body weight/litter at 40 mg/kg/day (maternal dose)
highest dose tested
neurobehavioural
neurobehavioural effects: reduced forelimb grip strength and motor activity; clinical signs
clinical signs
Abnormal respiratory sounds in a females in and decreased plasma albumin in males was reported in the 200 mg/kg body weight/day
Squamous hyperplasia in the forestomach.
Squamous hyperplasia in the forestomach.
Clinical signs; body weight; food consumption;
Based on mortality and decreased body weight in males and females and on increased duration of diestrous cycle in females at the highest dose (600 mg/kg-day)
Based on body weight reduction in adult females at 750 ppm
The EU RAR 2003 concluded that the NOAEL for systemic toxicity in this study is 50 mg/kg/day, based on consistent and significant reductions in body weight gain in both sexes and renal tubule degeneration in females only at 7500 ppm
Based on reduced body weights in males and females, delayed vaginal patency in females and preputial separation in males (associated with the reduced body weights) and reduced litter size at 7500 ppm
Based on body weight reduction in adult females at 750 ppm
The EU RAR 2003 concluded that the NOAEL for systemic toxicity in this study is 50 mg/kg/day, based on consistent and significant reductions in body weight gain in both sexes and renal tubule degeneration in females only at 7500 ppm
Based on reduced body weights in males and females, delayed vaginal patency in females and preputial separation in males (associated with the reduced body weights) and reduced litter size at 7500 ppm
overall effects
Kidney: Basophilic epithelium occasionally with mitotic figures in proximal convoluted tubules in males; Higher food and water consumption in females; lower cholesterol levels in females.
(corresponding to ca. 33.5 and 34 mg/kg bw/day for males and females, respectively)
(corresponding to ca. 107 and 113 mg/kg bw/day for males and females, respectively); based on reduced WBC counts in females and increased clotting time/decreased monocyte count in males.
Bodyweight gain in F0 generation and a yellowish tinge to the fur in all generations.
No appreciably modifies in growth curves or final weights.
Decreasing of the rate growth.
Decrease in thymus weight at 1000mg/kg
Thymus weight reduction.
see 'Remark'
Effects on reproductive indices were not observed at 1000 mg/kg, and that dose is therefore considered the reproductive NOEL.
Effects on pup body weight and a decrease in viability of pups were noted at 1000 mg/kg/day.
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Effects on body weight and organ weight in 1.0 (750 mg/kg) and 5.0% (3160 mg/kg) dose groups
see 'Remark'
the test substance caused dose-dependent kidney and liver effects
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no effects (clinical signs; mortality; body weight; food consumption; hematology; clinical chemistry; gross pathology; organ weights; histopathology) observed in all dose groups
based on suggestive evidence of hemolytic anemia such as marginal pigment deposit and extramedullary hematopoiesis in the spleen probabely caused by methemoglobin formation.
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no adverse effects
no adverse effects
Giant cell formation in the testis, decrease in sperm motility ratio and number of sperms in the cauda epididymis, increase in abnormal sperm ratio.
suppression of body weight gain during lactation period, lower food consumption during pre-mating, pregnancy and lactation periods.
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clinical signs; haematology
see 'Remark'
no adverse effects on body weight change and food consumption, no histological and morphological changes, no adverse effects on hematological and blood chemical findings
No findings of toxicological significance at 1% in diet (equivalent to 500 mg/kg bw).
Findings of toxicological significance at 5% in diet (equivalent to 2500 mg/kg bw).
No effect on estrous cycle
see 'Remark'
calculated for the high dose concentration in diet (20000 ppm) based on food consumption
The term LOAEL was not mentioned in the study report and is an assumption of the author of this IUCLID dossier
Effects observed at 381 mg/kg bw/day and above included histopathological changes in the pancreas, gross pathological changes in the liver, and a significant increase in relative kidney weight.
changes characteristic for erythocyte toxicity: splenic congestion, increased hematopoiesis, hemosiderosis and bone marrow hyperplasiea