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Description of key information

Studies on oral sub-chronic and chronic repeated dose toxicity were available for Diuron. Oral 90-day NOAEL for rat (males): 100 ppm (6.7 mg/kg bw/day). Oral 12-Months NOAEL for Dog: 1.8 mg/kg bw/day.
Studies on dermal sub-acute repeated dose toxicity were available for Diuron. Dermal 21-days NOAEL for rabbit: 250 mg/kg bw/day.
Studies on inhalation sub-acute repeated dose toxicity were available for Diuron. Inhalation 21-days NOAEC for rat: 37.4 mg/m³ for male and 4.1 mg/m³ for female.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1.8 mg/kg bw/day
Study duration:
chronic
Species:
dog

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
4.1 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Additional information

Oral

In a reliable repeated oral dose toxicity study comparable to OECD guideline 452, groups of 6 beagle dogs/sex were given food containing Diuron at 0, 50, 300 or 1800 ppm for a period of 52 weeks, equivalent to 0, 1.8, 11 or 64 mg/kg bw/d (Hoffmann & Schilde, 1985).All animals survived, and no remarkable clinical signs of toxicity were found at dose levels up to 64 mg/kg bw/d. In the top dose group, body weights were decreased in both sexes towards the end of the study. Haematological parameters were affected beginning at 300 ppm and being more pronounced at 1800 ppm. This was seen by reduced haemoglobin and erythrocyte counts and increases in mean cell volume, indicating a hypochromic anaemic process, accompanied by high incidences of Heinz bodies at the top dose level. Compensation of the anaemic process was evident by increased reticulocyte numbers. Histopathological examinations exhibited reactive fat-deficient bone marrow with increased siderin content. Increased incidences of iron-containing pigments were found in livers, spleens and kidneys in the mid and high dose groups. Spleen and liver weights were increased accordingly.The NOAEL under the conditions of this study is 1.8 mg/kg bw/d for both sexes (50 ppm).

In areliable repeated oral dose toxicity study comparable to OECD guideline 408, groups of 20 male and 20 female Wistar rats received diets containing 0, 100, 250 and 2500 ppm Diuron over a period of 90 days, which was equivalent to a mean test article intake of 0, 6.7, 17.0 and 176 mg/kg bw/day for males and 0, 8.7, 23.3 and 214 mg/kg bw/day for females. Half of the animals were allowed a 90-day recovery period after the treatment period (Malley, 2004).There were no test item-related mortalities or clinical signs of toxicity. Decreases in body weight and weight gain were noted in top dose males and females.Statistically significant changes in haematological parameters were observed during the entire study. Red blood cell parameters were adversely affected in males and females in a dose-dependent manner. Erythrocytes, haemoglobin and haematocrit were decreased corresponding with increased numbers of reticulocytes pointing to compensation of loss of blood oxygen carrying capacity. Clinical chemistry revealed significant changes with regard to increased bilirubin in both sexes. At the end of the treatment period, liver weights were increased in males and females at 2500 ppm. At all dose levels of females and at high dose level of males significant increases in spleen weights were recorded. At necropsy, histopathological examinations exhibited alterations of spleen, liver, kidney and bone marrow consisting of increased haematopoiesis, haemoglobin derived pigmentation and congestion. Moreover, animals of both sexes in the two higher dose groups revealed hyperplasia of the transitional epithelium of renal pelvic mucosa and urinary bladder mucosa. After a 90-day recovery period, all substance-related alterations had resolved in all males and the majority of females.Therefore, the NOAEL was set 100 ppm, equal to 6.7 mg/kg bw/day for males. No NOAEL for females could be set; the LOAEL was set 100 ppm, corresponding to 8.7 mg/kg bw/day for females.

In a supporting oral repeated dose study comparable to OECD 452, groups of 10 male and 10 female Wistar rats were offered diets containing 0, 4, 10 and 25 ppm Diuron over a period of six months, equivalent to 0, 0.3, 0.66 and 1.6 mg/kg bw/d for males and 0, 0.3, 0.77 and 1.8 mg/kg bw/d for females (Schmidt and Karbe, 1986).No test item-related mortalities or clinical signs of overt toxicity were observed until end of treatment. No relevant changes in body weight or food consumption were noted compared to the control group. Similarly to the results of other subchronic studies, the blood system was the target organ of Diuron-related adverse effects. This was evidenced by slightly lowered haemoglobin concentrations in top dose females after 12 and 26 weeks and increased reticulocyte counts in males and females after 12 weeks and in females at termination. Morphometric evaluation of spleens revealed an increased accumulation of ferriferous pigments in both sexes at the top dose. Organ weights were not significantly affected.The NOAEL was set 10 ppm, equal to 0.66 mg /kg bw/d in males and 0.77 mg/kg bw/d in females.

Based on the results of the repeated oral dose toxicity studies where consistent and significant adverse changes in haematologic parameters s are seen, Diuron therefore needs to be classified according to the criteria of Directives 67/548/EEC (DSD) and 1272/2008/EC (CLP).

Dermal

In a reliable 3 -week dermal repeated dose toxicity study equivalent or similar to OECD Guideline 410, rabbits were administered doses of 0, 50 and 250 mg/kg bw/d (Mihail and Schilde, 1984).Following repeated administration of Diuron at dose levels up to 250 mg/kg bw/d, no mortalities or toxic effects occurred. No behavioural changes were noted. Examination of the skin according to Draize or skin fold thickness determination did not show any alterations. Haematology, urinalysis and blood chemistry exhibited no differences between the groups. Neither relative nor absolute organ weights were affected. Histopathology revealed congestion of the spleen in only one male rabbit. No other toxicologically relevant histopathological findings were noted. In this study, no test item-related signs of evident systemic or dermal toxicity were noted (NOEL/NOAEL: 250 mg/kg bw/d).

In a subchronic dermal toxicity study, Diuron suspended in cotton seed oil was administered to Sprague-Dawley rats (12/sex/group) at doses of 0, 250, 500 or 1000 mg/kg bw/d for 13 weeks, 5/7 days a week for 6 hours to the shaved skin of about 10 % of the body surface (Wandrag, 1996).No mortalities or clinical signs directly related to the test item were noted. However, three animals died without any earlier clinical symptoms. High incidences of uroliths were found. Serum urea and bilirubin were adversely affected.At all dose levels, signs of haemolytic anaemia were observed as evidenced by decreases in erythrocyte counts, haematocrit and haemoglobin and increased mean corpuscular volume. According to this, no NOAEL could be set. However this study was disregarded as only a short abstract on method and result was available (Wandrag, 1996).

Inhalation

In a reliable sub-acute inhalation study comparable to guideline OECD 412, Wistar rats were exposed to nominal doses of 0, 20, 150 and 1000 mg/m3 (anal. conc. achieved: 0, 4.1, 37.4 and 268.1 mg/m³) of an aerosol of Diuron for 6 h per day, 5 days per week for 14 or 28 days. Rats exposed to concentrations up to 37.4 mg/m³ Diuron did not exhibit any test item-related signs of adverse effects. Therefore the LOAEC was determined to be 268.1 mg/m³ in males and 37.4 mg/m³ in females based on significant alterations in haematologic parameters and dark, enlarged spleens at higher dose levels. The NOAEC was assessed to be 37.4 mg/m³ for male and 4.1 mg/m³ for female animals (Pauluhn, 1986b).

In an inhalation study which was in principle conducted based on OECD guideline 412, Wistar rats were exposed to nominal doses of 0, 20, 150 and 1000 mg/m3 (anal. concentrations were 0, 6.6, 47.6 and 311 mg/m³) of an aerosol of Diuron for 6 h per day, 5 days per week for 21 days. Rats exposed to concentrations up to 47.6 mg/m³ Diuron did not exhibit any test item-related signs of adverse effects. Therefore, the LOAEC was set to 47.6 mg/m³, based on significant alterations in haematologic parameters and congested spleens at higher dose levels. The NOAEC was determined to be 6.6 mg/m³. (Pauluhn, 1986a).

Based on the results of the repeated inhalation dose toxicity studies where consistent and significant adverse changes in haematologic parameters are seen, Diuron therefore needs to be classified according to the criteria of Directives 67/548/EEC (DSD) and 1272/2008/EC (CLP).

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other

Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: other

Justification for classification or non-classification

Based on the available data on oral and inhalation repeated dose toxicity Diuron needs to be classified:

DSD: R48/22

CLP: STOT RE Category 2

The data on repeated dose toxicity for the dermal route is conclusive, but not sufficient for classification.