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Description of key information

Urea phosphate will directly dissociate into urea and phosphoric acid in aqueous environment. Based on a reliable oral OECD 422 study with diammonium hydrogenorthophoshate in rats, local effects were observed in the stomach at the lowest dose tested (250 mg/kg bw/day). However, the systemic NOAEL is determined to be 250 mg/kg bw/day based on horizontal banding of dental surface at mid dose (LOAEL), with effects on haematological and clinical chemistry parameters at highest dose level.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
250 mg/kg bw/day

Additional information

Urea phosphate will directly dissociate into urea and phosphoric acid in aqueous environment.

Oral toxicity

Urea

In 12 -month carcinogenicity screening assays (Fleischman et al, 1980), F-344 rats and C57BL/6 mice (50/sex/group) were exposed to urea in the diet at concentrations of 4500, 9000 or 45000 ppm for 12 months. Five animals/sex/group were sacrificed at the end of the 365-day exposure period and a comprehensive list of tissues was investigated histopathologically; interim deaths were similarly investigated. All remaining animals were sacrificed after the 4-month recovery period and investigated histopathologically. There were no signs of toxicity. Survival and bodyweights were unaffected by treatment. Gross and microscopic pathology did not reveal any treatment-related effects. It is concluded that urea is of very low chronic toxicity. Using default conversion factors, the dose level of 45000 ppm is calculated to be equivalent to approximately 2250 mg/kg bw/d in the rat and 6750 mg/kg bw/d in the mouse.

Diammonium hydrogenorthophosphate (containing the phosphate part like ureaphosphate)

In a reliable oral OECD 422 study, rats (5/sex/dose) were dosed 250, 750 and 1500 mg/kg bw/day diammonium hydrogenorthophoshate. Males and females were treated until termination during week 6 of treatment. The body weight gain of males at 1500 mg/kg/day appeared to be suppressed between Weeks 0 -5. There was a reduction in activated partial thromboplastin time for males at 750 and 1500 mg/kg/day, although this was not dosage related. No treatment related changes in these parameters were observed for females. Reviewer considers this not toxicologically relevant at 750 mg/kg bw, due to no dose response, high standard deviation, no effects in the liver, control value very high (historical control data Charles River, hematology parameters for the Crl:CDBR Rat, 1993). Males showed a non dosage-dependant elevation of alkaline phosphatase levels at 750 and 1500 mg/kg/day, reduced glucose and phosphorous levels at 1500 mg/kg/day, a small but dosage-dependant reduction in total protein at 750 and

1500 mg/kg/day with a slightly elevated albumin/globulin ratio at the top dosage. Changes in females were limited to a decrease in phosphorous levels at 1500 mg/kg/day although a non-significant increase in alkaline phosphatase levels at 1500 mg/kg/day in particular suggested a similar change to that recorded in males. Reviewer: Effect on total protein (at 750 mg/kg bw) although dose related was marginal (<10% compared to control), no change in albumin or A/G ratio and within the historical range of control data (Clinical Laboratory Parameters for Crl:CD(SD) rats, 2006, Charles River Laboratories). Therefore not considered adverse.

Bodyweight relative kidney and liver weights for toxicity subgroup females at 1500 mg/kg/day were increased, but in the absence of a histological correlate for these findings, this was of uncertain toxicological significance. A number of males and females at 750 and 1500 mg/kg/day had thickened stomachs and associated findings, and exhibited horizontal bands on the incisors. Stomachs of animals showed minimal or slight submucosal inflammation at all doses (0/5, 3/5, 4/5 and 2/5 males and 0/5, 2/5, 4/5 and 4/5 females at 0, 250, 750 and 1500 mg/kg bw respectively). It is thought that these findings may have been associated with an irritant effect of the test formulations rather than systemic toxicity. Reviewer considers this a comon local effect which is reversible.

Histological processing of the teeth that showed horizontal banding failed to detect any involvement of areas examined suggesting that the banding was probably restricted to the enamel of the teeth. This directs to an effect on the mineralisation process of tooth and bones. Reviewer: The roots of the teeth were not examined, so whether the cells that produce emaille are affected remains unknown.Based on this a systemic NOAEL of 250 mg/kg bw/day is derived.

Dermal toxicity

Urea

In 4 -week and 25 -week dermal toxicity studies, urea (formulated as an ointment) was applied to the shorn dorsal skin of groups of male and female Wistar rats. Bodyweights were measured; food and water consumption were assessed. Clinical chemistry, urinalysis and haematological parameters were investigated. At necropsy, organ weights were recorded; gross necropsy and histopathology were performed. No dose-dependent toxicity was observed. Bodyweights, food and water consumption were unaffected by treatment. Clinical chemistry, haematology and urinalysis parameters were comparable in all groups. There was no effect of treatment on organ weights or pathology (Sato et al, 1977).

Phosphoric acid

No reliable studies were available for the dermal route of exposure, a study via the oral route is already available.

Urea Phosphate

As the dermal repeated dose toxicity depends more on the phosphoric acid due to its skin corrosivity, and no studies for phosphoric acid are available, no NOAEL for dermal repeated dose toxicity has been included here.

Inhalation toxicity

Urea phosphate

No studies present, oral studies already present and inhalation exposure is very unlikely due to the low vapour pressure and the high particle size.

Justification for classification or non-classification

Based on the available data, urea phosphate does not have to be classified according to Directive 67/548/EC or the CLP Regulation with regard to repeated dose toxicity.

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