Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
292 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
292 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
580 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
580 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Physiological production of urea

Urea is produced in the body of mammals as a consequence of normal physiological processes, primarily by the detoxification of ammonia resulting from protein catabolism, via the urea cycle. The quantity of urea produced by an adult human is influenced by dietary protein intake but is reported to be typically between 20 -50 g/day. Urea is generated in the liver by the urea (ornithine) cycle by the action of the terminal enzyme arginase I on L-arginine. Reference ranges for urea in human blood are 70 -210 mg/L (7 -21 mg/dL). Therefore assuming a blood volume of 5L (for an adult) and serum proportion of 55%, the quantity of urea present in the blood at any one time is 192.5 -577.5 mg or (assuming a bodyweight of 70 kg), 2.75 -8.25 mg/kg bw.

The urea produced by the urea cycle is removed from the blood by glomerular filtration (as a small, water-soluble molecule), but is largely reabsorbed by the renal tubules. Some urea is transported by specific transport systems back into the urine. The clearance of urea is estimated to be 75 mL/minute, equivalent to approximately 1.5% of the total blood volume/minute. Urea also plays a physiological role in renal countercurrent exchange. Urea is present in saliva in appreciable concentrations (approximately 200 mg/L) and is also present in the epidermis at high levels, where it plays a role in skin hydration.

Uraemia may occur in cases of renal insufficiency or renal failure, and is typically observed in dialysis patients where the normal glomerular filtration rate has decreased by more than 50%.

As the kidney has many physiological roles (including hormone production and secretion, acid-base homeostasis, fluid and electrolyte regulation and waste-product elimination) the consequences of renal failure are numerous as these functions are not performed adequately. Various metabolic abnormalities such as anaemia, acidaemia, hyperkalaemia, hyperparathyroidism, malnutrition, and hypertension can occur. Uraemia usually develops only after the creatinine clearance falls to less than 10 mL/min, although some patients may be symptomatic at higher clearance levels, especially if renal failure acutely develops. Symptoms include nausea, vomiting, fatigue, anorexia, weight loss, muscle cramps, pruritus and change in mental status; it is unclear which of these symptoms are attributable to elevated urea levels and which are due to other metabolic disturbances.

Toxicokinetics

Urea is produced in large quantities by the human body as a product of normal metabolism and is excreted unchanged in the urine. Further studies characterising the toxicokinetics of urea are not required.

Dermal absorption

Urea is present at appreciable levels in the human epidermis, where it may play a role as a humectant, maintaining hydration of the stratum corneum. At very high levels of exposure, urea may act as a denaturant and may enhance the dermal absorption of other compounds. Bronaugh et al (1982), report a dermal absorption value of 7.2%, based on the results of a study in the rat in vivo and comparable results in vitro.

Acute toxicity

Urea is of very low acute oral toxicity in the rat and mouse. Sato et al (1977) report LD50 values of 14.3 (12.9 -15.9) and 15.0 (13.4 -16.8) g/kg bw in male and female rats; LD50 values of 11.5 (10.6 -12.5) and 13.0 (11.0 -15.4) g/kg bw in the mouse. Urea is of generally low acute oral toxicity in most species but higher toxicity is noted in ruminants due to the generation of ammonia by gastric flora. Stiles et al (1970) report an LDlo of approximately 600 mg/kg bw in cattle. No data are available for acute dermal toxicity: a waiver is proposed for this endpoint. Urea is demonstrated to be of very low acute toxicity by the oral, subcutaneous and intravenous routes in the rat and mouse. Testing for acute dermal toxicity is not justified on scientific grounds and for reasons of animal welfare. Specifically, the very low toxicity of urea by the subcutaneous and intravenous routes indicates that dermal toxicity would also be very low, even assuming rapid and total dermal penetration, which is not the case. No data are available from acute inhalation toxicity. The substance is a non-volatile solid and is produced as crystals with a particle size of >100 um. There is therefore no potential for inhalation exposure. In addition, the substance has been demonstrated to be of very low toxicity by other routes of exposure. Testing for acute inhalation toxicity is therefore not justified on scientific grounds or based on exposure considerations. Urea is also of very low acute toxicity by the subcutaneous route. Sato et al (1977) report LD50 values of 9.4 (8.2 -10.8) and 8.2 (7.1 -9.5) g/kg bw in male and female rats and LD50 values of 9.2 (8.6 -9.8) and 10.7 (9.5 -12.1) g/kg bw in male and female mice. It is notable that the subcutaneous LD50 values are greatly in excess of the limit dose for acute dermal toxicity testing. Urea is of very low toxicity following intravenous administration. Sato et al (1977) report LD50 values of 5.4 (4.9 -5.9) and 5.3 (4.8 -5.7) g/kg bw in male and female rats and LD50 values of 4.6 (4.3 -4.9) and 5.2 (4.8 -5.6) g/kg bw in male and female mice, respectively.

Irritation / corrosion

Frosch & Kligman (1977) (cited in WHO/JECFA evaluation) exposed human volunteers to three daily applications of urea (dissolved in water) at concentrations of between 7.5 -30%; applications were made to intact and scarified skin. On abraded skin, slight irritation was seen with 7.5% urea; marked irritation was seen with 30% urea. No effects were seen on intact skin. In a study by Lashmar et al (1989) application of 10% urea for 24 hours induced no discernible change in the histological appearance of the skin. It is notable that skin creams containing urea (at concentrations of between 5 -10%, and up to 25%) are widely used for the treatment of dry/irritant skin conditions, therefore it can be predicted that urea is not a skin irritant. Urea is also naturally present in the stratum corneum at a level of approximately 1%. Additionally, it is notable that no signs of local irritation were noted in 28 -day and 25 -week repeated dose dermal toxicity studies in the rat (Sato et al, 1977). No evidence of skin irritation was seen in a modern guideline study (Hooiveld, 2003).

Urea was found to be a mild eye irritant in a guideline-compliant study (Kirsch & Kersebohm, 1988), which would require a hazard classification as an eye irritant according to CLP criteria, but not to DSD criteria. A medical surveillance study in 9 urea producing facilities revealed however, that workers exposed directly to urea do not show any signs of eye irritation.

Sensitisation

No data are available: a waiver is proposed for this endpoint. Urea is naturally present at relatively high concentrations in human skin (up to 1% by weight) and is widely used in skin creams for the treatment of dry and irritant skin conditions without any reports of sensitisation reactions (Loden et al, 2002). A survey of 1905 patients does not reveal any reports of sensitisation (Stuttgen, 1992). A human volunteer study (Alchangian et al, 1986) does not report any sensitisation reactions. It is therefore considered to be very unlikely to be a skin sensitiser.

There are no validated animal tests for the assessment of respiratory sensitisation. Experience of extensive and historical occupational use of urea does not indicate any potential for occupational asthma.

Repeated dose toxicity

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 by the oral route. 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.

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). Urea is demonstrated to be of very low toxicity by the oral and subcutaneous routes. The substance is a non-volatile solid produced as crystals with particle sizes of >0.1 mm. There is therefore no potential for inhalation exposure. The data requirement is therefore waived on scientific grounds and on exposure considerations. Testing is not justified on animal welfare grounds. Twelve unilaterally nephrectomised dogs were injected subcutaneously with 10% urea solution (3000-4000 mg/kg bw) every 8 hours over a period of 45 days. Administration led to increased diuresis, plasma urea levels were 200 - 700 mg/100 ml. The dogs displayed mild drowsiness. Haematocrit, platelet counts and EEG were not affected. The study further indicates that urea is of very low toxicity in the dog following repeated administration (Balestri et al, 1971).

Genotoxicity

The potential mutagenicity of urea was investigated in a screening assay performed in S. typhimurium TA98, TA100 and TA1537 according to the published method of Ames et al (1977), with a pre-incubation step and in the absence and presence of an exogenous source of metabolic activation. No evidence of mutagenicity was seen under the conditions of this assay (Ishidate et al, 1981). The mutagenicity of urea was also determined in an Ames test using S. typhimurium and E. coli, with and without S9 metabolic activation. The substance was not mutagenic at any of the 7 concentrations tested (Shimizu et al, 1985). The potential mutagenicity of urea was investigated in a guideline-comparable Ames test (pre-incubation assay). Triplicate cultures of S. typhimurium TA97, TA98, TA100, TA1535 and TA1537 were exposed to urea (dissolved in water) at five concentrations between 10 -10000 µg/plate in the presence and absence of an exogenous metabolic activation system (Aroclor 1254 -induced male Sprague-Dawley rat and male Syrian hamster liver S9). Exposure to urea caused cytotoxicity in some strains. The numbers of revertant colonies were not increased by exposure to urea. Appropriate positive controls confirmed the sensitivity of the assay (Mortelmans et al, 1986). Ishidate et al (1981) report the results of a chromosomal aberration assay performed in CHL cells with a number of chemicals, including urea. Approximately 10e5 cells were plated and exposed to concentrations of urea up to the concentration causing 50% growth inhibition, in the absence and presence of PCB-induced Wistar rat liver S9-fraction. Cells were harvested at 24 and 48 hours (-S9) or at 24 hours following a 3-hour pre-incubation step (+S9). Chromosomal aberrations (including numerical aberrations) were scored from 100 well-spread metaphases per concentration. A positive result is reported in this assay, however the DT20 value (the concentration at which 20% of cells or approximately 4x background) of 13.0 mg/mL or 216 mM is well in excess of the limit concentration of 5 mg/ml or 10 mM recommended by OECD 473 (1997). The authors note a very low clastogenic potential. Considering the high concentrations of urea required to produce a response in this assay, which are well in excess of the limit concentration, it cannot be concluded that urea is clastogenic. The finding in this study is very likely to be a false positive due to osmotic effects. The same group (Ishidate & Odashima, 1977) also tested urea for the ability to cause chromosomal aberrations in a screening assay in CHL cells in vitro in the absence of metabolic activation and at concentrations up to those causing 50% growth inhibition. A positive result is reported at a concentration of 266.4 mMol/L, which is well in excess of the limit concentration of 10 mM. The result is considered to be a false positive and is attributable to the effects of osmolarity. The potential mutagenicity of urea was investigated in a mouse lymphoma assay in the absence of metabolic activation. A weak positive response was seen at concentrations of 265 -662 mMol/L, concentrations which also caused cytotoxicity and which are well in excess of the limit concentration of 10 mMol/L recommended in OECD 476 (1997). The result is considered to be a false positive. The authors conclude that the effect is due to the influence of high concentrations of urea on the osmolarity of the culture medium (Wangenheim & Bolcsfoldi, 1988). The ability of urea to cause DNA damage was assessed in two DNA-unwinding/alkaline elution assays. Garberg et al (1987), report positive effects in mouse lymphoma cells at high concentrations of 628 and 718 mMol/L, however negative results are reported by Sina et al (1983) at concentrations of up to 3 mMol/L in cultured rat hepatocytes.

Chaurasia & Sinha (1987) investigated the potential of urea to cause chromosomal aberrations in the bone marrow of Swiss mice. Mice (number unspecified) were administered urea in the diet at a dose level of 500 mg/day for 5 days. Animals were sacrificed after a recovery period of 7 days and the bone marrow harvested. A total 300 metaphases from treated animals and untreated controls were assessed for chromosomal aberration. A marked increase in the incidence of chromosomal aberrations was seen in the treated group (7x controls). However the dose level administered in this study is equivalent to 16 -17 g/kg bw/day and is thus far in excess of the limit dose of 1000 mg/kg bw. Signs of toxicity are not reported, but marked toxicity can be predicted at this dose level.

Positive results obtained in vitro are associated with concentrations well in excess of the recommended limit concentrations are not considered to be of biological relevance. A positive result in vivo is also associated with an excessive dose level. Considering the physiological role and presence of substantial quantities of urea in the human body, it is not considered likely that this substance is genotoxic. Further testing is therefore not proposed.

Carcinogenicity

The carcinogenicity of urea was investigated in NCI 12 -month screening studies in the rat and mouse (Fleischman et al, 1980). No evidence of carcinogenicity or toxicity was seen in either study at the very high dose level of 45000 ppm (4.5% in the diet).

F344 rats (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 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. A significant linear trend in the incidence of interstitial cell tumours was noted in male rats. The incidence was 21/50 in controls, 27/48, 25/48 and 35/50 in the low, intermediate and high dose groups respectively. The authors do not consider this finding to be of biological significance as the background incidence of this tumour type is noted to be up to 100% in F344 rats.

B6C3F1 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 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. A significantly increased incidence of haematopoietic tumours (malignant lymphoma) was seen in female rats in the mid-dose group. The incidence of this finding was 10/92 in controls; 7/43, 10/38 and 9/50 in low, mid and high dose group animals, respectively. There is no relationship to treatment in the absence of a dose-response relationship.

Reproductive and developmental toxicity

No data are available for reproductive toxicity. A study of limited design did not indicate any teratogenicity or effects on renal development in the rat (Seipelt et al, 1969), however slightly lower pup weights were seen at the dose level of 500 mg/kg bw/d in this study. A screening assay in chick eggs is considered to be of limited value (Mora et al, 1991). However, large quantities of urea are formed naturally in the human body as a consequence of normal protein catabolism. Urea is shown to be essentially without toxicity in the available studies and no effects (organ weight, gross pathology, histopathology) were observed on the reproductive organs of rats and mice exposed to urea at very high dietary levels for 12 months (Fleischman et al, 1980). The level of any primary, occupational or secondary exposure to urea is likely to be insignificant compared to the quantities (20-50 g/day) produced by normal metabolism and present at high concentrations in the blood. It is therefore considered that urea is very unlikely to be a reproductive toxin and testing cannot be justified scientifically.

DNEL derivation

 

The amount of urea typically produced by the body in one day is typically reported to be 20 -50 g, depending on the level of dietary protein intake. In an adult (70 kg bodyweight), this corresponds to a level of ~285 -715 mg/kg bw/day. It can therefore be concluded that this level of exposure to urea is without toxicological effect. In addition, it is calculated that the quantity of urea present in the blood of an adult (based on reference ranges) at any point in time is 192-577 mg (equivalent to 2.75-8.25 mg/kg bw).

 

The toxicity data for urea are limited, but the available confirm (consistent with its physiological role and production) that this substance is of inherently very low toxicity. A marginal LOAEL from a developmental toxicity study (based on slightly lower pup weights) of 500 mg/kg bw/day is reported; a NOAEL of 45000 ppm (approximately equivalent to 2250 mg/kg bw/d) is reported for a 12 -month rat study.

 

It is recognised that application of default assessment factors according to REACH guidance will result in the derivation of excessively conservative DNEL values representing a very small proportion of the quantities of urea normally produced by the body and therefore without toxicological consequence.

 

Local effects

 

No evidence of local effects is seen in any of the dermal studies performed with urea; there is no evidence of local effects from human studies or from experience of human exposure. It is notable that urea is widely used at high levels in skin creams used to treat dermal conditions in humans. Respiratory irritation is not predicted. DNELs for local effects are therefore not relevant and are not calculated for urea.

 

Systemic effects

 

The lower value (marginal LOAEL) of 500 mg/kg bw/d may be used as a relevant point of departure for the derivation of DNELs. This endpoint is taken from a developmental toxicity study, however a higher endpoint was seen in a chronic toxicity study therefore short-term and long-term DNEL values are the same as correction for duration of exposure is not required. Assuming a human bodyweight of 70 kg and 100% oral absorption, the dose level of 500 mg/kg bw/d is equivalent to 35 g urea/day. It is noted that this level of exposure is comparable to the normal production of urea by the human body (20 -50 g/day).

 

The starting point for DNEL derivation is therefore the oral LOAEL of 500 mg/kg bw/d

Worker DNEL values are calculated using the following assessment factors taken from the ECETOC Technical Report 86 (Derivation of Assessment Factors for Human Health Risk Assessment).

3 - to cover the use of a LOAEL rather than a NOAEL as the Point of Departure (PoD).

4 - to cover interspecies differences. The default factor is used to cover differences in metabolic rate between rats and humans. Urea is generated in rats and humans as a consequence of protein catabolism and is excreted in the same way, therefore the use of this factor is likely to represent a conservative position.

 

1 - to cover intraspecies differences. Urea is generated in humans as a consequence of protein catabolism and is rapidly excreted; intraspecies differences in the response to urea are likely to be low therefore a non-standard assessment factor of 1 is used.

Additional assessment factors to cover exposure duration are not required as urea is constantly being generated by protein catabolism and does not show any cumulative toxicity.

The overall assessment factor used for the derivation of the worker DNEL values is therefore 12 (3*4).

For dermal exposure the systemic DNEL is derived by applying the assessment factor of 12 to the oral NOAEL of 500 mg/kg bw/d and correcting for dermal absorption of 7.2%. A systemic dermal DNEL of 580 mg/kg bw/d is derived.

For inhalation exposure, the starting point of 500 mg/kg bw/d is corrected (assuming bodyweight of 70 kg, exposure for 8 hours/day and a breathing rate of 1.25 mg/m³) to 3500 mg/m3. A systemic inhalation DNEL of 292 mg/m3 is derived by applying the assessment factor of 12 to the corrected starting point.

 

Worker exposure at the proposed DNEL is equivalent to an approximate systemic exposure of 40 mg/kg bw/d. This level of systemic exposure must be considered in the light of the exposure to urea resulting from normal metabolism, of approximately 285-715 mg/kg bw/d. The maximum level of additional occupational exposure is therefore approximately 14% of the lower range of urea produced by normal metabolism in one day. This additional exposure is considered to be minimal and will be without toxicological effect.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
580 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
580 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
42 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
42 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
LOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The starting point for DNEL derivation is the oral LOAEL of 500 mg/kg bw/d

Worker DNEL values were calculated using the following assessment factors taken from the ECETOC Technical Report 86 (Derivation of Assessment Factors for Human Health Risk Assessment. DNEL values for the general public can be calculated using the same endpoints as the worker DNEL values.

 

3 - to cover the use of a LOAEL rather than a NOAEL as the Point of Departure (PoD).

4 - to cover interspecies differences. The default factor is used to cover differences in metabolic rate between rats and humans. Urea is generated in rats and humans as a consequence of protein catabolism and is excreted in the same way, therefore the use of this factor is likely to represent a conservative position.

 

1 - to cover intraspecies differences. Urea is generated in humans as a consequence of protein catabolism and is rapidly excreted; intraspecies differences in the response to urea are likely to be low therefore a non-standard assessment factor of 1 is used.

Additional assessment factors to cover exposure duration are not required as urea is constantly being generated by protein catabolism and does not show any cumulative toxicity.

The overall assessment factor used for the derivation of the DNEL values is therefore 12 (3*4).

For dermal exposure the systemic DNEL is derived by applying the assessment factor of 12 to the oral NOAEL of 500 mg/kg bw/d and correcting for dermal absorption of 7.2%. A systemic dermal DNEL of 580 mg/kg bw/d is derived.

For inhalation exposure, the starting point of 500 mg/kg bw/d is corrected (assuming bodyweight of 60 kg, exposure for 24 hours/day and a breathing rate of 20 m³/d) to 1500 mg/m3. A systemic inhalation DNEL of 125 mg/m3 is derived by applying the assessment factor of 12 to the corrected starting point.

For oral exposure the systemic DNEL is derived by applying the assessment factor of 12 to the oral NOAEL of 500 mg/kg bw/d. A systemic dermal DNEL of 42 mg/kg bw/d is derived.

Exposure at the proposed DNEL is equivalent to an approximate systemic exposure of 40 mg/kg bw/d. This level of systemic exposure must be considered in the light of the exposure to urea resulting from normal metabolism, of approximately 285-715 mg/kg bw/d. The maximum level of additional occupational exposure is therefore approximately 14% of the lower range of urea produced by normal metabolism in one day. This additional exposure is considered to be minimal and will be without toxicological effect.