Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 526 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

6.75

Dose descriptor starting point:

NOAEL

Value:

2 250 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

23 803 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction factors for oral-to-inhalation

Correction for the dose descriptor: 2250 mg/kg bw	Workers
a. respiratory volume humans versus rats	: 0.38 (8h)
b. increased respiratory rate of workers	X 6.7/10
c. absorption inhalation versus oral *	X6
d. absorption differences human versus rats **	-
NOAEC (mg/m³)	23803

* A much lower exposure (deposition) and absorption was assessed for the inhalation tract compared to the gastro-intestinal system. This was based on physicochemical and toxicological data (see separate toxicokinetics assessment for the substances) and/or on experimental data for source chemical Doscusate sodium (see separate justification documents for read across). For risk assessment, following conservative factors were accepted: 60% absorption via oral route; 10% absorption via inhalation route(Factor 6). ** No data

AF for dose response relationship:

1

Justification:

No correction is needed as the departure point is a NOAEL.

AF for differences in duration of exposure:

1

Justification:

No correction is needed as chronic application corresponds with chronic exposure in humans.

AF for interspecies differences (allometric scaling):

1

Justification:

For inhalation, the allometric scaling factor is already in the modification from NOAEL to NOAEC.

AF for other interspecies differences:

1

Justification:

Urea plays a physiological role in renal countercurrent exchange, and it is present in saliva in appreciable concentrations (approximately 200 mg/L) as well as in the epidermis at high levels, where it plays a role in skin hydration. From a toxicodynamic viewpoint, no substantial differences are expected between species.
Therefore, a remaining interspecies factor for toxicodynamic differences of 1 is accepted (instead of 2.5).

AF for intraspecies differences:

3

Justification:

Except in patients with renal diseases, no toxicity is expected from urea and differences within species are not expected. Therefore informed assessment factor of 3 is proposed instead of ECHA default value of 5 for workers.

AF for the quality of the whole database:

2.25

Justification:

The 12-month studies in rats and mice were rather intended as carcinogenicity studies than repeated dose toxicity studies. As not all parameters were covered by these studies compared to current standards, an AF of 2.25 was applied. This factor 2.25 is justified, as this makes the departure point comparable (2250 mg/kg bw / 2.25 = 1000 mg/kg bw) to the NOAEL of 1000 mg/kg bw from the developmental toxicity study as departure point.

AF for remaining uncertainties:

1

Justification:

No other uncertainties

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 526 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

6.75

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

LOAEC

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

500 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

27

Dose descriptor starting point:

NOAEL

Value:

2 250 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

13 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for oral-to-dermal

Correction for the dose descriptor: 2250 mg/kg bw	Workers
a. absorption dermal versus oral *	X6
b. absorption differences human versus rats **	-
NOAEL (mg/kg bw)	13500

* A much lower dermal absorption was estimated compared to gastro-intestinal absorption. This was based on the basic qualitative toxicokinetics assessment (physicochemical and toxicological data) and experimental data of dermal absorption (9.5% ). For risk assessment, following conservative factors were accepted: 60% absorption via oral route; 10% absorption via dermal route(Factor 6).
** Worst case assumption is that dermal penetration is the same in rats and humans. Rats however have a more permeable skin than humans (dermal absorption: man < pig < rat < rabbit).

AF for dose response relationship:

1

Justification:

No correction is needed as the departure point is a NOAEL.

AF for differences in duration of exposure:

1

Justification:

No correction is needed as chronic application corresponds with chronic exposure in humans.

AF for interspecies differences (allometric scaling):

4

Justification:

The absorption, distribution, metabolism and excretion of urea is well know. 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. 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. Bioaccumulation is not likely

AF for other interspecies differences:

1

Justification:

Urea plays a physiological role in renal countercurrent exchange, and it is present in saliva in appreciable concentrations (approximately 200 mg/L) as well as in the epidermis at high levels, where it plays a role in skin hydration. From a toxicodynamic viewpoint, no substantial differences are expected between species.
Therefore, a remaining interspecies factor for toxicodynamic differences of 1 is accepted (instead of 2.5).

AF for intraspecies differences:

3

Justification:

Except in patients with renal diseases, no toxicity is expected from urea and differences within species are not expected. Therefore informed assessment factor of 3 is proposed instead of ECHA default values of 5 for workers.

AF for the quality of the whole database:

2.25

Justification:

The 12-month studies in rats and mice were rather intended as carcinogenicity studies than repeated dose toxicity studies. As not all parameters were covered by these studies compared to current standards, an AF of 2.25 was applied. This factor 2.25 is justified, as this makes the departure point comparable (2250 mg/kg bw / 2.25 = 1000 mg/kg bw) to the NOAEL of 1000 mg/kg bw from the developmental toxicity study as departure point.

AF for remaining uncertainties:

1

Justification:

No other uncertainty

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

500 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETIC (see attached DNEL justification)

Overall assessment factor (AF):

27

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

LOAEL

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

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. It is formed in the liver from ammonia (NH3), a deamination product of amino acids.

Development Screening Information Data Set: 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 BUN = Blood Urea Nitrogen 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 BUN 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.

BUN reflects only the nitrogen content of urea (MW 28) and urea measurement reflects the whole of the molecule (MW 60), therefore urea is approximately twice (60/28 = 2.14) that of BUN (Higgins, 2016).

Approximate reference (normal) range BUN: Serum/plasma BUN 7.0-22 mg/dL Serum/plasma urea 2.5-7.8 mmol/L

Approximate reference (normal) range urea (BUN 10 mg/dL is equivalent to urea 21.4 mg/dL): Serum/plasma urea 15.0 – 45 mg/dL or Body urea (x 50 -dL x 0.55) 412.5 – 1237.5 mg or 5.90 -17.7 mg/kg bw

Although breath test using 13C-labeled urea (CAS 57-13-6, UBT) is becoming popular for the diagnosis of Helicobacter pylori (H. pylori) infection, disposition of exogenously given urea is not fully understood. The purpose of the present study is to elucidate the disposition of exogenous urea and to consider its relation with the UBT safety and biobehavior of endogenous urea. With 14C-labeled urea ([14C]urea), the absorption, distribution, metabolism and excretion including that into breathed air after its administration in trace to large doses in rats were investigated. [14C]Urea was given to fasted and non-fasted rats through intravenous and oral routes. It was found that the disposition of exogenous [14C]urea behaves in a similar way as endogenous urea, and a sufficiently large capacity for disposing urea in rats was suggested from the linear pharmacokinetics within the wide dose range of [14C]urea (2−1000 mg/kg). The safety of urea in UBT was also revealed by consideration of its dose and human urea body pool. It was also suggested that diet stimulates both systemic (as observed after the intravenous dose) and pre-systemic (as with the oral route) decompositions of urea into carbon dioxide and ammonia, but does not affect the renal elimination and distribution pattern in rat tissues. The findings in this study provide us with the quantitative information concerning not only the safety and disposition of urea as a diagnostic agent, but also the biobehavior of endogenous urea in ureotelism (Nomura et al., 2006).

The role of erythrocyte on the hepatic distribution kinetics of urea and thiourea was investigated in thein situisolated perfused rat liver. Perfusion experiments were conducted using Krebs-bicarbonate buffer delivered via the portal vein in a single pass mode at a total flow rate of 15 mL/min. With urea, superimposable unimodal effluent curves were obtained in the presence and absence of erythrocytes, indicating that its distribution kinetics is not affected by erythrocytes. With thiourea, effluent curves were unimodal in the absence of erythrocytes but bimodal in the presence of erythrocytes. The maximum frequency output at the first peak increased from 0.017 ± 0.002 to 0.042 ± 0.006 s−1 with an increase in the bolus hematocrit from 0.40 to 0.75, indicating that some thiourea fraction is retained by the erythrocytes on transit through the liver. Although the fractional output associated with the first peak was very similar (11.9% versus 11.5%), whether the perfusate contained unlabelled thiourea or not, this fraction was reduced from 17 to 5% with a decrease in the incubation time before injection from 30 min to 40 s. However, there was no evidence for a capacity limitation; a 30-min period of pre-incubation of either radiolabelled thiourea alone or combined with a high concentration of unlabelled thiourea had minimal effect on effluent profiles (Sahin & Rowland, 2007).

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. Approximately 20–35 g of urea is excreted in human urine per day (OECD SIDS, 2002). 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.

Repeated dose toxicity

Oral

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.

Dermal

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).

Inhalation

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 additionally not justified on animal welfare grounds.

Other routes

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/100ml. The dogs displayed mild drowsiness. Haematocrit, platelet counts and EEG were not affected. The study indicates that urea is of very low toxicity in the dog following repeated administration (Balestri et al, 1971).

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 043.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

11.25

Dose descriptor starting point:

NOAEL

Value:

2 250 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

11 739 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction factors for oral-to-inhalation

Correction for the dose descriptor: 2250 mg/kg bw	General population
a. respiratory volume humans versus rats	: 1.15 (24h)
b. increased respiratory rate of workers	-
c. absorption inhalation versus oral *	X6
d. absorption differences human versus rats **	-
NOAEC (mg/m³)	11739

* A much lower exposure (deposition) and absorption was assessed for the inhalation tract compared to the gastro-intestinal system. This was based on physicochemical and toxicological data (see separate toxicokinetics assessment for the substances) and/or on experimental data for source chemical Doscusate sodium (see separate justification documents for read across). For risk assessment, following conservative factors were accepted: 60% absorption via oral route; 10% absorption via inhalation route(Factor 6). ** No data

AF for dose response relationship:

1

Justification:

No correction is needed as the departure point is a NOAEL.

AF for differences in duration of exposure:

1

Justification:

No correction is needed as chronic application corresponds with chronic exposure in humans.

AF for interspecies differences (allometric scaling):

1

Justification:

For inhalation, the allometric scaling factor is already in the modification from NOAEL to NOAEC.

AF for other interspecies differences:

1

Justification:

Urea plays a physiological role in renal countercurrent exchange, and it is present in saliva in appreciable concentrations (approximately 200 mg/L) as well as in the epidermis at high levels, where it plays a role in skin hydration. From a toxicodynamic viewpoint, no substantial differences are expected between species. Therefore, a remaining interspecies factor for toxicodynamic differences of 1 is accepted (instead of 2.5).

AF for intraspecies differences:

5

Justification:

Except in patients with renal diseases, no toxicity is expected from urea and differences within species are not expected. Therefore informed assessment factor of 5 is proposed instead of ECHA default value of 10 for general population.

AF for the quality of the whole database:

2.25

Justification:

The 12-month studies in rats and mice were rather intended as carcinogenicity studies than repeated dose toxicity studies. As not all parameters were covered by these studies compared to current standards, an AF of 2.25 was applied. This factor 2.25 is justified, as this makes the departure point comparable (2250 mg/kg bw / 2.25 = 1000 mg/kg bw) to the NOAEL of 1000 mg/kg bw from the developmental toxicity study as departure point.

AF for remaining uncertainties:

1

Justification:

No other uncertainty

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 043.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

11.25

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

LOAEC

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

300 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA and ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

45

Dose descriptor starting point:

LOAEL

Value:

2 250 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

13 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for oral-to-dermal

Correction for the dose descriptor: 2250 mg/kg bw	General population
a. absorption dermal versus oral *	X6
b. absorption differences human versus rats **	-
NOAEL (mg/kg bw)	13500

* A much lower dermal absorption was estimated compared to gastro-intestinal absorption. This was based on the basic qualitative toxicokinetics assessment (physicochemical and toxicological data) and experimental data of dermal absorption (9.5% ). For risk assessment, following conservative factors were accepted: 60% absorption via oral route; 10% absorption via dermal route(Factor 6).
** Worst case assumption is that dermal penetration is the same in rats and humans. Rats however have a more permeable skin than humans (dermal absorption: man < pig < rat < rabbit)

AF for dose response relationship:

1

Justification:

No correction is needed as the departure point is a NOAEL.

AF for differences in duration of exposure:

1

Justification:

No correction is needed as chronic application corresponds with chronic exposure in humans.

AF for interspecies differences (allometric scaling):

4

Justification:

The absorption, distribution, metabolism and excretion of urea is well know. 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. 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. Bioaccumulation is not likely.

AF for other interspecies differences:

1

Justification:

Urea plays a physiological role in renal countercurrent exchange, and it is present in saliva in appreciable concentrations (approximately 200 mg/L) as well as in the epidermis at high levels, where it plays a role in skin hydration. From a toxicodynamic viewpoint, no substantial differences are expected between species. Therefore, a remaining interspecies factor for toxicodynamic differences of 1 is accepted (instead of 2.5).

AF for intraspecies differences:

5

Justification:

Except in patients with renal diseases, no toxicity is expected from urea and differences within species are not expected. Therefore informed assessment factor of 5 is proposed instead of ECHA default value of 10 for general population.

AF for the quality of the whole database:

2.25

Justification:

The 12-month studies in rats and mice were rather intended as carcinogenicity studies than repeated dose toxicity studies. As not all parameters were covered by these studies compared to current standards, an AF of 2.25 was applied. This factor 2.25 is justified, as this makes the departure point comparable (2250 mg/kg bw / 2.25 = 1000 mg/kg bw) to the NOAEL of 1000 mg/kg bw from the developmental toxicity study as departure point.

AF for remaining uncertainties:

1

Justification:

No other uncertainty

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

300 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA and ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

45

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

LOAEL

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

50 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC (see attached DNEL justification)

Overall assessment factor (AF):

45

Dose descriptor starting point:

NOAEL

Value:

2 250 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No correction is needed as the toxicity study was done orrally.

AF for dose response relationship:

1

Justification:

No correction is needed as the departure point is a NOAEL.

AF for differences in duration of exposure:

1

Justification:

No correction is needed as chronic application corresponds with chronic exposure in humans.

AF for interspecies differences (allometric scaling):

4

Justification:

The absorption, distribution, metabolism and excretion of urea is well know. 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. 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. Bioaccumulation is not likely.

AF for other interspecies differences:

1

Justification:

Urea plays a physiological role in renal countercurrent exchange, and it is present in saliva in appreciable concentrations (approximately 200 mg/L) as well as in the epidermis at high levels, where it plays a role in skin hydration. From a toxicodynamic viewpoint, no substantial differences are expected between species. Therefore, a remaining interspecies factor for toxicodynamic differences of 1 is accepted (instead of 2.5).

AF for intraspecies differences:

5

Justification:

Except in patients with renal diseases, no toxicity is expected from urea and differences within species are not expected. Therefore informed assessment factor of 5 is proposed instead of ECHA default values of 10 for general population.

AF for the quality of the whole database:

2.25

Justification:

The 12-month studies in rats and mice were rather intended as carcinogenicity studies than repeated dose toxicity studies. As not all parameters were covered by these studies compared to current standards, an AF of 2.25 was applied. This factor 2.25 is justified, as this makes the departure point comparable (2250 mg/kg bw / 2.25 = 1000 mg/kg bw) to the NOAEL of 1000 mg/kg bw from the developmental toxicity study as departure point.

AF for remaining uncertainties:

1

Justification:

No other uncertainty

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

50 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC (see attached DNEL justificatiion)