Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEL
DNEL value:
8.3 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
10.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
Only oral route is available
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation. Extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
AF for other interspecies differences:
1
Justification:
There is evidence from repeated-dose studies that the registered substance causes thyroid enlargement (hypertrophy/hyperplasia) when administered to rats in the drinking water. To further investigate the mode of action of thyroid effects, a 14-days in vivo mechanistic study was performed in rats with additional thyroid investigations (determination of thyroid hormones (total triiodothyronine (T3) and thyroxine (T4)) and thyroid stimulating hormone (TSH)) and assessment of liver enzyme amounts/activities. The results of this mechanistic study support the hypothesis that thyroid enlargement is probably related to increased TSH drive in response to decreases in circulating plasma levels of T3 and T4. Furthermore, an induction of liver enzymes in both sexes was observed. Although the results of the mechanistic investigations do not clearly prove that induction of specific Phase II enzymes responsible for hepatic clearance of T3 and T4 is the exclusively operating Mode of Action (MoA) of thyroid toxicity for the registered substance, it is considered that the rat is more sensistive to the thyroid effects comparaed to humans. Thus, no further assessment factor is applied for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
DNEL value:
8.3 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
116.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only oral route available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is evidence from repeated-dose studies that the registered substance causes thyroid enlargement (hypertrophy/hyperplasia) when administered to rats in the drinking water. To further investigate the mode of action of thyroid effects, a 14-days in vivo mechanistic study was performed in rats with additional thyroid investigations (determination of thyroid hormones (total triiodothyronine (T3) and thyroxine (T4)) and thyroid stimulating hormone (TSH)) and assessment of liver enzyme amounts/activities. The results of this mechanistic study support the hypothesis that thyroid enlargement is probably related to increased TSH drive in response to decreases in circulating plasma levels of T3 and T4. Furthermore, an induction of liver enzymes in both sexes was observed. Although the results of the mechanistic investigations do not clearly prove that induction of specific Phase II enzymes responsible for hepatic clearance of T3 and T4 is the exclusively operating Mode of Action (MoA) of thyroid toxicity for the registered substance, it is considered that the rat is more sensistive to the thyroid effects comparaed to humans. Thus, no further assessment factor is applied for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

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:
medium hazard (no threshold derived)

Additional information - workers

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)
No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. For dermal absorption, based on the physico-chemical properties of the substance (log Kow < -1 and water solubility > 10000 mg/L) low dermal uptake is expected. This is supported by the estimated Kp value of 1.67 E-04 cm/h using the Danish (Q)SAR Database (EPI Suite, DERMWIN V 2.09) indicative for a very low dermal penetration potential according to DK-EPA heuristics (User Manual for the Internet Version of the Danish (Q)SAR Database, Database Version 1, May 2005). Therefore, a ratio of 0.1 for oral to dermal absorption is provisionally suggested for DNEL derivation.
 
Acute toxicity
2-imidazolidone does not have to be classified for acute toxicity and therefore derivation of a DNEL (acute) is not necessary.
 
Repeated dose toxicity
The study considered for DNEL derivation of 2-imidazolidone is the 90-day repeated dose toxicity study (OECD 408 in rats. In this study, the administration of 2-Imidazolidone via the drinking water to male and female Wistar rats for 3 months caused test substance-related adverse signs of toxicity at a concentration of 500 ppm and above taking the thyroid gland findings and impaired body weight development into account.

The no observed adverse effect level (NOAEL) was 100 ppm in male (8.3 mg/kg bw/d) and in female (10.5 mg/kg bw/d) Wistar rat.

Supportingly, in a combined repeated dose toxicity study with the reproduction/toxicity screening test, the NOAEL was 500 ppm based on decreased body weight/body weight gain, decreased food consumption, and the occurrence of hypertrophy/ hyperplasia in the thyroid glands in males and females of test group 3 (2000 ppm).

In another subacute oral toxicity study, no NOAEL could be derived. The LOAEL was 1000 ppm (equal to 76 mg/kg bw/day in males and 92 mg/kg bw/day in females) based on hypertrophy of the follicular epithelium of the thyroid glands in two males and one female and thickening of the mucosa of the duodenum in all males and one female.

 

Mutagenicity

The substance was not mutagenic in the Ames test and not mutagenic in the HPRT test. Furthermore, the test substance did not induce micronuclei as determined by the in vitro micronucleus test in human lymphocytes.

 

Reproduction toxicity

No reproductive toxicity and some developmental toxicity was observed in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in rats with 2-imidazolidone (tested at 0, 100, 500 or 2000 ppm). Thus, the NOAEL for reproductive toxicity was considered 2000 ppm (correspondind to 155 mg/kg bw/day for male rats and 214 mg/kg bw/day for female rats), while the NOAEL for developmental toxicity was considered 500 ppm (corresponding to 37 mg/kg bw /day for male rats and 57 mg/kg bw/day for female rats), based on decreased pup viability. No DNEL has to be derived for developmental and reproductive toxicity.

Supportingly, no adverse effects regarding reproductive parameters were observedin an OECD Guideline 408 study withadditional examinations of male and female reproductive parameters (oestrous cycle, sperm parameters, and reproductive and other certain organs and tissues).

In a prenatal developmental toxicity study (OECD 414), the oral administration of 2-Imidazolidone to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 1000 mg/kg bw/d caused signs of maternal toxicity, such as a reduction in food consumption and a decrease in (corrected) body weight (change/gain). The NOAEL for maternal toxicity was established at the mid dose of 200 mg/kg bw/d. The NOAEL for prenatal developmental toxicity was the highest tested dose of 1000 mg/kg bw/d.

 

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure.

For long-term toxicity, regarding systemic effects, a NOAEL of 100 ppm (corresponding to 8.3 mg/kg bw/day in male rats, and 10.5 mg/kg bw/day in female rats) was observed in a 90-day repeated dose toxicity study (OECD 408). 2-imidazolidone was administered daily to rats via drinking water at doses of 0, 100, 500 or 2000 ppm. In this study, the administration of 2-Imidazolidone via the drinking water to male and female Wistar rats for 3 months caused test substance-related adverse signs of toxicity at a concentration of 500 ppm and above taking the thyroid gland findings and impaired body weight development into account.

The lowest NOAEL of 100 ppm corresponding to 8.3 mg/kg bw/day for male animals is used for the DNEL derivation.

Long-term dermal and inhalation toxicity data is not available.

 

Worker DNELs

Long-term –inhalation, systemic effects (based on subchronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 8.3 mg/kg bw/day

Thyroid toxicity and impaired bodyweight development.

Step 2) Modification of starting point

2

 

 

0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

7 d/5 d

Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2).

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2).

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker.

Modified dose-descriptor

8.3 / 2 / 0.38 x (6.7/10) x (7 d/5 d) = 10.2 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

5

Default assessment factor

Exposure duration

2

Default assessment factor for subchronic to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

 10.2 / (1 x 5 x 2 x 1 x 1) = 1.0 mg/m3

  

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.  

 

Long-term – dermal, systemic effects (based on subchronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 8.3 mg/kg bw/day

Thyroid toxicity and impaired bodyweight development.

Step 2) Modification of starting point

0.1

7 d/5 d

Based on low log Kow and very high water solubility, dermal absorption is expected to be low. This is supported by the estimated Kp valueof 1.67 E-04 cm/husing the Danish (Q)SAR Database (EPI Suite, DERMWIN V 2.09) indicative for a very low dermal penetration potential according to DK-EPA heuristics (User Manual for the Internet Version of the Danish (Q)SAR Database, Database Version 1, May 2005). A ratio of 0.1% for dermal to oral absorption is therefore provisionally suggested for DNEL derivation.

 

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker.

Modified dose-descriptor

8.3 / 0.1 x (7 d/5 d) = 116 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor

Exposure duration

2

Default assessment factor for subchronic to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

116 / (4 x 5 x 2 x 1 x 1) = 2.9 mg/kg bw/day

  

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating to skin, no local effects are also expected by repeated dermal exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.18 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEL
DNEL value:
8.3 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
3.6 mg/m³
Explanation for the modification of the dose descriptor starting point:
Only oral route available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation. Extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
AF for other interspecies differences:
1
Justification:
There is evidence from repeated-dose studies that the registered substance causes thyroid enlargement (hypertrophy/hyperplasia) when administered to rats in the drinking water. To further investigate the mode of action of thyroid effects, a 14-days in vivo mechanistic study was performed in rats with additional thyroid investigations (determination of thyroid hormones (total triiodothyronine (T3) and thyroxine (T4)) and thyroid stimulating hormone (TSH)) and assessment of liver enzyme amounts/activities. The results of this mechanistic study support the hypothesis that thyroid enlargement is probably related to increased TSH drive in response to decreases in circulating plasma levels of T3 and T4. Furthermore, an induction of liver enzymes in both sexes was observed. Although the results of the mechanistic investigations do not clearly prove that induction of specific Phase II enzymes responsible for hepatic clearance of T3 and T4 is the exclusively operating Mode of Action (MoA) of thyroid toxicity for the registered substance, it is considered that the rat is more sensistive to the thyroid effects comparaed to humans. Thus, no further assessment factor is applied for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.04 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Dose descriptor starting point:
NOAEL
DNEL value:
8.3 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only oral route is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is evidence from repeated-dose studies that the registered substance causes thyroid enlargement (hypertrophy/hyperplasia) when administered to rats in the drinking water. To further investigate the mode of action of thyroid effects, a 14-days in vivo mechanistic study was performed in rats with additional thyroid investigations (determination of thyroid hormones (total triiodothyronine (T3) and thyroxine (T4)) and thyroid stimulating hormone (TSH)) and assessment of liver enzyme amounts/activities. The results of this mechanistic study support the hypothesis that thyroid enlargement is probably related to increased TSH drive in response to decreases in circulating plasma levels of T3 and T4. Furthermore, an induction of liver enzymes in both sexes was observed. Although the results of the mechanistic investigations do not clearly prove that induction of specific Phase II enzymes responsible for hepatic clearance of T3 and T4 is the exclusively operating Mode of Action (MoA) of thyroid toxicity for the registered substance, it is considered that the rat is more sensistive to the thyroid effects comparaed to humans. Thus, no further assessment factor is applied for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

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:
0.1 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Dose descriptor starting point:
NOAEL
DNEL value:
8.3 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
8.3 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is evidence from repeated-dose studies that the registered substance causes thyroid enlargement (hypertrophy/hyperplasia) when administered to rats in the drinking water. To further investigate the mode of action of thyroid effects, a 14-days in vivo mechanistic study was performed in rats with additional thyroid investigations (determination of thyroid hormones (total triiodothyronine (T3) and thyroxine (T4)) and thyroid stimulating hormone (TSH)) and assessment of liver enzyme amounts/activities. The results of this mechanistic study support the hypothesis that thyroid enlargement is probably related to increased TSH drive in response to decreases in circulating plasma levels of T3 and T4. Furthermore, an induction of liver enzymes in both sexes was observed. Although the results of the mechanistic investigations do not clearly prove that induction of specific Phase II enzymes responsible for hepatic clearance of T3 and T4 is the exclusively operating Mode of Action (MoA) of thyroid toxicity for the registered substance, it is considered that the rat is more sensistive to the thyroid effects comparaed to humans. Thus, no further assessment factor is applied for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)
No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. For dermal absorption, based on the physico-chemical properties of the substance (log Kow < -1 and water solubility > 10000 mg/L) low dermal uptake is expected. This is supported by the estimated Kp value of 1.67 E-04 cm/h using the Danish (Q)SAR Database (EPI Suite, DERMWIN V 2.09) indicative for a very low dermal penetration potential according to DK-EPA heuristics (User Manual for the Internet Version of the Danish (Q)SAR Database, Database Version 1, May 2005). Therefore, a ratio of 0.1 for oral to dermal absorption is provisionally suggested for DNEL derivation.
 

Acute toxicity
2-imidazolidone does not have to be classified for acute toxicity and therefore derivation of a DNEL (acute) is not necessary.
 
Repeated dose toxicity
The study considered for DNEL derivation of 2-imidazolidone is the 90-day repeated dose toxicity study (OECD 408 in rats. In this study, the administration of 2-Imidazolidone via the drinking water to male and female Wistar rats for 3 months caused test substance-related adverse signs of toxicity at a concentration of 500 ppm and above taking the thyroid gland findings and impaired body weight development into account.

The no observed adverse effect level (NOAEL) was 100 ppm in male (8.3 mg/kg bw/d) and in female (10.5 mg/kg bw/d) Wistar rat.

Supportingly, in a combined repeated dose toxicity study with the reproduction/toxicity screening test, the NOAEL was 500 ppm based on decreased body weight/body weight gain, decreased food consumption, and the occurrence of hypertrophy/ hyperplasia in the thyroid glands in males and females of test group 3 (2000 ppm).

In another subacute oral toxicity study, no NOAEL could be derived. The LOAEL was 1000 ppm (equal to 76 mg/kg bw/day in males and 92 mg/kg bw/day in females) based on hypertrophy of the follicular epithelium of the thyroid glands in two males and one female and thickening of the mucosa of the duodenum in all males and one female.

 

Mutagenicity

The substance was not mutagenic in the Ames test and not mutagenic in the HPRT test. Furthermore, the test substance did not induce micronuclei as determined by the in vitro micronucleus test in human lymphocytes.

 

Reproduction toxicity

No reproductive toxicity and some developmental toxicity was observed in acombined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in ratswith2-imidazolidone(tested at0, 100, 500 or 2000 ppm). Thus, the NOAEL for reproductive toxicity was considered 2000 ppm (correspondind to 155 mg/kg bw/day for male rats and 214 mg/kg bw/day for female rats), while the NOAEL for developmental toxicity was considered 500 ppm (corresponding to 37 mg/kg bw /day for male rats and 57 mg/kg bw/day for female rats), based on decreased pup viability. No DNEL has to be derived for developmental and reproductive toxicity.

Supportingly, no adverse effects regarding reproductive parameters were observedin an OECD Guideline 408 study withadditional examinations of male and female reproductive parameters (oestrous cycle, sperm parameters, and reproductive and other certain organs and tissues).

In a prenatal developmental toxicity study (OECD 414), the oral administration of 2-Imidazolidone to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 1000 mg/kg bw/d caused signs of maternal toxicity, such as a reduction in food consumption and a decrease in (corrected) body weight (change/gain). The NOAEL for maternal toxicity was established at the mid dose of 200 mg/kg bw/d. The NOAEL for prenatal developmental toxicity was the highest tested dose of 1000 mg/kg bw/d.

 

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure.

For long-term toxicity, regarding systemic effects, a NOAEL of 100 ppm (corresponding to 8.3 mg/kg bw/day in male rats, and 10.5 mg/kg bw/day in female rats) was observed ina 90-dayrepeated dose toxicity study (OECD 408). 2-imidazolidone was administered daily to rats via drinking water at doses of 0, 100, 500 or 2000 ppm.In this study, the administration of 2-Imidazolidone via the drinking water to male and female Wistar rats for 3 months caused test substance-related adverse signs of toxicity at a concentration of 500 ppm and above taking the thyroid gland findings and impaired body weight development into account.

The lowest NOAEL of 100 ppm corresponding to 8.3 mg/kg bw/day for male animals is used for the DNEL derivation.

Long-term dermal and inhalation toxicity data is not available.

General population DNELs

Long-term – inhalation, systemic effects (based on subchronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 8.3 mg/kg bw/day

Thyroid toxicity and impaired bodyweight development.

Step 2) Modification of starting point

2

 

 

1.15 m3/kg bw

 

 

Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Modified dose-descriptor

8.3 / 2 x (1/1.15) = 3.6 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

10

Default assessment factor

Exposure duration

2

Default assessment factor for subchronic to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

3.6 / (1 x 10 x 2 x 1 x 1) = 0.18 mg/m3

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

  

Long-term – dermal, systemic effects (based on subchronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 8.3 mg/kg bw/day

Thyroid toxicity and impaired bodyweight development.

Step 2) Modification of starting point

0.1

Based on low log Kow and very high water solubility, dermal absorption is expected to be low. This is supported by the estimated Kp value of 1.67 E-04 cm/h using the Danish (Q)SAR Database (EPI Suite, DERMWIN V 2.09) indicative for a very low dermal penetration potential according to DK-EPA heuristics (User Manual for the Internet Version of the Danish (Q)SAR Database, Database Version 1, May 2005). A ratio of 0.1% for dermal to oral absorption is therefore provisionally suggested for DNEL derivation.

Modified dose-descriptor

8.3 / 0.1 = 83 mg/kg bw/day

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

Default assessment factor for subchronic to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

83 / (4 x 10 x 2 x 1 x 1) = 1.04 mg/kg bw/day

  

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived. As the substance is not irritating to skin, no local effects are also expected by repeated dermal exposure.

 

Long-term – oral, systemic effects (based on subchronic oral toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 8.3 mg/kg bw/day

Thyroid toxicity and imüpaired bodyweight development.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

2

Default assessment factor for sub-acute to chronic exposure

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

8.3 / (4 x 10 x 2 x 1 x 1) = 0.1 mg/kg bw/day