Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.85 µg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
250 000
Dose descriptor starting point:
T25
Value:
65 mg/kg bw/day
Modified dose descriptor starting point:
T25
Value:
213 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route-specific bioavailability 100% (inhalation = oral)= 1 : x 1

Adjustment of route of exposure: from rat (oral) in mg/kg/d to rat inhalation (0.8L/min/kg, 8h): 0.384 m³/kg/8h: x 1 / 0,384

Activity-driven differences: At rest / light activity: 6.7 /10 in line with the „10 m³“ approach: x 6,7 / 10

Differences between occupational and lifetime exposure conditions: x 75 / 40 = x 1,875

Corrected descriptor: T25 (rat, inhalation) = 213 mg/m3

AF for dose response relationship:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for differences in duration of exposure:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for interspecies differences (allometric scaling):
1
Justification:
Factor 4 is already applied in route-to-route modification.
AF for other interspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for intraspecies differences:
1
Justification:
not applied
AF for the quality of the whole database:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for remaining uncertainties:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

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:
DMEL (Derived Minimum Effect Level)
Value:
0.24 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 000 000
Dose descriptor starting point:
T25
Value:
65 mg/kg bw/day
Modified dose descriptor starting point:
T25
Value:
244 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-specific bioavailability 50% (dermal versus oral): x 2

Differences between occupational and lifetime exposure conditions: x 75 / 40 = x 1,875

Corrected descriptor: T25 (rat, dermal) = 244 mg/kg/d

AF for dose response relationship:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for differences in duration of exposure:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for interspecies differences (allometric scaling):
4
Justification:
For the “linearity” approach only the allometric scaling factor of 4 is applied: /4
AF for other interspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for intraspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for the quality of the whole database:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for remaining uncertainties:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Dermal LD50 > 2500 mg/kg bw.

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:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Monuron has a harmonised classification according to Annex VI of Regulation (EC) No; 1272/2008 (CLP Regulation) for carcinogenicity as Carc. 2, H351 (suspected of causing cancer).

Although no mutagenicity was observed in the bacterial and mammalian gene mutation study, positive findings with Monuron were observed in the in vitro Chromosome Aberration Test and Sister Chromatid Exchange assay and in the in vivo Micronucleus assay in mice, indicating that this compound is a clastogen. However, as the effect was not dose proportional, questions were raised about the mode of action of this chemical and the nature of its clastogenicity (Sharma et al., 1987: Mutagenic potential of a substituted urea herbicide, Monuron, Cytologica 52: 841-846, 1987). Despite the positive results for Monuron in eukaryotic systems, there is no evidence that Monuron causes germ cell damage. A classification for mutagenicity is therefore not warranted according to CLP.

For the DNEL/DMEL derivation, the assessment below is based on theECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health (Version 2.1, November 2012).

Discussion

Based on the carcinogenicity classification, a Derived No Effect Level (DNEL) cannot be derived based on a threshold mechanism. Instead, a linearized approach will be followed to derive a Derived Minimal Effect Level (DMEL). The linear approach is used when there is an absence of sufficient information on modes of action or when mode of action information indicates that the dose-response curve at low dose is or is expected to be linear.According to the Guidance, the T25 (chronic dose rate that will give 25% of the animals’ tumours at a specific tissue site after correction for spontaneous incidence, within the standard life time of that species) is one of the descriptors that should be used as the default dose-descriptor in relation to linear extrapolation. The lowest tumorigenic doses showing a significant response (on statistical or biological basis) are generally used for obtaining the dose-descriptor value.

Carcinogenesis studies of Monuron were conducted in rats and mice by feeding diets lasting for 103-104 weeks. In rats, target concentrations were 0, 750, or 1500 ppm and effective concentrations were 0, 747 and 1514 ppm , corresponding with 60 and 121 mg/kg bw. There was clear evidence of carcinogenicity for male rats showing increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the liver. Monuron induced cytomegaly of the renal tubular epithelial cells in both male and female rats. There was no evidence of carcinogenicity for female rats (NTP, 1988; IARC, 1991). In mice target concentrations were 0, 5000, or 10000 ppm and effective concentrations were 4965 and 10004 ppm, corresponding to 993 and 2001 mg/kg bw. There was no evidence of carcinogenicity for male or female B6C3F1 mice.

The Carcinogenicity Potency Database (CPDB) reports a TD50 (dose that is tumorigenic in 50% of rats) of 131 mg/kg bw, with kidney and liver as target organs (as explained above). This dose takes into account worst case values and dose response of the tumours; based on the TD50 this would correspond with a T25 of 65 mg/kg bw. This can be used a starting descriptor for DMEL derivation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.23 µg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
250 000
Dose descriptor starting point:
T25
Value:
65 mg/kg bw/day
Modified dose descriptor starting point:
T25
Value:
56.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route-specific bioavailability 100% (inhalation = oral): x 1

Adjustment of route of exposure: from rat (oral) in mg/kg/d to rat inhalation (0.8L/min/kg, 8h): 0.384 m³/kg/8h: /1,15

Activity-driven differences: At rest / light activity: 6.7 /10 in line with the „10 m³“ approach”: -

Differences between occupational and lifetime exposure conditions: -

Corrected descriptor: T25 (rat, inhalation) = 56,5 mg/m3

AF for dose response relationship:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for differences in duration of exposure:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for interspecies differences (allometric scaling):
1
Justification:
Factor 4 is already applied in route-to-route modification.
AF for other interspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for intraspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for the quality of the whole database:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for remaining uncertainties:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

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:
DMEL (Derived Minimum Effect Level)
Value:
0.13 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 000 000
Dose descriptor starting point:
T25
Value:
65 mg/kg bw/day
Modified dose descriptor starting point:
T25
Value:
130 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-specific bioavailability 50% (dermal versus oral): x 2

Differences between occupational and lifetime exposure conditions: -

Corrected descriptor: T25 (rat, dermal) = 130 mg/kg/d

AF for dose response relationship:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for differences in duration of exposure:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for interspecies differences (allometric scaling):
4
Justification:
For the “linearity” approach only the allometric scaling factor of 4 is applied: /4
AF for other interspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for intraspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for the quality of the whole database:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for remaining uncertainties:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

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:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.065 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 000 000
Dose descriptor starting point:
T25
Value:
65 mg/kg bw/day
Modified dose descriptor starting point:
T25
Value:
65 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-specific bioavailability 100% (oral versus oral): x 1

Differences between occupational and lifetime exposure conditions: -

Corrected descriptor: T25 (rat, oral) = 65 mg/kg/d

AF for dose response relationship:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for differences in duration of exposure:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for interspecies differences (allometric scaling):
4
Justification:
For the “linearity” approach only the allometric scaling factor of 4 is applied: /4
AF for other interspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for intraspecies differences:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for the quality of the whole database:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
AF for remaining uncertainties:
1
Justification:
For DMEL derivation, linear approach is followed (See separate DMEL justification attached).
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Monuron has a harmonised classification according to Annex VI of Regulation (EC) No; 1272/2008 (CLP Regulation) for carcinogenicity as Carc. 2, H351 (suspected of causing cancer).

Although no mutagenicity was observed in the bacterial and mammalian gene mutation study, positive findings with Monuron were observed in thein vitroChromosome Aberration Test and Sister Chromatid Exchange assay and in thein vivoMicronucleus assay in mice, indicating that this compound is a clastogen. However, as the effect was not dose proportional, questions were raised about the mode of action of this chemical and the nature of its clastogenicity (Sharma et al., 1987: Mutagenic potential of a substituted urea herbicide, Monuron, Cytologica 52: 841-846, 1987). Despite the positive results for Monuron in eukaryotic systems, there is no evidence that Monuron causes germ cell damage. A classification for mutagenicity is therefore not warranted according to CLP.

For the DNEL/DMEL derivation, the assessment below is based on theECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health (Version 2.1, November 2012).

Discussion

Based on the carcinogenicity classification, a Derived No Effect Level (DNEL) cannot be derived based on a threshold mechanism. Instead, a linearized approach will be followed to derive a Derived Minimal Effect Level (DMEL). The linear approach is used when there is an absence of sufficient information on modes of action or when mode of action information indicates that the dose-response curve at low dose is or is expected to be linear.According to the Guidance, the T25 (chronic dose rate that will give 25% of the animals’ tumours at a specific tissue site after correction for spontaneous incidence, within the standard life time of that species) is one of the descriptors that should be used as the default dose-descriptor in relation to linear extrapolation. The lowest tumorigenic doses showing a significant response (on statistical or biological basis) are generally used for obtaining the dose-descriptor value.

Carcinogenesis studies of Monuron were conducted in rats and mice by feeding diets lasting for 103-104 weeks. In rats, target concentrations were 0, 750, or 1500 ppm and effective concentrations were 0, 747 and 1514 ppm , corresponding with 60 and 121 mg/kg bw. There was clear evidence of carcinogenicity for male rats showing increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the liver. Monuron induced cytomegaly of the renal tubular epithelial cells in both male and female rats. There was no evidence of carcinogenicity for female rats (NTP, 1988; IARC, 1991). In mice target concentrations were 0, 5000, or 10000 ppm and effective concentrations were 4965 and 10004 ppm, corresponding to 993 and 2001 mg/kg bw. There was no evidence of carcinogenicity for male or female B6C3F1 mice.

The Carcinogenicity Potency Database (CPDB) reports a TD50 (dose that is tumorigenic in 50% of rats) of131 mg/kg bw, with kidney and liver as target organs (as explained above). This dose takes into account worst case values and dose response of the tumours; based on the TD50 this would correspond with aT25 of 65 mg/kg bw. This can be used a starting descriptor for DMEL derivation.