Registration Dossier
Registration Dossier
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EC number: 212-634-7 | CAS number: 834-12-8
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.621 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 12
- Modified dose descriptor starting point:
- NOAEC
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
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.088 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 50
- Modified dose descriptor starting point:
- NOAEL
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:
- no hazard identified
Additional information - workers
Acute DNELs:
Worker: Production of Ametryn is in excess of 10 t/y. According to REACh guidance “Guidance on Information Requirement and Chemical Safety Assessment Part B: Hazard Assessment”, above 10t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on long-term exposure is normally sufficient to ensure that adverse effects do not occur. Thus, as long-term DNELs are available for Ametryn and this substance is not classified for acute toxicity via any route of exposure, separate acute DNELs were not derived. As Ametryn is not expected to be a skin irritant; default to systemic DNEL for local effects.
Long term DNELs:
DNELs are based on the oral rat study (key study selected) entitled "Combined Chronic Toxicity and Carcinogenicity Study with Ametryn Technical in Wistar Rats". With respect to the most sensitive endpoint, although the study was for cancer, the chemical was not found to be a carcinogen; thus the most sensitive endpoint was selected as repeated-dose toxicity.
Starting Dose for DNEL Calculation = 100 ppm (NOEL) = equivalent to a mean daily intake of 4.4 mg/kg bw in combined sex (as reported by authors)
Modified doses for DNEL Calculations:
Worker – Inhalation = 4.4 mg/kg bw x 1/0.38 m3/kg x 6.7/10 = 7.76 mg/m3
Worker – Dermal = 4.4 mg/kg bw
Absorption: Ametryn was rapidly absorbed following oral exposure. Ametryn reaching the systemic circulation was extensively metabolized to mostly polar compounds. These metabolites were excreted primarily via the urine, with large amounts detected also in the feces, regardless of oral or intravenous exposure (1,2,3,4). No studies were available in which the toxicokinetics/toxicity of Ametryn following dermal or inhalation exposure were assessed.
Modified doses for DNEL Calculations with Absorption Values:
Worker – Inhalation = 7.76 mg/m3
Worker – Dermal = 4.4 mg/kg bw
Assessment Factors (AF):
Worker – Inhalation = 2.5 (for non-metabolic species differences) x 5 (for intraspecies difference); no scaling factor required (as per REACh guidance) x 1 for duration of study; no assessment factor for dose-response; no assessment factor for quality of database = 12.5
Worker – Dermal = 4 (rat scaling factor) x 2.5 (for non-metabolic species differences) x 5 (for intraspecies difference) x 1 for duration of study; no assessment factor for dose-response; no assessment factor for quality of database = 50
Final DNELs:
Worker – Inhalation = 0.621 mg/m3
Worker – Dermal = 0.088 mg/kg bw/day
Reference List:
[1] Purshottam, 1998, Absorption, distribution, and excretion of radiolabelled 14C Ametryn technical in Wistar rats, Toxicology department Rallis Research Centre Rallis India Limited Post Box No. 5813, Plot Nos. 21 and 22 Peenya II Phase, Bangalore-560 058, India, Report number TOXI-2114-96.
[2] Reynolds, 1990, Metabolism of 14C-Ametryn in rats – Phase I preliminary study, Xenobiotic Laboratories, Inc.,,, Report number RPT0007.
[3] Braun, 1990, Absorption, distribution, and excretion studies of 14C-AMetryn in the rat, Biological Test Center 2525 McGaw Avenue Irvine, CA 92713 (714) 660-3184, Report number P01744.
[4] Wu, 1990, Analysis, quantitation, and structure elucidation of metabolites in urine and feces from the rat dosed with 14C-Ametryn, XenoBiotic Laboratories, Inc. P.O. Box 3205, Princeton, NJ 08543, Report number RPT0022.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.153 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 25
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
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.044 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 100
- Modified dose descriptor starting point:
- NOAEL
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:
- 0.044 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 100
- Modified dose descriptor starting point:
- NOAEL
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
Acute DNELs:
General Population: Production of Ametryn is in excess of 10 t/y. According to REACh guidance “Guidance on Information Requirement and Chemical Safety Assessment Part B: Hazard Assessment”, above 10t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on long-term exposure is normally sufficient to ensure that adverse effects do not occur. Thus, as long-term DNELs are available for Ametryn and this substance is not classified for acute toxicity via any route of exposure, separate acute DNELs were not derived. As Ametryn is not expected to be a skin irritant; default to systemic DNEL for local effects.
Long term DNELs:
DNELs are based on the oral rat study (key study selected) entitled "Combined Chronic Toxicity and Carcinogenicity Study with Ametryn Technical in Wistar Rats". With respect to the most sensitive endpoint, although the study was for cancer, the chemical was not found to be a carcinogen; thus the most sensitive endpoint was selected as repeated-dose toxicity.
Starting Dose for DNEL Calculation = 75 ppm (NOEL) = equivalent to a mean daily intake of 4.4 mg/kg bw in combined sex (as reported by authors)
Modified doses for DNEL Calculations:
General Population – Oral = 4.4 mg/kg bw
General Population – Inhalation = 4.4 mg/kg bw x 1/1.15 m3/kg = 3.82 mg/m3
General Population – Dermal = 4.4 mg/kg bw
Absorption: Ametryn was rapidly absorbed following oral exposure. Ametryn reaching the systemic circulation was extensively metabolized to mostly polar compounds. These metabolites were excreted primarily via the urine, with large amounts detected also in the feces, regardless of oral or intravenous exposure (1,2,3,4). No studies were available in which the toxicokinetics/toxicity of Ametryn following dermal or inhalation exposure were assessed.
Modified doses for DNEL Calculations with Absorption Values:
General Population – Oral = 4.4 mg/kg bw
General Population – Inhalation = 3.82 mg/m3
General Population – Dermal = 4.4 mg/kg bw
Assessment Factors (AF):
General Population – Oral = 4 (rat scaling factor) x 2.5 (for non-metabolic species differences) x 10 (for intraspecies difference) x 1 for duration of study (chronic); no assessment factor for dose-response; no assessment factor for quality of database = 100
General Population – Inhalation = 2.5 (for non-metabolic species differences) x 10 for (intraspecies difference); no scaling factor required (as per REACh guidance) x 1 for duration of study (chronic); no assessment factor for dose-response; no assessment factor for quality of database = 25
General Population – Dermal = 4 (rat scaling factor) x 2.5 (for non-metabolic species differences) x 10 (for intraspecies difference) x 1 for duration of study (chronic); no assessment factor for dose-response; no assessment factor for quality of database = 100
Final DNELs:
General Population – Oral = 0.044 mg/kg bw
General Population – Inhalation = 0.153 mg/m3
General Population – Dermal = 0.044 mg/kg bw
Reference List:
[1] Purshottam, 1998, Absorption, distribution, and excretion of radiolabelled 14C Ametryn technical in Wistar rats, Toxicology department Rallis Research Centre Rallis India Limited Post Box No. 5813, Plot Nos. 21 and 22 Peenya II Phase, Bangalore-560 058, India, Report number TOXI-2114-96.
[2] Reynolds, 1990, Metabolism of 14C-Ametryn in rats – Phase I preliminary study, Xenobiotic Laboratories, Inc.,,, Report number RPT0007.
[3] Braun, 1990, Absorption, distribution, and excretion studies of 14C-AMetryn in the rat, Biological Test Center 2525 McGaw Avenue Irvine, CA 92713 (714) 660-3184, Report number P01744.
[4] Wu, 1990, Analysis, quantitation, and structure elucidation of metabolites in urine and feces from the rat dosed with 14C-Ametryn, XenoBiotic Laboratories, Inc. P.O. Box 3205, Princeton, NJ 08543, Report number RPT0022.
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