Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 422 under GLP (2010). The substance was administered to 30 male and 30 female Crl:WI(Han) strain rats by oral gavage at dose levels of 100, 300 and 1000 ppm for up to 7 weeks. In addition, 10 male and 20 female control rats were treated with the formulation vehicle, without test item.  Although there was no recovery phase, this is not a guideline requirement. No toxicologically relevant changes were noted during clinical or functional observations or in body weight and food intake during treatment up to 1000 mg/kg/day. Blood analysis at 1000 mg/kg/day revealed slightly higher potassium values in males (within normal ranges), higher mean cholesterollevels in females (only slightly outside normal ranges) and higher bile acid levels in some females. Given that these changes were generally slight in nature, were not present as a group response (bile acids) and occurred in the absence of supportive morphological changes, these were considered to be of no toxicological relevance. Haematology parameters were normal in all groups. The higher liver weight and Iiver to body weight ratio, and lower prostate and prostate to body weight ratio for males at 1000 mg/kg/day was not supported by any histopathological changes. Moreover, since these changes were slight in nature (only slightly outside the normal range), these were considered to be of no toxicological relevance. Histopathological changes were confined to the stomach, and consisted of Iymphogranulocytic inflammation and hyperplasia of the squamous epithelium of the forestomach in both sexes at 100, 300 and 1000 mg/kg/day, and ulcer formation in the forestomach in three males at 300 mg/kg/day (correlating to red/black foci in the forestomach of two males) and in one male at 1000 mg/kg/day. Hyperplasia of the squamous epithelium was the microscopic correlate to the irregular surface and yellowish discolouration of the forestomach recorded at necropsy at 300 and 1000 mg/kg/day. Congestion of the glandular stomach (correlating to red discolouration of of the glandular mucosa) was observed in two males at 1000 mg/kg/day. There was no microscopic correlate to thickening of the glandular mucosa recorded in three females at 1000 mg/kg/day.

Based on these results, the following systemic No Observed Adverse Effect Level (NOAEL) was derived:

Systemic Toxicity - NOAEL = >= 1000 mg/kg/day (no hazard identified)

For the same study (OECD 422, 2010) a summary of reproductive and developmental findings is described herein:

Reproduction data- No toxicologically significant effects on reproductive parameters were noted. Mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites were unaffected by treatment.

Developmental data- No toxicologically significant effects on developmental parameters were observed. Gestation index, duration of gestation, number of dead and living pups at first litter check, sex ratio, postnatal loss, viability index, and early postnatal pup development (mortality, clinical signs, body weight and extern al macroscopy) were unaffected by treatment. No deficiencies in maternal care were observed. Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. No signs of difficult or prolonged parturition were noted among the pregnant females.  Incidental clinical symptoms of pups consisted of small size, red spots on the head/nose and a pale appearance. No relationship with treatment was established for these observations and they were considered to be of no toxicological relevance. A total of three pups of the control group, and one pup each at 100, 300 and 1000 mg/kg/day were found dead or missing during lactation. No toxicological relevance was ascribed to these dead/missing pups since the mortality incidence did not show a dose-related trend and remained within the range considered normal for pups of this age. Incidental macroscopic findings among pups found dead included autolysis, cannibalism and absence of milk in the stomach. Some surviving pups were small in size. The nature and incidence of these findings remained within the range considered normal for pups of this age, and were therefore considered to be unrelated to treatment.

Based on these considerations, a No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was therefore concluded to be >=1000 mg/kg/day (no hazard identified)

No systemic hazards were identified for this substance based on the subacute OECD 422 study. Therefore, the registrant can conclude that for long-term systemic effects, no hazard identified can be concluded, and no exposure assessment or risk characterisation is required for these hazard parameters.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

In accordance with Annex VIII, Section 8.5.2, Column 2 of REACH, testing by the inhalation route was waived due to low vapour pressure and a use pattern resulting in exposure to humans being considered negligible.  No acute toxicity hazard (leading to classification & labelling) has been identified for the substance following oral and dermal exposure.  No acute inhalation hazard is therefore identified for this substance.

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:
no hazard identified
DNEL related information
Justification:
.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic 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 for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Long-term systemic hazard assessment for this substance is based on a subacute toxicity study conducted on rats in accordance with OECD 422 under GLP (2010). The substance was administered to 30 male and 30 female Crl:WI(Han) strain rats by oral gavage at dose levels of 100, 300 and 1000 ppm for up to 7 weeks. In addition, 10 male and 20 female control rats were treated with the formulation vehicle, without test item.  Although there was no recovery phase, this is not a guideline requirement. No toxicologically relevant changes were noted during clinical or functional observations or in body weight and food intake during treatment up to 1000 mg/kg/day. Blood analysis at 1000 mg/kg/day revealed slightly higher potassium values in males (within normal ranges), higher mean cholesterollevels in females (only slightly outside normal ranges) and higher bile acid levels in some females. Given that these changes were generally slight in nature, were not present as a group response (bile acids) and occurred in the absence of supportive morphological changes, these were considered to be of no toxicological relevance. Haematology parameters were normal in all groups. The higher liver weight and Iiver to body weight ratio, and lower prostate and prostate to body weight ratio for males at 1000 mg/kg/day was not supported by any histopathological changes. Moreover, since these changes were slight in nature (only slightly outside the normal range), these were considered to be of no toxicological relevance. Histopathological changes were confined to the stomach, and consisted of Iymphogranulocytic inflammation and hyperplasia of the squamous epithelium of the forestomach in both sexes at 100, 300 and 1000 mg/kg/day, and ulcer formation in the forestomach in three males at 300 mg/kg/day (correlating to red/black foci in the forestomach of two males) and in one male at 1000 mg/kg/day. Hyperplasia of the squamous epithelium was the microscopic correlate to the irregular surface and yellowish discolouration of the forestomach recorded at necropsy at 300 and 1000 mg/kg/day. Congestion of the glandular stomach (correlating to red discolouration of of the glandular mucosa) was observed in two males at 1000 mg/kg/day. There was no microscopic correlate to thickening of the glandular mucosa recorded in three females at 1000 mg/kg/day.

Based on these results, the following systemic No Observed Adverse Effect Level (NOAEL) was derived:

Systemic Toxicity - NOAEL = >= 1000 mg/kg/day (no hazard identified)

For the same study (OECD 422, 2010) a summary of reproductive and developmental findings is described herein:

Reproduction data- No toxicologically significant effects on reproductive parameters were noted. Mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites were unaffected by treatment.

Developmental data- No toxicologically significant effects on developmental parameters were observed. Gestation index, duration of gestation, number of dead and living pups at first litter check, sex ratio, postnatal loss, viability index, and early postnatal pup development (mortality, clinical signs, body weight and extern al macroscopy) were unaffected by treatment. No deficiencies in maternal care were observed. Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. No signs of difficult or prolonged parturition were noted among the pregnant females.  Incidental clinical symptoms of pups consisted of small size, red spots on the head/nose and a pale appearance. No relationship with treatment was established for these observations and they were considered to be of no toxicological relevance. A total of three pups of the control group, and one pup each at 100, 300 and 1000 mg/kg/day were found dead or missing during lactation. No toxicological relevance was ascribed to these dead/missing pups since the mortality incidence did not show a dose-related trend and remained within the range considered normal for pups of this age. Incidental macroscopic findings among pups found dead included autolysis, cannibalism and absence of milk in the stomach. Some surviving pups were small in size. The nature and incidence of these findings remained within the range considered normal for pups of this age, and were therefore considered to be unrelated to treatment.

Based on these considerations, a No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was therefore concluded to be >=1000 mg/kg/day (no hazard identified)

No systemic hazards were identified for this substance based on the subacute OECD 422 study. Therefore, the registrant can conclude that for long-term systemic effects, no hazard identified can be concluded, and no exposure assessment or risk characterisation is required for these hazard parameters.

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