Registration Dossier
Registration Dossier
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EC number: 285-203-4 | CAS number: 85049-34-9
Endpoint summary
Administrative data
Description of key information
Oral (OECD 408, rat): NOAEL≥ >= 1000 mg/kg bw/day
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 Jun - 09 Jan 1992
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Comparable to guideline study with acceptable restrictions. Lack of test material details and only 5 days/week dosing protocol.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- lack of test material details and only 5 days/week dosing protocol
- GLP compliance:
- yes
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Sprague-Dawley CD, SPF quality
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: 4 weeks
- Weight at study initiation: 58 - 80 g (males), 62 - 82 g (females)
- Housing: animals were housed in groups of 2-3 in Makrolon 3 cages with softwood bedding (ARWI-Center, Essen, Germany).
- Diet: Haltungsdiät Altromin 1324 DK Chargen-Nr. 2105901304 (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 40-92
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared daily by dissolving the test substance in peanut oil yielding a final concentration of 20, 60 and 200 mg/mL.
VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL - Duration of treatment / exposure:
- 94/95 days (control and treatment groups)
127 days (recovery groups) - Frequency of treatment:
- once daily, 5 days/week
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10 (control)
10 (dose groups)
5 (control and high-dose group as recovery groups) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: According to the author; yielding of a high security range, observation of a not cumulative toxic dose and identification of toxicological relevant ranges as well as the identification of reversibility of a possibly cumulative toxic effect were aimed.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on weekdays
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD AND WATER CONSUMPTION:
- Food consumption per group in cages: Yes
- Time schedule for examinations: weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: one day before section
- Dose groups that were examined: control and high-dose group
HAEMATOLOGY: Yes
- Time schedule: 6 weeks after application and at study termination
- Blood collection: retroorbital
- Parameters checked: erythrocyte count, hematocrit, mean cell volume, hemoglobin, leucocyte count, thrombocyte count, differential blood count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6 weeks after application and at the end of the study period
- Parameters checked: gamma glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, sodium, potassium, glucose, urea, protein, calcium, creatinine, cholesterol, chloride, bilirubin - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, whole body, especially eyes, skin, abdomen, chest and skull. Organ weights were examined for brain, testes, heart, liver, spleen, adrenal glands, kidney and thymus.
HISTOPATHOLOGY: Yes, aorta thoracica, eye, colon, proventriculus, small intestine, cerebrum, urinary bladder, skin, heart, testes, hypophysis cerebellum, liver, lung, trachea, axillary lymphnodes, mesentery lymphnodes, spleen, epididymis, adrenal gland, peripheral nerve, kidney, ovary, pancreas, prostate, vesicula seminalis, thyroid gland, salivary gland, esophagus, skeletal muscles, thymus, uterus, tongue, rumen. - Statistics:
- t-test according to Dunnett, C.W. (1955)
Stell-test according to Stell, R.G.D. (1959) - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 300 mg/kg bw/day (one male): a lump of the size of a walnut was observed in Week 11 on the right leg which was of the size of a pinhead at the end of the study, non-adverse. No mortality occurred during the study period.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 300 mg/kg bw/day (one male): a lump of the size of a walnut was observed in Week 11 on the right leg which was of the size of a pinhead at the end of the study, non-adverse. No mortality occurred during the study period.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 300 mg/kg bw/day (males): slight increase in mean body weight until Week 2 due to increased body weights at the start of the study, non-adverse.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day (females): higher food consumption in Week 4, non-adverse.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 and 300 mg/kg bw/day (males): decrease of HCT-value; 1000 mg/kg bw/day (males): decrease of RBC-, HGB-, HCT- value and decrease of lymphocytes ("stabkernige"), increase pf monocytes. females: decrease of WBC-values, non-adverse.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day (males): increase in protein-, glucose- and cholesterine- content, increase in calcium and creatinine-content; 100 mg/kg bw/day (males): increase in calcium-content, non-adverse.
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- single spontaneous findings in all groups including coloured thymus, spleen deformation, hydrometra (see Details on results), non-adverse.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- single spontaneous findings in all groups including calcification of the arteria pulmonalis, germinal hyperplasia of the mandibulary lymph node, non-adverse.
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study period. No compound-related symptoms were observed in the study. One male animal in the 300 mg/kg bw/day dose group had a lump of the size of a walnut in Week 11 on the right leg which was of the size of a pinhead at the end of the study and considered to be non-adverse.
BODY WEIGHT AND WEIGHT GAIN
The total body weight gain of all groups showed no deviation and was comparable to the control group. The slight increase in mean body weight of the low-dose group up to Week 2 was due to increased body weight at the start of the study and therefore considered to be non-adverse.
FOOD AND WATER CONSUMPTION
The mean food consumption in all treated groups was comparable to the control group. The increase in food consumption in the female high-dose group at the beginning of Week 4 up to the end of the study was due to food wasting by the animals.
The mean water intake of all groups was comparable to the control group.
HAEMATOLOGY
The intermediate and the final haematological examinations revealed a decrease of the haematocrit in the male treatment groups. The decrease of the HCT seems to be compound- and partially dose-related (see Table 1 under “Any other information on results incl. tables”). Additionally, the intermediate analysis showed slightly reduced red blood cell count-values for the male high-dose group. The observed deviation of the hematocrit is considered to be incidental, because the diagnosed values are within the +/- 1 SD limits of the historical control. In addition to this, there are no corresponding deviations of the erythrocyte count- or mean cell volume-values to prove the biological relevance of these findings. All other findings were considered to be spontaneous and therefore not related to the treatment.
CLINICAL CHEMISTRY
The biochemical examinations revealed some compound- and dose-independent findings. In the high-dose group (males) a significant increase in protein-, glucose-, cholesterine- -calcium and creatinine-content was observed. In the low-dose group (males) an increase in calcium-content in comparison to the control value was apparent (see Table 2 under "Any other information on results incl. tables").
OPHTHALMOSCOPIC EXAMINATION
The examination of the eyes by slit lamp microscope showed no compound-related effects.
ORGAN WEIGHTS
The absolute and relative organ weights in all groups showed no deviations and were comparable to the control.
GROSS PATHOLOGY
The macroscopical examination of the organs displayed some observations like discolouration of the thymus, deformation of the spleen, cyst of the kidney, hydronephrosis, atrophy of the testes, hydrometra and necrosis of the fatty tissue which were considered to be spontaneous. Compound-related macroscopical effects were not observed. The male and female animals of the high-dose recovery group showed no macroscopical compound-related alterations.
Possible target organs have not been diagnosed. In the male and female animals of all groups (including the recovery groups) the livers, the heart and the mandibulary lymph node showed effects which were due to a bacteriosis of unknown etiology. The observed germinal hyperplasia of the mandibulary lymph node can be interpreted as a consequence of this bacteriosis. The liver and the heart of the recovery groups (high-dose group and control group) showed the same signs of bacteriosis and therefore prove the persistence of the bacteriosis.
HISTOPATHOLOGY: NON-NEOPLASTIC
The microscopical examination revealed no compound-related effects. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Due to bacteriosis in all test groups, possible no adverse effects in the liver could have been covered.
- Key result
- Critical effects observed:
- no
- Conclusions:
- The NOAEL is determined to be > 1000 mg/kg bw/day.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 18 Jun - 09 Jan 1992
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Comparable to guideline study with acceptable restrictions. Lack of test material details and only 5 days/week dosing protocol.
- Justification for type of information:
- Please refer section 13 for read across justification.
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- lack of test material details and only 5 days/week dosing protocol
- GLP compliance:
- yes
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Sprague-Dawley CD, SPF quality
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: 4 weeks
- Weight at study initiation: 58 - 80 g (males), 62 - 82 g (females)
- Housing: animals were housed in groups of 2-3 in Makrolon 3 cages with softwood bedding (ARWI-Center, Essen, Germany).
- Diet: Haltungsdiät Altromin 1324 DK Chargen-Nr. 2105901304 (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26
- Humidity (%): 40-92
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared daily by dissolving the test substance in peanut oil yielding a final concentration of 20, 60 and 200 mg/mL.
VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL - Duration of treatment / exposure:
- 94/95 days (control and treatment groups)
127 days (recovery groups) - Frequency of treatment:
- once daily, 5 days/week
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10 (control)
10 (dose groups)
5 (control and high-dose group as recovery groups) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: According to the author; yielding of a high security range, observation of a not cumulative toxic dose and identification of toxicological relevant ranges as well as the identification of reversibility of a possibly cumulative toxic effect were aimed.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on weekdays
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD AND WATER CONSUMPTION:
- Food consumption per group in cages: Yes
- Time schedule for examinations: weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: one day before section
- Dose groups that were examined: control and high-dose group
HAEMATOLOGY: Yes
- Time schedule: 6 weeks after application and at study termination
- Blood collection: retroorbital
- Parameters checked: erythrocyte count, hematocrit, mean cell volume, hemoglobin, leucocyte count, thrombocyte count, differential blood count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6 weeks after application and at the end of the study period
- Parameters checked: gamma glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, sodium, potassium, glucose, urea, protein, calcium, creatinine, cholesterol, chloride, bilirubin - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, whole body, especially eyes, skin, abdomen, chest and skull. Organ weights were examined for brain, testes, heart, liver, spleen, adrenal glands, kidney and thymus.
HISTOPATHOLOGY: Yes, aorta thoracica, eye, colon, proventriculus, small intestine, cerebrum, urinary bladder, skin, heart, testes, hypophysis cerebellum, liver, lung, trachea, axillary lymphnodes, mesentery lymphnodes, spleen, epididymis, adrenal gland, peripheral nerve, kidney, ovary, pancreas, prostate, vesicula seminalis, thyroid gland, salivary gland, esophagus, skeletal muscles, thymus, uterus, tongue, rumen. - Statistics:
- t-test according to Dunnett, C.W. (1955)
Stell-test according to Stell, R.G.D. (1959) - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 300 mg/kg bw/day (one male): a lump of the size of a walnut was observed in Week 11 on the right leg which was of the size of a pinhead at the end of the study, non-adverse. No mortality occurred during the study period.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 300 mg/kg bw/day (one male): a lump of the size of a walnut was observed in Week 11 on the right leg which was of the size of a pinhead at the end of the study, non-adverse. No mortality occurred during the study period.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 300 mg/kg bw/day (males): slight increase in mean body weight until Week 2 due to increased body weights at the start of the study, non-adverse.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day (females): higher food consumption in Week 4, non-adverse.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 and 300 mg/kg bw/day (males): decrease of HCT-value; 1000 mg/kg bw/day (males): decrease of RBC-, HGB-, HCT- value and decrease of lymphocytes ("stabkernige"), increase pf monocytes. females: decrease of WBC-values, non-adverse.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day (males): increase in protein-, glucose- and cholesterine- content, increase in calcium and creatinine-content; 100 mg/kg bw/day (males): increase in calcium-content, non-adverse.
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- single spontaneous findings in all groups including coloured thymus, spleen deformation, hydrometra (see Details on results), non-adverse.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- single spontaneous findings in all groups including calcification of the arteria pulmonalis, germinal hyperplasia of the mandibulary lymph node, non-adverse.
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortality occurred during the study period. No compound-related symptoms were observed in the study. One male animal in the 300 mg/kg bw/day dose group had a lump of the size of a walnut in Week 11 on the right leg which was of the size of a pinhead at the end of the study and considered to be non-adverse.
BODY WEIGHT AND WEIGHT GAIN
The total body weight gain of all groups showed no deviation and was comparable to the control group. The slight increase in mean body weight of the low-dose group up to Week 2 was due to increased body weight at the start of the study and therefore considered to be non-adverse.
FOOD AND WATER CONSUMPTION
The mean food consumption in all treated groups was comparable to the control group. The increase in food consumption in the female high-dose group at the beginning of Week 4 up to the end of the study was due to food wasting by the animals.
The mean water intake of all groups was comparable to the control group.
HAEMATOLOGY
The intermediate and the final haematological examinations revealed a decrease of the haematocrit in the male treatment groups. The decrease of the HCT seems to be compound- and partially dose-related (see Table 1 under “Any other information on results incl. tables”). Additionally, the intermediate analysis showed slightly reduced red blood cell count-values for the male high-dose group. The observed deviation of the hematocrit is considered to be incidental, because the diagnosed values are within the +/- 1 SD limits of the historical control. In addition to this, there are no corresponding deviations of the erythrocyte count- or mean cell volume-values to prove the biological relevance of these findings. All other findings were considered to be spontaneous and therefore not related to the treatment.
CLINICAL CHEMISTRY
The biochemical examinations revealed some compound- and dose-independent findings. In the high-dose group (males) a significant increase in protein-, glucose-, cholesterine- -calcium and creatinine-content was observed. In the low-dose group (males) an increase in calcium-content in comparison to the control value was apparent (see Table 2 under "Any other information on results incl. tables").
OPHTHALMOSCOPIC EXAMINATION
The examination of the eyes by slit lamp microscope showed no compound-related effects.
ORGAN WEIGHTS
The absolute and relative organ weights in all groups showed no deviations and were comparable to the control.
GROSS PATHOLOGY
The macroscopical examination of the organs displayed some observations like discolouration of the thymus, deformation of the spleen, cyst of the kidney, hydronephrosis, atrophy of the testes, hydrometra and necrosis of the fatty tissue which were considered to be spontaneous. Compound-related macroscopical effects were not observed. The male and female animals of the high-dose recovery group showed no macroscopical compound-related alterations.
Possible target organs have not been diagnosed. In the male and female animals of all groups (including the recovery groups) the livers, the heart and the mandibulary lymph node showed effects which were due to a bacteriosis of unknown etiology. The observed germinal hyperplasia of the mandibulary lymph node can be interpreted as a consequence of this bacteriosis. The liver and the heart of the recovery groups (high-dose group and control group) showed the same signs of bacteriosis and therefore prove the persistence of the bacteriosis.
HISTOPATHOLOGY: NON-NEOPLASTIC
The microscopical examination revealed no compound-related effects. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Due to bacteriosis in all test groups, possible no adverse effects in the liver could have been covered.
- Key result
- Critical effects observed:
- no
- Conclusions:
- The NOAEL is determined to be > 1000 mg/kg bw/day.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1993
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- GLP-Guideline study, tested with the source substance Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS No. 68583-51-7). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (Dec 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Züchter Winkelmann, Borchen, Germany
- Age at study initiation: approx. 4 weeks
- Weight at study initiation: 46 - 58 g (males), 46 - 57 g (females)
- Housing: 2-3 animals of the same sex per cage in Makrolon-cages Typ M 5 (EBECO, Castrop-Rauxel, Germany)
- Diet: pelleted Haltungsdiät Altromin 1324 DK (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 38-70
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Dosing solutions were prepared daily immediately before dosing by dissolving appropriate amounts of the test material in peanut oil yielding a final concentration of 20%.
VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility of test substance
- Concentration in vehicle: 2.0, 6.0 and 20.0% (w/v)
- Amount of vehicle (if gavage): 5 mL/kg bw/day - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- once daily, 5 days/week
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10 (main study)
5 (satellite control and high dose group) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: achievement of a high security margin, identification of the not cumulative toxic dose and the identification of the reversibility of a possible cumulative toxic effect.
- Rationale for selecting satellite groups: high dose and control groups to identify a possible reversiblity of the effects
- Post-exposure recovery period in satellite groups: 34 days - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during acclimation period, twice daily during application period and daily on weekends and holidays.
- Cage side observations checked: mortality, intoxication symptoms
BODY WEIGHT: Yes
- Time schedule for examinations: at study initiation, once during acclimatisation period, daily during the application period.
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly.
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: day before sacrifice.
- Dose groups that were examined: high dose and control satellite groups.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6 weeks after application and at study termination.
- How many animals: all test animals
- Parameters checked: erythrocyte count, hematocrit, mean cell volume, hemoglobin, leucocyte count, thrombocyte count, differential blood count.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6 weeks after application and at study termination.
- How many animals: all test animals
- Parameters checked: gamma glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatise, sodium, potassium, glucose, urea, protein, calcium, creatinine, cholesterol, chloride, bilirubin.
OTHER: organ weights: absolute and relative organ weights of brain, testes, heart, liver, spleen, adrenal gland, kidney, thymus. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, whole body, especially eyes, skin, abdomen, chest and skull.
HISTOPATHOLOGY: Yes, aorta thoracica, eye, colon, proventriculus, small intestine, cerebrum, urinary bladder, skin, heart, testes, hypophysis, cerebellum, liver, lung, trachea, axillary lymphnodes, mesentery lymphnodes, spleen, epididymis, adrenal gland, peripheral nerve, kidney, ovary, pancreas, prostate, vesicula seminalis, thyroid gland, salivary gland, esophagus, skeletal muscles, thymus, uterus, tongue, rumen. - Statistics:
- - t-test according to Sachs to evaluate significant differences in body weight.
- t-test according to Dunnett to evaluate significant differences in clinical chemistry and haematology.
- steel test to evaluate significant differences in organ weight. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg bw/day: 1 female died; 300 mg/kg bw/day: 1 male and 1 female died; 1000 mg/kg bw/day: 1 female and 1 male died, non-adverse
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 100 mg/kg bw/day: 1 female died; 300 mg/kg bw/day: 1 male and 1 female died; 1000 mg/kg bw/day: 1 female and 1 male died, non-adverse
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- no adverse effects
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
100 mg/kg bw/day: 1 female died at the last investigation and blood collection; 300 mg/kg bw/day: 1 male died in week 7 at the intermediate investigation and blood collection and 1 female died at the last investigation and blood collection; 1000 mg/kg bw/day: 1 female and 1 male died both at the last investigation and blood collection. No substance-related lethality was observed.
BODY WEIGHT AND WEIGHT GAIN
Normal weight gain was observed in all test groups and comparable to the body weight gain in the control groups.
FOOD CONSUMPTION
1000 mg/kg bw/day (males, additional group): higher food consumption due to higher body weight at start of the study; 1000 mg/kg bw/day (females): increase in food consumption in week 10, 12 and 13 due to one individually caged animal. 100, 300 and 1000 mg/kg bw/day (females): a not concentration dependent decrease in food consumption was observed in the mean of the test animals (none adverse).
WATER CONSUMPTION
The water consumption of the male test groups showed not dose-related variations. The water consumption of the female test groups showed a not dose-related reduction. Furthermore, an increase in the female high dose group in week 10, 12 and 13 was observed due to the increased food consumption. Water consumption in the additional female high dose group was comparable to the control group. The mean water conversion for male and female test animals during week 1-6 and 8-13 showed no substance-related differences.
OPHTHALMOSCOPIC EXAMINATION
No treatment related findings. Single spontaneous findings were observed e.g. periorbital edema due to the blood collection. In the mandibular lymph nodes infrequent findings of ink pigments, originated from the earmarks.
HAEMATOLOGY
The mean values of all tested parameters of the intermediate and final examination showed no differences in comparison to the control values.
CLINICAL CHEMISTRY
The mean values of all tested parameters of the intermediate and final examination showed no differences in comparison to the control values.
ORGAN WEIGHTS
In females in the 100 mg/kg bw/day group the relative organ weights of the kidneys and the brain were slightly increased. This difference in organ weights revealed no correlation to further parameters and was therefore evaluated as random.
GROSS PATHOLOGY
No treatment related findings. Single spontaneous findings were found in all groups e.g. hydrometra and edema formation in the area of the salivary gland. In the additional male high dose group one animal showed high grade urinary stone formation in the bladder.
HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment related findings. Single spontaneous findings were observed in all investigated animals e.g. interstitial infiltrates in the lung, calcareous deposits, hydronephrosis, cystitis, hydrometra and mammary hyperplasia.
OTHER FINDINGS
1000 mg/kg bw/day: one animal was caged individually due to aggressive behaviour until week 6 of the study period. In one male a temporary prominent eye ball was observed after the last blood taking.
300 mg/kg bw/day: one male animal showed a swelling of the right ear. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- The NOAEL is determined to be > 1000 mg/kg bw/day
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1993
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- GLP-Guideline study, tested with the source substance Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS No. 68583-51-7). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (Dec 2012)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
- Justification for type of information:
- Please refer section 13 for read across justification.
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Züchter Winkelmann, Borchen, Germany
- Age at study initiation: approx. 4 weeks
- Weight at study initiation: 46 - 58 g (males), 46 - 57 g (females)
- Housing: 2-3 animals of the same sex per cage in Makrolon-cages Typ M 5 (EBECO, Castrop-Rauxel, Germany)
- Diet: pelleted Haltungsdiät Altromin 1324 DK (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 38-70
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Dosing solutions were prepared daily immediately before dosing by dissolving appropriate amounts of the test material in peanut oil yielding a final concentration of 20%.
VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility of test substance
- Concentration in vehicle: 2.0, 6.0 and 20.0% (w/v)
- Amount of vehicle (if gavage): 5 mL/kg bw/day - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- once daily, 5 days/week
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10 (main study)
5 (satellite control and high dose group) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: achievement of a high security margin, identification of the not cumulative toxic dose and the identification of the reversibility of a possible cumulative toxic effect.
- Rationale for selecting satellite groups: high dose and control groups to identify a possible reversiblity of the effects
- Post-exposure recovery period in satellite groups: 34 days - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during acclimation period, twice daily during application period and daily on weekends and holidays.
- Cage side observations checked: mortality, intoxication symptoms
BODY WEIGHT: Yes
- Time schedule for examinations: at study initiation, once during acclimatisation period, daily during the application period.
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly.
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: day before sacrifice.
- Dose groups that were examined: high dose and control satellite groups.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6 weeks after application and at study termination.
- How many animals: all test animals
- Parameters checked: erythrocyte count, hematocrit, mean cell volume, hemoglobin, leucocyte count, thrombocyte count, differential blood count.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6 weeks after application and at study termination.
- How many animals: all test animals
- Parameters checked: gamma glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatise, sodium, potassium, glucose, urea, protein, calcium, creatinine, cholesterol, chloride, bilirubin.
OTHER: organ weights: absolute and relative organ weights of brain, testes, heart, liver, spleen, adrenal gland, kidney, thymus. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, whole body, especially eyes, skin, abdomen, chest and skull.
HISTOPATHOLOGY: Yes, aorta thoracica, eye, colon, proventriculus, small intestine, cerebrum, urinary bladder, skin, heart, testes, hypophysis, cerebellum, liver, lung, trachea, axillary lymphnodes, mesentery lymphnodes, spleen, epididymis, adrenal gland, peripheral nerve, kidney, ovary, pancreas, prostate, vesicula seminalis, thyroid gland, salivary gland, esophagus, skeletal muscles, thymus, uterus, tongue, rumen. - Statistics:
- - t-test according to Sachs to evaluate significant differences in body weight.
- t-test according to Dunnett to evaluate significant differences in clinical chemistry and haematology.
- steel test to evaluate significant differences in organ weight. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg bw/day: 1 female died; 300 mg/kg bw/day: 1 male and 1 female died; 1000 mg/kg bw/day: 1 female and 1 male died, non-adverse
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 100 mg/kg bw/day: 1 female died; 300 mg/kg bw/day: 1 male and 1 female died; 1000 mg/kg bw/day: 1 female and 1 male died, non-adverse
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- no adverse effects
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
100 mg/kg bw/day: 1 female died at the last investigation and blood collection; 300 mg/kg bw/day: 1 male died in week 7 at the intermediate investigation and blood collection and 1 female died at the last investigation and blood collection; 1000 mg/kg bw/day: 1 female and 1 male died both at the last investigation and blood collection. No substance-related lethality was observed.
BODY WEIGHT AND WEIGHT GAIN
Normal weight gain was observed in all test groups and comparable to the body weight gain in the control groups.
FOOD CONSUMPTION
1000 mg/kg bw/day (males, additional group): higher food consumption due to higher body weight at start of the study; 1000 mg/kg bw/day (females): increase in food consumption in week 10, 12 and 13 due to one individually caged animal. 100, 300 and 1000 mg/kg bw/day (females): a not concentration dependent decrease in food consumption was observed in the mean of the test animals (none adverse).
WATER CONSUMPTION
The water consumption of the male test groups showed not dose-related variations. The water consumption of the female test groups showed a not dose-related reduction. Furthermore, an increase in the female high dose group in week 10, 12 and 13 was observed due to the increased food consumption. Water consumption in the additional female high dose group was comparable to the control group. The mean water conversion for male and female test animals during week 1-6 and 8-13 showed no substance-related differences.
OPHTHALMOSCOPIC EXAMINATION
No treatment related findings. Single spontaneous findings were observed e.g. periorbital edema due to the blood collection. In the mandibular lymph nodes infrequent findings of ink pigments, originated from the earmarks.
HAEMATOLOGY
The mean values of all tested parameters of the intermediate and final examination showed no differences in comparison to the control values.
CLINICAL CHEMISTRY
The mean values of all tested parameters of the intermediate and final examination showed no differences in comparison to the control values.
ORGAN WEIGHTS
In females in the 100 mg/kg bw/day group the relative organ weights of the kidneys and the brain were slightly increased. This difference in organ weights revealed no correlation to further parameters and was therefore evaluated as random.
GROSS PATHOLOGY
No treatment related findings. Single spontaneous findings were found in all groups e.g. hydrometra and edema formation in the area of the salivary gland. In the additional male high dose group one animal showed high grade urinary stone formation in the bladder.
HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment related findings. Single spontaneous findings were observed in all investigated animals e.g. interstitial infiltrates in the lung, calcareous deposits, hydronephrosis, cystitis, hydrometra and mammary hyperplasia.
OTHER FINDINGS
1000 mg/kg bw/day: one animal was caged individually due to aggressive behaviour until week 6 of the study period. In one male a temporary prominent eye ball was observed after the last blood taking.
300 mg/kg bw/day: one male animal showed a swelling of the right ear. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- The NOAEL is determined to be > 1000 mg/kg bw/day
Referenceopen allclose all
Table 1. Results of haematology, gorup mean values.
Dose group [mg/kg bw/day] |
Week |
HCT |
HGB |
RBC |
WBC |
|
males |
control 100 300 1000 |
6 |
43.8 42.2* 41.8** 41.5** |
16.7 16.3 16.3 16.2* |
8.2 8.0 7.9 7.9* |
17.0 18.9 17.2 18.9 |
females |
control 100 300 1000 |
6 |
40.3 39.8 39.9 39.8 |
15.8 15.6 15.7 15.7 |
7.4 7.3 7.3 7.3 |
14.5 15.1 13.6 13.2 |
males |
control 100 300 1000 |
13 |
43.6 41.8** 41.5** 41.2** |
16.7 16.1 16.1 16.1* |
8.7 8.5 8.5 8.4 |
16.4 17.8 17.2 17.2 |
females |
control 100 300 1000 |
13 |
40.0 39.4 39.6 39.6 |
15.9 15.7 15.8 15.9 |
7.5 7.6 7.6 7.5 |
12.1 11.5 10.6 9.0* |
*: Level of significance 95% in comparison with control value.
**: Level of significance 99% in comparison with control value.
HCT: Hematocrit; HGB: hemoglobin; RBC: erythrocyte count; WBC: leucocyte count
Table 2: Results of clinical chemistry, group mean values.
Dose group [mg/kg bw/day] |
Week |
glucose [mmol/L] |
calcium [mmol/L] |
creatinin [µmol/L] |
cholesterine [mmol/L] |
proteine [g/L] |
chloride [mmol/L] |
|
males |
control 100 300 1000 |
6 |
6.4 6.8 6.6 7.0 |
2.5 2.5 2.5 2.6** |
50 51 53 57** |
1.9 2.4 2.2 2.3 |
64 64 64 67** |
103 104 103 103 |
females |
control 100 300 1000 |
6 |
5.5 5.9 5.4 5.7 |
2.6 2.6 2.6 2.6 |
60 59 57 57 |
2.2 2.2 2.2 2.1 |
66 66 67 68 |
102 102 103 102 |
males |
control 100 300 1000 |
13 |
7.4 8.3 7.9 8.7* |
2.5 2.6** 2.6 2.6** |
56 56 58 60 |
1.9 2.4 2.1 2.5* |
66 66 65 68 |
103 103 102 102* |
females |
control 100 300 1000 |
13 |
6.8 7.1 6.5 7.1 |
2.6 2.6 2.6 2.6 |
70 67 67 71 |
2.3 2.2 2.2 2.2 |
69 69 69 71 |
101 102 102 102 |
*: Level of significance 95% in comparison with control value.
**: Level of significance 99% in comparison with control value.
Table 1. Results of haematology, gorup mean values.
Dose group [mg/kg bw/day] |
Week |
HCT |
HGB |
RBC |
WBC |
|
males |
control 100 300 1000 |
6 |
43.8 42.2* 41.8** 41.5** |
16.7 16.3 16.3 16.2* |
8.2 8.0 7.9 7.9* |
17.0 18.9 17.2 18.9 |
females |
control 100 300 1000 |
6 |
40.3 39.8 39.9 39.8 |
15.8 15.6 15.7 15.7 |
7.4 7.3 7.3 7.3 |
14.5 15.1 13.6 13.2 |
males |
control 100 300 1000 |
13 |
43.6 41.8** 41.5** 41.2** |
16.7 16.1 16.1 16.1* |
8.7 8.5 8.5 8.4 |
16.4 17.8 17.2 17.2 |
females |
control 100 300 1000 |
13 |
40.0 39.4 39.6 39.6 |
15.9 15.7 15.8 15.9 |
7.5 7.6 7.6 7.5 |
12.1 11.5 10.6 9.0* |
*: Level of significance 95% in comparison with control value.
**: Level of significance 99% in comparison with control value.
HCT: Hematocrit; HGB: hemoglobin; RBC: erythrocyte count; WBC: leucocyte count
Table 2: Results of clinical chemistry, group mean values.
Dose group [mg/kg bw/day] |
Week |
glucose [mmol/L] |
calcium [mmol/L] |
creatinin [µmol/L] |
cholesterine [mmol/L] |
proteine [g/L] |
chloride [mmol/L] |
|
males |
control 100 300 1000 |
6 |
6.4 6.8 6.6 7.0 |
2.5 2.5 2.5 2.6** |
50 51 53 57** |
1.9 2.4 2.2 2.3 |
64 64 64 67** |
103 104 103 103 |
females |
control 100 300 1000 |
6 |
5.5 5.9 5.4 5.7 |
2.6 2.6 2.6 2.6 |
60 59 57 57 |
2.2 2.2 2.2 2.1 |
66 66 67 68 |
102 102 103 102 |
males |
control 100 300 1000 |
13 |
7.4 8.3 7.9 8.7* |
2.5 2.6** 2.6 2.6** |
56 56 58 60 |
1.9 2.4 2.1 2.5* |
66 66 65 68 |
103 103 102 102* |
females |
control 100 300 1000 |
13 |
6.8 7.1 6.5 7.1 |
2.6 2.6 2.6 2.6 |
70 67 67 71 |
2.3 2.2 2.2 2.2 |
69 69 69 71 |
101 102 102 102 |
*: Level of significance 95% in comparison with control value.
**: Level of significance 99% in comparison with control value.
Table 1. Body weight gain.
body weight gain [g] |
males females dose [mg/kg bw/day] |
|||||||
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
|
week 1-7 |
167 |
168 |
181 |
169 |
90 |
79 |
78 |
80 |
week 7-14 |
80 |
82 |
86 |
88 |
37 |
35 |
33 |
34 |
week 1-14 |
247 |
250 |
267 |
257 |
127 |
114 |
111 |
114 |
Table 2. Food and water consumption.
|
males females dose [mg/kg bw/day] |
|||||||
|
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
Food consumption |
144 |
145 |
154 |
149 |
117 |
108 |
106 |
114 |
Water consumption |
246 |
240 |
252 |
243 |
194 |
174 |
174 |
182 |
Table 3. Kidney and brain weights.
|
males females dose [mg/kg bw/day] |
|||||||
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
|
Kidney weight (absolute) [g] after 13 weeks treatment |
2.12 |
2.04 |
2.3 |
2.22 |
1.36 |
1.37 |
1.31 |
1.28 |
Brain weight (absolute) [g] after 13 weeks treatment |
2.02 |
1.99 |
2.05 |
2.01 |
1.81 |
1.88 |
1.85 |
1.83 |
Kidney weight (relative) [g] expressed as a percentage of body weights |
0.6 |
0.58 |
0.61 |
0.61 |
0.6 |
0.64* |
0.61 |
0.6 |
Brain weight (relative) [g] expressed as a percentage of body weights |
0.57 |
0.57 |
0.55 |
0.56 |
0.8 |
0.88** |
0.87 |
0.86 |
*:Level of significane 99% in comparison with control value.
**: Level of significane 95% in comparison with control value
Table 1. Body weight gain.
body weight gain [g] |
males females dose [mg/kg bw/day] |
|||||||
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
|
week 1-7 |
167 |
168 |
181 |
169 |
90 |
79 |
78 |
80 |
week 7-14 |
80 |
82 |
86 |
88 |
37 |
35 |
33 |
34 |
week 1-14 |
247 |
250 |
267 |
257 |
127 |
114 |
111 |
114 |
Table 2. Food and water consumption.
|
males females dose [mg/kg bw/day] |
|||||||
|
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
Food consumption |
144 |
145 |
154 |
149 |
117 |
108 |
106 |
114 |
Water consumption |
246 |
240 |
252 |
243 |
194 |
174 |
174 |
182 |
Table 3. Kidney and brain weights.
|
males females dose [mg/kg bw/day] |
|||||||
0 |
100 |
300 |
1000 |
0 |
100 |
300 |
1000 |
|
Kidney weight (absolute) [g] after 13 weeks treatment |
2.12 |
2.04 |
2.3 |
2.22 |
1.36 |
1.37 |
1.31 |
1.28 |
Brain weight (absolute) [g] after 13 weeks treatment |
2.02 |
1.99 |
2.05 |
2.01 |
1.81 |
1.88 |
1.85 |
1.83 |
Kidney weight (relative) [g] expressed as a percentage of body weights |
0.6 |
0.58 |
0.61 |
0.61 |
0.6 |
0.64* |
0.61 |
0.6 |
Brain weight (relative) [g] expressed as a percentage of body weights |
0.57 |
0.57 |
0.55 |
0.56 |
0.8 |
0.88** |
0.87 |
0.86 |
*:Level of significane 99% in comparison with control value.
**: Level of significane 95% in comparison with control value
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- The available information comprises adequate, reliable (Klimisch score 2 partially due to read-across) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII - IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
There are no data for repeated dose toxicity available for the target substance. In accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 read-across from appropriate substances is conducted to fulfill the standard information requirements set out in Regulation (EC) No 1907/2006, Annex IX, 8.6.
According to Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met”. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”.
The target substance Fatty acids, C16-18 and C18-unsatd., esters with propylene glycol represents a UVCB substance predominantly comprised of diesters of an aliphatic diol (1,2-propyleneglycol (PG)) chemically linked to mainly oleic acid (C18:1) but as well to palmitic acid (C16), palmitoleic acid (C16:1), stearic acid (C18) and/or linoleic acid (C18:2).
Glycol esters are in general known to be stepwise hydrolysed by gastrointestinal enzymes into the free fatty acid component and the respective alcohol (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972).
Based on the common metabolic fate of glycol esters, the read-across approach is based on the presence of common functional groups, common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals, common functional groups, structural similarities and similar physico-chemical, toxicological and toxicokinetic behaviour. For further details on the read-across approach, please refer to the analogue justification in section 13 of the technical dossier.
As no data are available on repeated dose toxicity of the target substance, read-across to reliable data on the analogue substances Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) and Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) was conducted.
CAS 151661-88-0
Repeated dose toxicity of Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol was evaluated in a GLP-compliant study performed similar to OECD guideline 408 (Pittermann, 1991). Groups of 10 Wistar rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day of the test material in peanut oil by gavage, 5 days/week for ca. 13.5 weeks. A concurrent negative control group receiving the vehicle only was included. Furthermore, additional satellite control and high-dose groups with 5 animals per sex and dose were included in the study for a 32-33-day recovery period. No mortality or clinical signs of toxicity occurred during the study period. The total body weight gain of all groups showed no deviation and was comparable to the control group. The mean food and water consumption in all treated groups was comparable to the control group. Relative and absolute organ weights showed no substance-related differences to the control group.
Haematological parameters showed few and slight differences to the control values and were considered incidental. The biochemical examinations revealed dose-independent findings which were not considered to be substance-related. The opthalmoscopic examinations showed no compound-related effects. The absolute and relative organ weights in all groups showed no deviations and were comparable to the control. The macroscopical examination of the organs displayed some spontaneous observations like discolouration of the thymus but no compound-related macroscopical effects were observed. However, in the male and female animals of all groups (including the recovery and control groups) the livers, the heart and the mandibulary lymph node showed effects due to a bacteriosis of unknown etiology. The liver and the heart of the recovery groups (high-dose group and control group) showed the same signs of bacteriosis and therefore prove the persistence of the bacteriosis. The histopathologic examination revealed no compound-related effects.
Based on the lack of adverse effects, a NOAEL of ≥ 1000 mg/kg bw/day (m, f) was identified in this study.
CAS 68583-51-7
Decanoic acid, mixed diesters with octanoic acid and propylene glycol was tested for subchronic oral toxicity in a 90-day study according to OECD guideline 408 in compliance with GLP (Pittermann, 1993).
Groups of 10 Wistar rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day of the test material in peanut oil by gavage, 5 days/week for 13 weeks. A concurrent negative control group receiving the vehicle only was included. Furthermore, additional satellite control and high-dose groups with 5 animals per sex were included in the study for investigating the reversibility of possible effects after a 34-day post-exposure recovery period. No clinical signs or mortality occurred in relation to the test substance during the study period in any animal. During the study period, 5 animals out of different groups died at blood collection time points (no further information). No adverse effects on body weight or body weight gain were noted. Higher food consumption in the additional male high-dose group was observed due to higher body weight at start of the study. An increase in food consumption in the female high-dose group in Week 10, 12 and 13 was observed due to one animal caged individually. The water consumption of the male and female test groups showed no dose-related variations or reductions. Ophthalmoscopic examinations revealed no treatment related findings. No treatment-related changes in the haematological and clinical parameters and organs weights were measured. During gross pathology and histopathology no treatment-related findings were observed. Furthermore, the animals of the recovery groups showed no macroscopical compound-related alterations in the observed organs.
Based on the lack of adverse effects, a NOAEL of ≥ 1000 mg/kg bw/day (m, f) was identified in this study.
Conclusion on subchronic repeated dose toxicity, oral
In summary, subchronic oral administration of the two read-across analogue substances Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) and Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) consistently showed no adverse systemic effects resulting in NOAELs of ≥ 1000 mg/kg bw/day. Therefore, the target substance is not considered as hazardous after subchronic exposure.
There are no data available on the repeated dose toxicity after dermal application and inhalation.
References
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Agency for Toxic Substances and Disease Registry (ATSDR) (2010). Toxicological Profile for Ethylene Glycol. US Department of Health and Human Services. Atlanta, US.
Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.Long, C.L. et al. (1958). Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys, 77(2):428-439.
Mattson, F.H. and Volpenhein, R.A. (1972). Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of the rat pancreatic juice. Journal of Lipid Research 13: 325-328
Miller, O.N., Bazzano, G. (1965).Propanediol metabolism and its relation to lactic acid -metabolism. Annals of the New York Academy of Sciences 119:957-973.
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Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: Hazard assessment is conducted by means of read-across from structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).
Justification for classification or non-classification
Based on the analogue read-across approach, the available data on oral repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.
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