Fatty acids, tall-oil, reaction products with ethanolamine, ethoxylated

Endpoint summary

Description of key information

No test-item related adverse effects were observed after daily oral administration of the test item for 4 weeks by gavage to rats up to the highest dose level tested (1000 mg/kg bw/d). The no observed adverse effect level (NOAEL) under the conditions of this study was 1000 mg/kg bw/d. Furthermore, a 28-day oral repeated dose toxicity study conducted with structurally similar, C12-18 and C18-unsatd. DEA in rats revealed a NOAEL of >750 mg/kg bw/d based on absence of treatment-related effects at any of the tested dose levels (please refer to ch. 13 for read-across justification). 
Regarding the dermal route, the following dose descriptors resulted from 90-d and 2-yr NTP studies: 
• Sub-chronic dermal rat: NOAEL (systemic effects): 100 mg/kg bw/d based on body weight, organ weight and clinical chemistry alterations at the ≥200 mg/kg bw/d; NOAEL (local effects): 25 mg/kg bw/d based on non-neoplastic lesions of the skin at ≥50 mg/kg bw/d. Sub-chronic dermal mouse LOAEL for systemic effects: 50 mg/kg bw/d based organ weight changes at ≥50 mg/kg bw/d; LOAEL for local effects: 50 mg/kg bw/d based on non-neoplastic lesion of the skin
• Chronic dermal rat: NOAEL (systemic effects): 50 mg/kg bw/d based on BW changes at the LOAEL; LOAEL (local effects): 50 mg/kg bw/d based on non-neoplastic lesion of the skin at all tested doses. Chronic dermal mouse: NOAEL (systemic effects): 15 mg/kg bw/d based on body weight changes; LOAEL (local effects): 15 mg/kg bw/d based on non-neoplastic lesions of the skin. 
Giving preference to rat species as well as considering the highest NOAEL below the lowest LOAEL, the NOAEL for systemic effects of 50 mg/kg bw/d from the 2-yr study in rats will be used. For the local effects, since the 90-d and 2-yr rat studies results in LOAELs of 50 mg/kg bw/d this dose level will be further used.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The result is supported by a subacute study with a read-across substance (please refer to ch. 13 for justification) that also gave no indication for adverse effects up to the limit dose (>750 mg/kg bw/d).

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:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The information requirements for this tonnage band is sufficiently met with the available data.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

Study duration:

chronic

Species:

rat

Quality of whole database:

The information requirements for this tonnage band is sufficiently met with the available data.

Additional information

Oral:

In the key sub-acute repeated dose toxicity study (BASF SE, 2013; 30C0104/12C056), the target substancewas administered orally (by gavage) to groups of 5 male and 5 female Wistar rats at dose levels of 100, 300 and 1000 mg/kg bw/d over a period of 4 weeks. Concurrent control animals received the respective vehicle (corn oil) only.

Body weight and food consumption were determined once weekly. All animals were checked for any signs of toxicity, moribund state or mortality daily prior application and within two and 5 hours post application. Detailed clinical examinations (DCO) in an open field were conducted prior the start of the administration period and subsequently once weekly (in the morning) thereafter. Estrous cycle determination was performed in all female animals from study day 7 onwards, for at least 21 consecutive days. Functional observational battery (FOB) and measurement of Motor activity (MA) were carried out separately by sex, in all animals and randomized sequence towards the end of administration period. Clinico-chemical and hematological examination as well as urinalysis were performed towards the end of administration period. After the administration period, all surviving rats were sacrificed; selected organs were weighed and the animals assessed by gross pathology, followed by histopathological examinations and sperm assessment.

 

The oral administration of the test item by gavage to rats at a dose level of 1000 mg/kg bw/day for 4 weeks resulted in no test substance-related adverse changes in all dose groups. Therefore, under the conditions of this study, the determined NOAEL (no observed adverse effect level) was 1000 mg/kg bw/d for male and female animals. 

Dermal:

Two sub-chronic NTP studies (NTP report 481, 1999) were conducted to evaluate the cumulative toxic effects following repeated dermal exposure to oleic acid diethanolamine condensate (ODEA) in F344/N rats as well as inB6C3F1 mice.

In the rat study, groups of 10 male and 10 female rats were dermally exposed to 0, 25, 50, 100, 200, or 400 mg ODEA/kg bw/day in ethanol at a frequency of 5 d/wk for a period of 13 weeks. All animals survived until study termination. The final mean body weights and body weight gains of 200 and 400 mg/kg bw/day males and the mean body weight gain of 400 mg/kg bw/day females were significantly less than those of the vehicle controls. The only chemical-related clinical finding was irritation of the skin at the site of application in most males administered 100 mg/kg bw/day or greater and in all females administered 50 mg/kg bw/day or greater. Segmented neutrophil counts and alkaline phosphatase concentrations were increased significantly on specific days in the 200 and/or 400 mg/kg bw/day male and female groups. Kidney weights of 200 and 400 mg/kg females were significantly greater than those of the vehicle controls. There was a dose dependent increase in the incidence of non-neoplastic lesions of the skin at the site of application, including epidermal hyperplasia, parakeratosis, chronic active dermal inflammation, suppurative epidermal inflammation, and sebaceous gland hypertrophy in dosed rats. However, these effects were minimal in the 50 mg/kg bw/day dose group.

Under the conditions of the 13-week study in rats, the NOAEL for systemic and local effects can be considered to be at 100 and 25 mg/kg bw/day respectively.

In the mice study, groups of 10 male and 10 female mice were dermally exposed to 0, 50, 100, 200, 400 or 800 mg ODEA/kg bw/day in ethanol at a frequency of 5 d/wk for a period of 13 weeks. All male and female mice except one 800 mg/kg bw/day male survived until the end of the study. Final mean body weights and body weight gains of 800 mg/kg bw/day males and females and 400 mg/kg bw/day females were significantly less than those of the vehicle controls. Clinical findings in dosed mice included irritation of the skin at the site of application. Irritation occurred in all surviving dosed males and in most females administered ≥100 mg/kg bw/day. The heart weights of 400 and 800 mg/kg bw/day males and females and 200 mg/kg bw/day females and the kidney weights of 50, 100, and 400 mg/kg bw/day males were significantly greater than those of the vehicle controls. Relative to the vehicle controls, the liver weights were increased in all dosed groups. Dose dependent increase in the incidences of non-neoplastic skin lesions included epidermal hyperplasia, parakeratosis, suppurative epidermal inflammation, chronic active dermal inflammation, sebaceous gland hypertrophy, and ulcer.

Under the conditions of the 13-week study in mice, the LOAEL for both systemic and local effects can be considered to be at 50 mg/kg bw/day.

Two year chronic dermal studies (NTP report 481, 1999) performed to assess the carcinogenic affects ofoleic acid diethanolamine condensate (ODEA)conducted in rats and mice allow derivations of NOAEL (rat) and LOAEL (mouse) as described in the following:

 

F344/N rats were administered doses of 0, 50, or 100 mg ODEA/kg bw/d of the test substance to 50 male and female test animals in each group. Five exposures per week were given for 104 weeks.The mean body weights of males and females (week 24 onwards) were reduced than those of the vehicle control group at 100 mg/kg bw/day. Dose dependent increase in irritation (i.e., mild to moderate) and non-neoplastic lesions (i.e., minimal to moderate) of the skin was observed at the site of application in males and females. The non-neoplastic lesions included epidermal hyperplasia, sebaceous gland hyperplasia, hyperkeratosis, parakeratosis, chronic active dermal inflammation, and ulcer. No significant neoplastic lesions or evidence of carcinogenic activity was observed at any tested dose levels in skin, testis and thyroid gland.Under the test conditions, no evidence of carcinogenic activity was observed with the test substance at any tested dose levels in rats.As a result, for systemic effects, theNOAEL can be considered to be at 50 mg/kg bw/d and for local effects the LOAEL can be considered at the lowest dose of 50 mg/kg bw/d.

B6C3F1 micewere administered doses of0, 15 or 30 mg ODEA/kg bw/d to 50 male/female test animals in each group. 5 exposures per week were given for 105 weeks.5 males and 5 females were considered for the 3 -month interim evaluation mice. The mean body weights of females (week 76 onwards) were reduced than those of the vehicle control group at 30 mg/kg bw/day. The only significant treatment related clinical finding was irritation of the skin at the site of application in 30 mg/kg bw/day males. The incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and chronic active inflammation of the dermis in all dosed groups were significantly increased relative to the vehicle controls at 3 months and at 2 years. The increased incidences of hyperkeratosis in dosed males at 3 months and in dosed males and females at 2 years, of parakeratosis in 30 mg/kg bw/day males at 3 months and 2 years, and of ulcer in 30 mg/kg bw/day males and exudate in 30 mg/kg bw/day males and females at 2 years were also attributed to the test substance administration. No significant neoplastic lesions or evidence of carcinogenic activity was observed at any tested dose levels in skin and lymph nodes.Under the test conditions, no evidence of carcinogenic activity was observed with the test substance at any tested dose levels in mice. As a result, for systemic effects, the NOAEL can be considered to be at 15 mg/kg bw/d and for local effects, the LOAEL can be considered to be at 15 mg/kg bw/d (NTP 481report, 1999).

Inhalation

Due to the low vapour pressure, inhalation exposure is unlikely to occur under the conditions of normal and foreseeable use and therefore health effects from inhalatory exposure to the substance is considered not to be of concern.

The following information is taken into account for the risk assessment:

Regarding the dermal route, 90-d and 2-yr chronic studies on ODEA have been conducted in both rats and mice. The following dose descriptors have been derived based on the studies:

• Sub-chronic dermal rat: NOAEL for systemic effects: 100 mg/kg bw/d based on body weight and organ weight changes, clinical chemistry alterations at the ≥200 mg/kg bw/d; NOAEL for local effects: 25 mg/kg bw/d based on irritation at≥100 mg/kg bw/dand non-neoplastic lesions of the skin at ≥50 mg/kg bw/d.

• Sub-chronic dermal mouse LOAEL for systemic effects: 50 mg/kg bw/d based organ weight changes at ≥50 mg/kg bw/d; LOAEL for local effects: 50 mg/kg bw/d based on non-neoplastic lesion of the skin at all doses.

• Chronic dermal rat: NOAEL for systemic effects: 50 mg/kg bw/d based on body weight changes at the LOAEL; LOAEL for local effects: 50 mg/kg bw/d based on irritation and non-neoplastic lesion of the skin and hyperkeratosis and chornic active infammation of the forestomach at both the tested doses.

• Chronic dermal mouse: NOAEL for systemic effects: 15 mg/kg bw/d based on body weight changes at 30 mg/kgt bw/d; LOAEL for local effects: 15 mg/kg bw/d based on incidences of non-neoplastic lesions of the skin.

 

Giving preference to rat species and longer duration study as well as considering the highest NOAEL below the lowest LOAEL (i.e., 100 mg/kg bw/d) approach, the NOAEL for systemic effects of 50 mg/kg bw/d from the chronic dermal study in rats will be used as the POD to derive the DNEL dermal systemic value as a conservative approach.

 

Since both the sub-chronic and chronic dermal rat studies available for ODEA results in LOAELs of 50 mg/kg bw/d for the local effects, this dose level will be further used in this chemical safety assessment as POD for dermal DNEL for long term local effects.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
New GLP and OECD compliant study conducted with the target substance.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Rat long term study and provides the highest NOAEL below the lowest LOAEL (i.e., 100 mg/kg bw/d) approach, the NOAEL for systemic effects of 50 mg/kg bw/d from the chronic dermal study in rats will be used to derive the DNEL dermal systemic value as a conservative approach.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Since both the sub-chronic and chronic dermal rat studies available for ODEA results in LOAELs of 50 mg/kg bw/d for the local effects, this dose level will be further used in this chemical safety assessment to derive the dermal DNEL for long term local effects.

Repeated dose toxicity: dermal - systemic effects (target organ) other: all gross lesions and masses

Justification for classification or non-classification

The test item did not induce adverse effects indicative of serious damage at dose levels relevant for classification and labelling when tested for oral repeated dose toxicity. No target organ was identified. Thus, the test item is not subjected to classification and labelling for repeated dose toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC.