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Description of key information

A NOAEL of > 750 mg/kg bw/day was derived based on no treatment-related effects observed at any of the dose levels tested in a 28-day oral study conducted on amides, C12-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl). A 90-day oral study conducted on a structurally similar substance, from which a NOEL of 50 mg/kg bw/day was established, showed effects at higher dose levels, however it is unclear whether the effects noted were related to the test substance itself or were as a result of the nutritional deficiencies due to the unpalatability of the diet (evidenced by scattering of food, Sharrat et al., 1961). In conclusion, it is considered scientifically justified to use the subacute oral rat NOAEL of 750 mg/kg bw/day as the point of departure in the chemical safety assessment. .
Dermal 90 day and 2 year chronic studies have been conducted in both rats and mice. The following dose descriptors have been derived based on the studies described in Table 28:
• Subchronic dermal rat NOAEL: 50 mg/kg bw/day based on renal tubule regeneration
• Subchronic dermal mouse NOAEL: 100 mg/kg bw/day organ-weight changes
• Chronic dermal rat NOAEL: 50 mg/kg bw/day based on skin irritation at site of application in the 100 mg/kg bw dose (females) and significant increases in the epithelial ulcer of the forestomach
• Chronic dermal mouse LOAEL: 100 mg/kg bw/day based on body weight changes and skin irritation at site of application in the 200 mg/kg bw dose (females) and several non-neoplastic lesions at all dose levels
Since both subchronic and chronic dermal studies are available for structurally similar amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) and since the NOAELs for both subacute and chronic studies in rats were 50 mg/kg bw/day, the NOAEL from the chronic rat study was used in the chemical safety assessment as the point of departure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Sufficient data is available to evaluate this endpoint.

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:
Sufficient data available to evaluate this endpoint.

Additional information

Oral

A 28 day oral study conducted in rats (Potokar, 1983), resulted in a NOAEL of > 750 mg/kg bw/day (male/females) since no treatment-related effects were noted in any of the biologically relevant parameters investigated at any of the dose levels tested (i.e. 70, 250 and 750 mg/kg bw/day of amides, C12-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl)). Changes in the forestomach were noted in some treated and control animals, however the authors attributed this to the use of olive oil and found these changes to be reversible at the end of the exposure period.

In a 90 day oral study conducted in rats (Gaunt IFet al., 1965), the NOEL was determined to be 50 mg/kg bw/day for structurally similar LDEA (CAS No. 120-40-1) based on growth retardation, biochemical changes and an increase in kidney weights seen in the 250 mg/kg bw/day dose group, and growth retardation, haematological effects (anaemia) and increased kidney and liver weights seen in the 500 and 1000 mg/kg bw/day dose groups. The growth retardation seen in 250 mg/kg bw/day dose group and above was considered to be caused by the decrease in food intake due to the palatability of the diet, which may have also influenced the other effects noted in the higher dose groups.

Dermal

In a subchronic dermal study (NTP report 479, 2001) 0, 25, 50, 100, 200 or 400 mg/kg bw of the structurally similar amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) administered in ethanol for 14 weeks to groups of 10 male and 10 female F344/N rats resulted in a NOAEL of 50 mg/kg bw/day. The NOAEL was established based on the significant decrease in mean body weights and body weight gains in the 200 and 400 mg/kg bw dose groups, skin irritation at the site of application in the 100, 200 and 400 mg/kg bw (males and females) dose groups as well as haematological changes (minimal microcytic anaemia) and decreased cholesterol and triglyceride concentrations. Histopathological skin lesions at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, chronic active inflammation, parakeratosis and ulcer at doses of 100 mg/kg bw and above (the incidences and severities of these skin lesions generally increased with increasing dose). Greater incidences of renal tubule regeneration in 100, 200, and 400 mg/kg bw females were also observed.

In a subchronic dermal study (NTP report 479, 2001) 0, 25, 50, 100, 200, 400 or 800 mg/kg bw/day of structurally similar amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) administered for 14 weeks to groups of 10 male and 10 female B6C3F1 mice resulted in a NOAEL of 100 mg/kg bw/day. The NOAEL was established based on the incidence of chronic active inflammation in all dose groups at 200 mg/kg bw and above. The incidences and severities of these skin lesions generally increased with increasing dose. At 400 mg/kg bw/day a significant increase in relative liver weights was noted in females and at 800 mg/kg bw/day, a significant increase in relative liver, kidney (male and females) and lung weights (females) in males and females occurred.

 

Two year chronic dermal studies (NTP report 479) performed to assess the carcinogenic effects of structurally similar amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) conducted in rats and mice allow derivations of NOAEL (rat) and LOAEL (mouse) as described in the following:

F344/N rats (50 male and female test animals in each group) were administered five doses per week of 0, 50, or 100 mg/kg bw amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) (0, 85 or 170 mg/mL in ethanol) for 104 weeks. The animals were observed twice daily and body weights and clinical findings were recorded periodically. Necropsy and histopathology was performed on all animals. The survival rates of treated male and female rats were similar to those of the vehicle controls. The mean body weights of dosed males and females were similar to those of the vehicle controls throughout the study. The only treatment-related clinical finding was skin irritation at the site of application in the 100 mg/kg bw dose group (females). There were marginal increases in the incidences of renal tubule adenoma or carcinoma (combined) in the 50 mg/kg bw dose group (females). The severity of nephropathy increased with increasing dose in female rats. Non-neoplastic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, parakeratosis, and hyperkeratosis, and the incidences and severities of these lesions increased with increasing dose. The incidences of chronic active inflammation, epithelial hyperplasia, and epithelial ulcer of the forestomach increased with increasing dose in female rats, and the increases were significant in the 100 mg/kg bw group. A NOAEL of 50 mg/kg bw could be established based on skin irritation at the site of application in the 100 mg/kg bw dose (females) and significant increases in the epithelial ulcer of the forestomach (NTP report 479, 2001).

 

B6C3F1 mice (50 male and female test animals in each group) were administered five doses per week of 0, 100 or 200 mg/kg bw test material (0, 50 or 100 mg/mL in ethanol) for 104 to 105 weeks. The animals were observed twice daily, and body weights and clinical findings were recorded periodically. Necropsy was performed on all animals and complete histopathology was performed. Survival of dosed male and female mice was generally similar to that of the vehicle controls. Female mean bodyweights in the 100 mg/kg bw and 200 mg/kg bw dose groups werer lower than vehicle controls, from Week 93 and Week 77 onwards, respectively. The only treatment-related clinical finding was skin irritation at the site of application in males administered 200 mg/kg bw. The incidences of hepatic neoplasms (hepatocellularadenoma, hepatocellular carcinoma, and hepatoblastoma) were significantly increased in male and/or female mice. The incidences of eosinophilic foci in dosed groups of male mice were increased relative to that in the vehicle controls. The incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) were significantly increased in 200 mg/kg bw males. Several non-neoplastic lesions of the skin at the site of application were considered treatment-related. Incidences of epidermal hyperplasia, sebaceous glandhyperplasia, and hyperkeratosis were greater in all dosed groups of males and females compared to vehicle controls. The incidences of thyroid gland follicular cell hyperplasia in all treated males and females were significantly greater than those in the vehicle control groups. A LOAEL of 100 mg/kg bw can be established based on body weight changes and skin irritation at the site of application in the 200 mg/kg bw dose (females) and several non-neoplastic lesions at all dose levels (NTP report 479, 2001).

The following information is taken into account for any hazard / risk assessment:

A NOAEL of >750 mg/kg bw/day was derived based on no treatment-related effects observed at any of the dose levels tested in a 28-day oral study conducted on amides, C12-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl). A 90-day oral study conducted on a structurally similar substance, from which a NOEL of 50 mg/kg bw/day was established, showed effects at higher dose levels, however it is unclear whether the effects noted were related to the test substance itself or were as a result of the nutritional deficiencies due to the unpalatability of the diet (evidenced by scattering of food, Sharrat et al., 1961). In conclusion, it is considered scientifically justified to use the subacute oral rat NOAEL of 750 mg/kg bw/day as the point of departure in the chemical safety assessment. .

Dermal 90 day and 2 year chronic studies have been conducted in both rats and mice. The following dose descriptors have been derived based on the studies described in Table 28:

  • Subchronic dermal rat NOAEL: 50 mg/kg bw/day based on renal tubule regeneration

  • Subchronic dermal mouse NOAEL: 100 mg/kg bw/day organ-weight changes

  • Chronic dermal rat NOAEL: 50 mg/kg bw/day based on skin irritation at site of application in the 100 mg/kg bw dose (females) and significant increases in the epithelial ulcer of the forestomach

  • Chronic dermal mouse LOAEL: 100 mg/kg bw/day based on body weight changes and skin irritation at site of application in the 200 mg/kg bw dose (females) and several non-neoplastic lesions at all dose levels

Since both subchronic and chronic dermal studies are available for structurally similar amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) and since the NOAELs for both subacute and chronic studies in rats were 50 mg/kg bw/day, the NOAEL from the chronic rat study was used in the chemical safety assessment as the point of departure. A chronic study takes precedence over a subchronic study, thus the uncertainty involved in deriving the DNEL dermal value for long term systemic effects is reduced.

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
One good quality study available.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Good quality study available.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Repeated dose toxicity: dermal - systemic effects (target organ) digestive: stomach; other: skin

Justification for classification or non-classification

Based on the NOAEL derived from the subacute study (750 mg/kg bw/day), in which no treatment-related effects were observed, and the LOAEL in subchronic dermal studies (50 mg/kg bw day in rats and 100 mg/kg bw/day in mice), based on renal tubule regeneration in rats and organ-weight changes in mice, and chronic dermal studies in rats (NOAEL: 50 mg/kg bw/day) and mice (LOAEL: 100 mg/kg bw/day), it can be concluded that amides, C12-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) does not require classification according to EC (67/548/EEC) and CLP (EC 1272/2008) criteria.