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Description of key information

A NOAEL of > 750 mg/kg bw/day was derived based on no treatment-related effects at any of the dose levels tested in the 28 days oral toxicity study conducted on amides, C12-18 (even numbered) and C18-unsatd., N-hydroxyethyl. A 90 day oral toxicity study conducted on a structurally similar substance, from which a NOAEL 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 was a result of the nutritional deficiencies due to the palatability of the diet (Sharrat et al., 1961). Based on this, it is scientifically justified to use the subacute oral rat NOAEL of 750 mg/kg bw/day for this safety assessment as the point of departure.
Dermal 90 day and two year chronic studies on structurally similar substances have been conducted in both rats and mice. The following dose descriptors have been derived:
• Subchronic dermal rat NOAEL: 50 mg/kg bw/day based on renal tubule regeneration at the LOEL
• Subchronic dermal mouse NOAEL: 100 mg/kg bw/day organ-weight changes at the LOEL
• 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

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: inhalation - systemic 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:
Sufficient data is available to evaluate this endpoint.

Additional information

Oral

A 28 day oral toxicity study conducted in rats with amides, C12-18 (even numbered) and C18-unsatd., N-hydroxyethyl (Gloxhuber and Potokar, 1983) resulted in a free standing NOEL of > 750 mg/kg bw/day (male/females) since no treatment-related effects were noted at the highest dose tested. There were changes in the forestomach at some doses including controls, however the authors attributed these to the use of olive oil and found the forestomach changes to be reversible at the end of the exposure period.

Similarly, a 28 day oral toxicity study conducted in rats with structurally similar amides, C12-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) (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 parameters investigated at any of the dose levels tested (i.e. 70, 250, 750 mg/kg bw/day). Again, there were changes in the forestomach at some doses including controls, however the authors attributed these to the use of olive oil and found the forestomach changes to be reversible at the end of the exposure period.

In a 90 day oral toxicity study conducted in rats (Gaunt IFet al., 1965), the NOEL was determined to be 50 mg/kg bw/day for structurally similar lauric acid diethanolamine (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 at 500 and 1,000 mg/kg bw/day. The growth retardation at 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 as noted by the investigator.

Dermal

In a subchronic dermal toxicity study (NTP report 479, 2001) 0, 25, 50, 100, 200, or 400 mg/kg bw of structurally similar amides, C8-18 (even numbered) 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 no 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 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 toxicity study (NTP report 479, 2001) 0, 25, 50, 100, 200, 400, or 800 mg/kg bw/day of structurally similar amides, C8-18 (even numbered) 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 at 200 mg/kg bw and above. The incidences and severities of these skin lesions generally increased with dose. At 400 mg/kg bw/day, a significant increase in relative liver weights was noted in females. At 800 mg/kg bw/day, a significant increase in relative liver (male and female), kidney (male and females) and lung (females) weights was observed.

 

Two year chronic dermal toxicity studies performed to assess the carcinogenic affects of structurally similar amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) in rats and mice allowed derivations of NOAEL (rat) and LOAEL (mouse) as described in the following:

                                                                                                                                                               

F344/N rats were administered doses of 0, 50, or 100 mg/kg bw of amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) (0, 85, or 170 mg/mL in ethanol) 50 male and female animals in each group. Five exposures per week were given for 104 weeks. The animals were observed twice daily, 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) at 50 mg/kg bw (females).The severity of nephropathy increased with 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 dose. The incidences of chronic active inflammation, epithelial hyperplasia and epithelial ulcer of the forestomach increased with 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 at 100 mg/kg bw (females) and significant increases in the epithelial ulcer of the forestomach (NTP report 479, 2001).

 

B6C3F1 mice (50 males and female) were administered doses of 0, 100 or 200 mg/kg bw of the test substance (0, 50 or 100 mg/mL in ethanol). Five exposures per week were given for 104 to 105 weeks. The animals were observed twice daily, body weights and clinical findings were recorded periodically. Necropsy and complete histopathology was performed on all animals. Survival of dosed male and female mice was generally similar to that of the vehicle controls. Female Mean bodyweights of 100 mg/kg bw from Week 93 and 200 mg/kg bw from Week 77 were lower than those of the vehicle controls. The only clinical finding attributed to treatment 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 gland hyperplasia, and hyperkeratosis were greater in all dosed groups of males and females than in the 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. Therefore, a LOAEL of 100 mg/kg bw was 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).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Good quality KL1 study has been selected.

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

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

Amides, C12-18 (even numbered) and C18-unsatd., N-hydroxyethyl and amides, C12-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) were bothtested in 28 days oral gavage studies in rats according to the same study protocol in the same laboratory with the same outcome. No adverse effects were seen at the highest dose (NOEL > 750 mg/kg bw/day (male/females)). Subchronic and chronic data onstructurally similar amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) and LDEA provides further justification that amides, C12-18 (even numbered) and C18-unsatd., N-(hydroxyethyl) does not require classification for repeated dose toxicity or specific target organ toxicity following repeated exposure according to EC (67/548/EEC) and CLP (EC 1272/2008) criteria.