Amides, C18-unsatd., N,N-bis(hydroxyethyl)

Carcinogenicity

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 29 April 1993 to 10 May 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Principles of method if other than guideline:

A 2 year toxicity study in B6C3F1 mice was conducted to evaluate the carcinogenic potential by the repeated dermal exposure to the test substance.

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Taconic Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: 6 wks
- Housing: Housed individually in Polycarbonate cages
- Method of distribution: Animals were distributed randomly into groups of approximately equal initial mean body weights.
- Bedding: Sani-Chip® heat-treated hardwood chips (P.J. Murphy Forest Products Corp., Montville, NJ), changed weekly
- Diet: NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum
- Water: Tap water (Columbus municipal supply) via automatic watering system (Edstrom Industries, Inc., Waterford, WI), available ad libitum
- Acclimation period:Time held before studies: Males: 11 d and Females: 12 d
- Cages: Polycarbonate (Lab Products, Inc., Maywood, NJ), changed weekly and rotated every 2 wks
- Animal number per cage: 1
- Cage Filters: Spun-bonded polyester Du Pont 2024 (Snow Filtration, Co., Cincinnati, OH), changed every 2 wks
- Racks: Stainless steel drawer-type (Lab Products, Inc., Maywood, NJ), changed and rotated every 2 wks

ENVIRONMENTAL CONDITIONS
- Temperature: 21.1-25.0°C
- Relative humidity: 36-68%
- Air changes: 10/h
- Photoperiod: 12 h dark/12 h light

IN-LIFE DATES: From: 1993-04-29 To: 1995-05-10

Route of administration:

dermal

Vehicle:

ethanol

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The dose formulations were prepared every 3 weeks by mixing the test substance by stirring or sonicating with 95% ethanol to give the required concentrations.The test substance formulations were applied on shaved skin of the test animals.
The dose formulations were stored at room temperature, protected from light, in amber glass bottles for up to 28 days.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Periodic analyses of the dose formulations of the test substance from the beginning, middle, and end of the studies were analyzed at the study laboratory using HPLC. All the samples from the formulations were analysed every 9 weeks during the 2-year study and were within 10% of the target concentration.

Stability of dose formulations: Stability was confirmed for at least 28 days when stored in sealed containers, protected from ultraviolet light, at up to room temperature or for 3 hours when stored open to air and light.

Duration of treatment / exposure:

2-yr

Frequency of treatment:

5 exposures/wk

Post exposure period:

No

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

15 mg/kg bw/day (actual dose received)

Dose / conc.:

30 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

50/sex/dose; 5 M/F (for 3-month interim evaluation in mice)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose selection is based primarily on the incidences and severities of skin lesions observed at the site of application during the 13-week dermal studies. All groups of mice administered 100 mg/kg bw/day or greater exhibited high incidences of skin lesions at the site of application; thus, 100 mg/kg bw/day or greater were considered inappropriate for the 2-year study.

- The severities of the skin lesions increased with increasing dose in groups administered doses greater than 100 mg/kg bw/day; however, the severities of other lesions generally were increased only slightly between 100 and 800 mg/kg compared to the eightfold increase in dose. Therefore, the skin response appeared to plateau at 100 mg/kg, and higher doses did not produce a proportional increase in response. The incidences of skin lesions in groups administered 50 mg/kg bw/day were slightly less (minimal to mild) than those observed in groups administered 100 mg/kg bw/day. The skin response at the site of application in 50 mg/kg bw/day groups was such that 50 mg/kg bw/day was also considered inappropriate for a 2-year study; however, the slight reduction in incidences and the lower severities observed in the 50 mg/kg bw/day groups compared to those in the 100 mg/kg bw/day groups indicated that 50 mg/kg was below the plateau and at the upper end of a dose range in which skin response at the site of application exhibited a greater dose dependency. Therefore, at doses below 50 mg/kg bw/day, a proportional reduction in incidences and severities of skin lesions at the site of application would be expected. Accordingly, a high dose of 30 mg/kg and a low dose of 15 mg/kg were selected for the 2-year study in mice.

Positive control:

Not included in this study

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical findings were recorded monthly and at the end of the studies.

BODY WEIGHT: Yes
- Time schedule for examinations: Weighed initially, weekly for 13 wks, approximately monthly thereafter and again at the end of the studies

DERMAL IRRITATION (if dermal study): Yes

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

Sacrifice and pathology:

SACRIFICE: At the end of 3rd month 5 males and females were sacrificed for skin evaluation and at the end of the 2-year study all animals were sacrificed by carbon dioxide asphyxiation.

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
- Skin from the site of application was examined from all mice at the 3-month interim evaluation.
- Complete histopathology was performed on all the rats at the end of the study. In addition to gross lesions and tissue masses, the tissues examined were: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart with aorta, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum and ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin (site of application), spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus.
- All major tissues were fixed and preserved in 10% neutral buffered formalin processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 to 6 μm, and stained with hematoxylin and eosin for microscopic examination.

Other examinations:

None

Statistics:

Survival Analyses: The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Possible dose-related effects on survival were analysed by Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses were two sided.

Analysis of neoplasm and non-neoplastic lesion incidences: The Poly-k test (Bailer and Portier, 1988; Portier and Bailer, 1989; Piegorsch and Bailer, 1997) was used to assess neoplasm and nonneoplastic lesion prevalence. Tests of significance included pair wise comparisons of each dosed group with controls and a test for an overall dose-related trend. Continuity-corrected tests were used in the analysis of lesion incidence, and reported P values are one sided. Values of P greater than 0.5 are presented as 1-P with the letter N added to indicate a lower incidence or negative trend in neoplasm occurrence relative to the control group (e.g. P=0.99 is presented as P=0.01N).

Analysis of Continuous Variables: Organ and body weight data were analysed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).

Clinical signs:

no effects observed

Description (incidence and severity):

The only significant treatment-related clinical finding was irritation of the skin at the site of application in 30 mg/kg bw males (vehicle control, 0/55; 15 mg/kg bw, 1/55; 30 mg/kg bw, 20/55).

Dermal irritation (if dermal study):

effects observed, treatment-related

Description (incidence and severity):

The only significant treatment-related clinical finding was irritation of the skin at the site of application in 30 mg/kg bw males (vehicle control, 0/55; 15 mg/kg bw, 1/55; 30 mg/kg bw, 20/55).

Mortality:

no mortality observed

Description (incidence):

Survival of dosed male and female mice was similar to that of the vehicle control groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of dosed males and 15 mg/kg bw females were similar to those of the vehicle controls throughout the study. Mean body weights of 30 mg/kg bw females were less than those of the vehicle controls beginning week 76.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Skin lesions: Minimal to mild non-neoplastic lesions of the skin at the site of application were observed in females more than 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. There was increased incidence of hyperkeratosis in dosed males at 3 months and in dosed males and females at 2-years. The increased incidences of parakeratosis in 30 mg/kg bw/day males at the 3-month interim evaluation and at 2-years and 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.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

- Skin lesions: No significant treatment related effects were observed. Few neoplastic lesions observed (i.e., one fibrosarcoma in vehicle control female and two fibrosarcomas in females at 15 mg/kg bw/day) were not considered significant as they did not follow a dose dependent pattern.

- Malignant lymphoma: No significant treatment related effects were observed. The increased incidence of the lymphomas observed in females at 30 mg/kg bw/day was found to be similar to the incidences observed in the other dermal studies with ethanol as the vehicle (i.e., comparable to historical control values).

Other effects:

not examined

Relevance of carcinogenic effects / potential:

No, there were no significant neoplasms associated with administration of the test substance.

Key result

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

ca. 30 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no evidence of carcinogenic activity at any tested dose levels

Key result

Dose descriptor:

NOAEL

Remarks:

(systemic effects)

Effect level:

ca. 15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weight changes at 30 mg/kg bw/d

Key result

Dose descriptor:

LOAEL

Remarks:

(local effects)

Effect level:

ca. 15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: incidences of non-neoplastic lesions of the skin

For detailed results table kindly refer to the attached background materials section of the IUCLID.

Conclusions:

Under the study conditions, no evidence of carcinogenic activity was observed at any tested dose levels in mice.

Executive summary:

A study was conducted to evaluate the dermal carcinogenicity in B6C3F1 mice of the test substance, C18-unsatd. DEA, in compliance with GLP. Groups of 50 male and 50 female mice were dermally exposed to 0, 15 or 30 mg/kg bw/day in ethanol at a frequency of 5 d/week for a period of 105 weeks. 5 males and 5 females were considered for the 3 month interim assessment. Survival, clinical findings, body weight and histopathology were evaluated at specific time intervals. Survival of the dosed male and female rats was similar to that of the vehicle control groups. The mean body weights of females (Week 76 onwards) were reduced compared to 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 dose levels in skin and lymph nodes. Under the study conditions, no evidence of carcinogenic activity was observed at any tested dose levels in mice (NTP, 1999).  

Reference 2

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 06 May 1993 to 16 May 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Principles of method if other than guideline:

A 2-year toxicity study in F344/N rats was conducted to evaluate the carcinogenic potential by the repeated dermal exposure to the test substance.

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Taconic Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: 7 wk
- Housing: Housed individually in Polycarbonate cages
- Method of distribution: Animals were distributed randomly into groups of approximately equal initial mean body weights.
- Bedding: Sani-Chip® heat-treated hardwood chips (PJ Murphy Forest Products Corp., Montville, NJ), changed weekly
- Diet: NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum
- Water: Tap water (Columbus municipal supply) via automatic watering system (Edstrom Industries, Inc., Waterford, WI), available ad libitum
- Acclimation period:Time held before studies: Males: 13 d and Females: 14 d
- Cages: Polycarbonate (Lab Products, Inc., Maywood, NJ), changed weekly and rotated every 2 wks
- Animal number per cage: 1
- Cage Filters: Spun-bonded polyester Du Pont 2024 (Snow Filtration, Co., Cincinnati, OH), changed every 2 wks
- Racks: Stainless steel drawer-type (Lab Products, Inc., Maywood, NJ), changed and rotated every 2 wks

ENVIRONMENTAL CONDITIONS
- Temperature: 21.1-23.3°C
- Relative humidity: 31-73%
- Air changes: 10/h
- Photoperiod: 12 h dark/12 h light

IN-LIFE DATES: From: 1993-05-06 To: 1995-05-16

Route of administration:

dermal

Vehicle:

ethanol

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The dose formulations were prepared every 3 weeks by mixing the test substance by stirring or sonicating with 95% ethanol to give the required concentrations. The test substance formulations were applied on shaved skin of the test animals.
The dose formulations were stored at room temperature, protected from light, in amber glass bottles for up to 28 days.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Periodic analyses of the dose formulations of the test substance from the beginning, middle, and end of the studies were analyzed at the study laboratory using HPLC. All the samples from the formulations were analysed every 9 weeks during the 2-year study and were within 10% of the target concentration.

Stability of dose formulations: Stability was confirmed for at least 28 days when stored in sealed containers, protected from ultraviolet light, at up to room temperature or for 3 hours when stored open to air and light.

Duration of treatment / exposure:

2-yrs

Frequency of treatment:

5 exposures/wk

Post exposure period:

No

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Dose / conc.:

100 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

50/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection rationale: The dose selection was based primarily on the incidences and severities of skin lesions observed at the site of application during the 13-week dermal studies. The doses of 200 and 400 mg/kg bw/day exhibited reduced mean body weight and body weight gain along with high incidences of skin lesions at the site of application; thus were considered inappropriate for a 2-year study. Further, lesions of the skin were also present at the site of application in groups administered 100 mg/kg bw/day; however, the incidence were less than those observed in the 200 and 400 mg/kg bw/day groups. Moreover, it was considered unlikely that these lesions would progress and become life threatening over the period of a 2-year study. Therefore, 100 mg/kg bw/day was selected as the high dose for rats in the 2-year study. In groups treated with 50 mg/kg bw/day, the incidences of skin lesions diminished considerably and lesion severities were minimal. Therefore, 50 mg/kg bw/day was selected as the low dose.

Positive control:

No

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical findings were recorded monthly and at the end of the studies.

BODY WEIGHT: Yes
- Time schedule for examinations: Weighed initially, weekly for 13 weeks, approximately monthly thereafter and again at the end of the studies

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

Sacrifice and pathology:

SACRIFICE: At the end of the 2-year study animals were sacrificed by carbon dioxide asphyxiation.

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
- Complete histopathology was performed on all the rats at the end of the study. In addition to gross lesions and tissue masses, the tissues examined were: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart with aorta, large intestine (cecum, colon and rectum), small intestine (duodenum, jejunum and ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin (site of application), spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus.
- All major tissues were fixed and preserved in 10% neutral buffered formalin processed and trimmed, embedded in paraffin, sectioned to a thickness of 5 to 6 μm, and stained with hematoxylin and eosin for microscopic examination.

Other examinations:

None

Statistics:

Survival Analyses: The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Possible dose-related effects on survival were analysed by Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses were two sided.

Analysis of neoplasm and non-neoplastic lesion incidences: The Poly-k test (Bailer and Portier, 1988; Portier and Bailer, 1989; Piegorsch and Bailer, 1997) was used to assess neoplasm and nonneoplastic lesion prevalence. Tests of significance included pair wise comparisons of each dosed group with controls and a test for an overall dose-related trend. Continuity-corrected tests were used in the analysis of lesion incidence, and reported P values are one sided. Values of P greater than 0.5 are presented as 1-P with the letter N added to indicate a lower incidence or negative trend in neoplasm occurrence relative to the control group (e.g., P=0.99 is presented as P=0.01N).

Analysis of Continuous Variables: Organ and body weight data were analysed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The only significant treatment-related clinical finding was mild to moderate irritation of the skin at the site of application in dosed males and females (males: vehicle control, 0/50; 50 mg/kg bw, 17/50; 100 mg/kg bw, 32/50; females: 3/50, 46/50, 50/50).

Dermal irritation (if dermal study):

effects observed, treatment-related

Description (incidence and severity):

The only significant treatment-related clinical finding was mild to moderate irritation of the skin at the site of application in dosed males and females (males: vehicle control, 0/50; 50 mg/kg bw, 17/50; 100 mg/kg bw, 32/50; females: 3/50, 46/50, 50/50).

Mortality:

no mortality observed

Description (incidence):

Survival of dosed male and female rats was similar to that of the vehicle control groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of 100 mg/kg bw males were slightly less than those of the vehicle control group throughout most of the study. Mean body weights of 100 mg/kg bw females were less than those of the vehicle controls from week 24 until the end of the study.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

- Skin lesions: Minimal to moderate non-neoplastic lesions of the skin at the site of application were observed. The major alterations included (thickening of the epidermis, sebaceous gland and epidermal hyperplasia, hyperkeratosis, parakeratosis, chronic active dermal inflammation and ulcer) which were significantly increased in dosed males and females relative to the vehicle control.

- Forestomach lesions: No significant treatment related effects were observed. The increased incidence of hyperkeratosis and ulceration in 50 mg/kg bw/day males were not considered to be treatment related as these effects were not observed in females.

- Testis: No significant treatment related effects were observed.

- Thyroid gland lesions: No significant treatment related effects were observed.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

- Skin lesions: No significant treatment related effects were observed. Few observed skin neoplasms (one subcutaneous fibroma in one vehicle control male and one subcutaneous fibrosarcoma in each of the 50 and 100 mg/kg bw/day male groups) were not considered to be significant as the incidences did not follow a pattern indicative of an association with the test substance.

- Testis: No significant treatment related effects were observed. Increased interstitial cell adenoma in males at 100 mg/kg bw/day was not considered significant as similar incidences were reported in vehicle controls in historical NTP dermal studies.

- Thyroid gland: No significant treatment related effects were observed. Marginal increase in the incidence of follicular cell adenoma or carcinoma observed in males at 50 mg/kg bw/day was not considered dose related and no follicular cell hyperplasias were observed .

Relevance of carcinogenic effects / potential:

No, there were no significant neoplasms associated with administration of the test substance.

Key result

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

ca. 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no evidence of carcinogenic activity at any tested dose levels

Key result

Dose descriptor:

NOAEL

Remarks:

(systemic effects)

Effect level:

ca. 50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weight changes at the LOAEL

Key result

Dose descriptor:

LOAEL

Remarks:

(local effects)

Effect level:

ca. 50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: irritation and non-neoplastic lesion of the skin at both the tested doses

For detailed results table kindly refer to the attached background materials section of the IUCLID.

Conclusions:

Under the study conditions, no evidence of carcinogenic activity was observed with the test substance at any tested dose levels in rats.

Executive summary:

A study was conducted to evaluate the dermal carcinogenicity in F344 rats of the test substance, C18-unsatd. DEA, in compliance with GLP. Groups of 50 male and 50 female rats were dermally exposed to 0, 50 or 100 mg/kg bw/day in ethanol at a frequency of 5 d/week for a period of 104 weeks. Survival, clinical findings, body weight and histopathology of different organs were assessed at specific time intervals. Survival of the dosed male and female rats was similar to that of the vehicle control groups. The mean body weights of males and females (week 24 onwards) were reduced compared to those of the vehicle control group at 100 mg/kg bw/day. A dose dependent increase in irritation (mild to moderate) and non-neoplastic lesions (minimal to moderate) of the skin were observed at the site of application in all animals. 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 study conditions, no evidence of carcinogenic activity was observed with the test substance at any tested dose levels in rats (NTP, 1999). 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Quality of whole database:

Exceeds the information requirements for this tonnage band.

Justification for classification or non-classification

The available data suggests that C18-unsatd. DEA is neither genotoxic nor carcinogenic. Therefore, the substance does not require classification for carcinogenicity according to CLP (EC 1272/2008) criteria.  

Additional information

A study was conducted to evaluate the dermal carcinogenicity in B6C3F1 mice of the test substance, C18-unsatd. DEA, in compliance with GLP. Groups of 50 male and 50 female mice were dermally exposed to 0, 15 or 30 mg/kg bw/day in ethanol at a frequency of 5 d/week for a period of 105 weeks. 5 males and 5 females were considered for the 3 month interim assessment. Survival, clinical findings, body weight and histopathology were evaluated at specific time intervals. Survival of the dosed male and female rats was similar to that of the vehicle control groups. The mean body weights of females (Week 76 onwards) were reduced compared to 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 dose levels in skin and lymph nodes. Under the study conditions, no evidence of carcinogenic activity was observed at any tested dose levels in mice (NTP, 1999).  

A study was conducted to evaluate the dermal carcinogenicity in F344 rats of the test substance, C18-unsatd. DEA, in compliance with GLP. Groups of 50 male and 50 female rats were dermally exposed to 0, 50 or 100 mg/kg bw/day in ethanol at a frequency of 5 d/week for a period of 104 weeks. Survival, clinical findings, body weight and histopathology of different organs were assessed at specific time intervals. Survival of the dosed male and female rats was similar to that of the vehicle control groups. The mean body weights of males and females (week 24 onwards) were reduced compared to those of the vehicle control group at 100 mg/kg bw/day. A dose dependent increase in irritation (mild to moderate) and non-neoplastic lesions (minimal to moderate) of the skin were observed at the site of application in all animals. 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 study conditions, no evidence of carcinogenic activity was observed with the test substance at any tested dose levels in rats (NTP, 1999).