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Toxicological information

Carcinogenicity

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Description of key information

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

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Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Principles of method if other than guideline:
A two-year dermal study was conducted in rat to evaluate the carcinogenic potential of the test material.

GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Laboratory Animals and Services, (Germantown, NY)
- Age at study initiation: 6 wk
- Housing: Housed individually in Polycarbonate cages (Lab Products, Inc., Maywood, NJ)
- Bedding: Sani-Chip heat-treated hardwood chips (PJ Murphy Forest Products Corp., Montville, NJ)
- Diet : NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), ad libitum
- Water : Tap water (Columbus municipal supply), ad libitum
- Acclimation period: 11 to 12 d

ENVIRONMENTAL CONDITIONS
- Temperature : 20.0-23.9°C
- Humidity : 33-70%
- Air changes : 10/hr
- Photoperiod : 12 h dark/12 h light

IN-LIFE DATES: From: Feb. 1, 1993 To: Jan. 31, 1995

Route of administration:
dermal
Vehicle:
ethanol
Details on exposure:
The test material formulation was applied to the shaved skin of test animals. No further details provided.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were analysed approximately every 2 months using HPLC. In addition to dose formulation analysis prior to dosing, samples collected after dosing (animal room samples) were analysed periodically. All dose formulations analysed during the 2 yr studies were within 10% of the target concentration.
Duration of treatment / exposure:
104 wk
Frequency of treatment:
Five exposures per week
Post exposure period:
No
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Remarks:
Corresponding to 85 mg/mL in ethanol
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Corresponding to 170 mg/mL in ethanol
No. of animals per sex per dose:
50/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Doses of 200 or 400 mg/kg bw in the 14 wk study were associated with reduced mean body weights, mild anemia, and significantly increased incidences and severities of lesions of the skin at the site of application. Therefore, these doses were considered inappropriate for a 2-year study. At 100 mg/kg bw, the incidences of skin lesions, especially ulceration, were less than at 200 mg/kg bw, and in general, the severities were minimal to mild. Therefore, 100 mg/kg bw was selected as the high dose for this 2-yr study.
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed twice daily



DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical findings were recorded initially, at 4 wk intervals during the study, and at the end of the study


DERMAL IRRITATION (if dermal study): Yes


BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed initially, weekly during week 1 through 13, at 4 wk intervals thereafter, and at the end of the studies







Sacrifice and pathology:
SACRIFICE: Carbon dioxide asphyxiation

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes, Complete histopathology was performed on all rats. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone and marrow, brain, clitoral gland, esophagus, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, 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, spleen, stomach (forestomach and glandular), testis (and
epididymis and seminal vesicle), thymus, thyroid gland, trachea, urinary bladder, and uterus
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 Nonneoplastic 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 pairwise 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.

Analysis of Continuous Variables: Organ and body weight data, which historically have approximately normal distributions, were analyzed with the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972). Jonckheere's test (Jonckheere, 1954) was used to assess the significance of the dose-related trends. Average severity values were analyzed for significance with the Mann-Whitney U test. Treatment effects were investigated by applying a multivariate analysis of variance (Morrison, 1976) to the transformed data to test for simultaneous equality of measurements across dose levels.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The only clinical finding attributed to dosing was irritation of the skin at the site of application in 100 mg/kg bw females.
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
The only clinical finding attributed to dosing was irritation of the skin at the site of application in 100 mg/kg bw females.
Mortality:
mortality observed, treatment-related
Description (incidence):
Survival rates of dosed male and female rats were similar to those of the vehicle controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weights of dosed male and female rats were similar to those of the vehicle controls throughout 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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Skin: No neoplasms of the skin were attributed to treatment with test material. Incidences of squamous cell papilloma, keratoacanthoma, trichoepithelioma, basal cell adenoma, or carcinoma (combined) were significantly decreased in 100 mg/kg bw male rats. Incidences of epidermal hyperplasia, sebaceous gland hyperplasia, parakeratosis, and hyperkeratosis in all dosed groups were significantly greater than those in the vehicle control groups. The severities of these lesions generally increased with increasing dose and ranged from minimal to mild. Females in the 100 mg/kg bw group had a significantly greater incidence of ulceration at the site of application than did the vehicle controls.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Kidney: Incidences of renal tubule hyperplasia in dosed females were significantly greater than those of the vehicle controls, and the incidence of renal tubule adenoma in 50 mg/kg bw males was marginally increased. Incidences of chronic nephropathy were similar between vehicle control and dosed groups of male and female rats; however, the severity of nephropathy increased with increasing dose in female rats. The incidences of renal tubule adenoma in all groups of males and of renal tubule carcinoma in 50 mg/kg bw females exceeded the historical control ranges. An extended evaluation of the kidney revealed additional renal tubule adenomas in vehicle control and dosed males, and renal tubule adenomas and/or carcinomas in dosed females. When the single and step sections were combined, the incidences of renal tubule hyperplasia in dosed females and of renal tubule adenoma or carcinoma (combined) in 50 mg/kg bw females were significantly greater than those of the controls. In female rats, the combined single and step section evaluations of the kidney revealed a significant dose- related increase in the incidence of renal tubule hyperplasia and two adenomas and two carcinomas in the 50 mg/kg bw group but only one neoplasm (an adenoma), in the 100 mg/kg bw group. Renal tubule neoplasms are uncommon in female F344/N rats, and the presence of four neoplasms in the 50 mg/kg bw group, combined with the increased incidence of hyperplasia, is suggestive of an association with chemical exposure. However, the absence of an increase in neoplasms in the 100 mg/kg bw group in the presence of increased hyperplasia makes the association with chemical exposure uncertain.

Forestomach: The incidences of chronic active inflammation (vehicle control, 1/50; 50 mg/kg bw, 3/50; 100 mg/kg bw, 10/50), epithelial hyperplasia (2/50, 5/50, 13/50), and epithelial ulcer (1/50, 3/50, 11/50) were significantly increased in the forestomach of 100 mg/kg bw females. The severities of these lesions were similar among all groups.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Pancreas: The incidence of pancreatic acinar atrophy in 100 mg/kg bw male rats was significantly greater than that in the vehicle controls.
Relevance of carcinogenic effects / potential:
Yes
Key result
Dose descriptor:
NOAEL
Based on:
other:
Sex:
male/female
Remarks on result:
not determinable
Remarks:
No NOAEL identified. There was an equivocal evidence of carcinogenic activity in female rats based on a marginal increase in the incidences of renal tubule neoplasms. However, the absence of an increase in neoplasms in the 100 mg/kg bw/day group in the presence of increased hyperplasia makes the association with treatment uncertain.

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

Conclusions:
Under the study conditions, there was no evidence of carcinogenic activity of the test substance in male rats at any dose. There was an equivocal evidence of carcinogenic activity in female rats based on a marginal increase in the incidences of renal tubule neoplasms. However, the absence of an increase in neoplasms in the 100 mg/kg bw/day group in the presence of increased hyperplasia makes the association with treatment uncertain.
Executive summary:

A study was conducted to evaluate the long-term repeated dose dermal carcinogenicity of the test substance, C8-18 and C18-unsatd. DEA, in Fischer 344 rats, in compliance with GLP. Groups of 50 male and 50 female rats were exposed to 0, 50 or 100 mg/kg bw/day of the substance in ethanol by dermal application, 5 times per week, for 104 weeks. Mortality, clinical signs and bodyweight were recorded throughout the study. At necropsy, a gross macroscopic examination and complete histopathology were carried out. The survival rates of treated male and female rats were similar to those of controls. There were no significant differences in bodyweight throughout the groups. The only treatment-related clinical finding was irritation of the skin at the site of application in 100 mg/kg bw/day females. 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. There were marginal increases in the incidences of renal tubule adenoma or carcinoma (combined) in 50 mg/kg bw/day females. The severity of nephropathy increased with increasing dose in female rats. 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/day group. Under the study conditions, there was no evidence of carcinogenic activity of the test substance in male rats at any dose. There was an equivocal evidence of carcinogenic activity in female rats based on a marginal increase in the incidences of renal tubule neoplasms. However, the absence of an increase in neoplasms in the 100 mg/kg bw/day group in the presence of increased hyperplasia makes the association with treatment uncertain (NTP, 2001).

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Principles of method if other than guideline:
A two-year dermal study was conducted in mice to evaluate the carcinogenic potential of the test material.

GLP compliance:
yes
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Laboratory Animals and Services, (Germantown, NY)
- Age at study initiation: 6 wk
- Housing: Housed individually in Polycarbonate cages (Lab Products, Inc., Maywood, NJ)
- Bedding: Sani-Chip heat-treated hardwood chips (PJ Murphy Forest Products Corp., Montville, NJ)
- Diet : NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), ad libitum
- Water : Tap water (Columbus municipal supply), ad libitum
- Acclimation period: 13 to 14 d

ENVIRONMENTAL CONDITIONS
- Temperature : 20.6-23.9°C
- Humidity : 30-67%
- Air changes : 10/hr
- Photoperiod : 12 h dark/12 h light

IN-LIFE DATES: From: Jan. 20, 1993 To: Jan. 20, 1995

Route of administration:
dermal
Vehicle:
ethanol
Details on exposure:
The test material formulation was applied to the shaved skin of test animals. No further details provided.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were analyzed approximately every 2 months using HPLC. In addition to dose formulation analysis prior to dosing, samples collected after dosing (animal room samples) were analysed periodically. All dose formulations analysed during the 2-yr studies were within 10% of the target concentration.
Duration of treatment / exposure:
104-105 wk
Frequency of treatment:
Five exposures per week
Post exposure period:
No
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Corresponding to 50 mg/mL in ethanol
Dose / conc.:
200 mg/kg bw/day (nominal)
Remarks:
Corresponding to 100 mg/mL in ethanol
No. of animals per sex per dose:
50/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Exposure to coconut oil acid diethanolamine condensate in the 14 wk study produced only a minimal toxic response in mice except in the skin at the site of application. The incidences of chronic active inflammation as well as several other skin lesions were significantly increased at doses of 200 mg/kg bw and greater in both male and female mice. The incidences of ulceration were increased in males exposed to 400 and 800 mg/kg bw and in females exposed to 800 mg/kg bw. Therefore, 400 and 800 mg/kg bw were considered inappropriate for a 2-year study. However, ulceration was present in only one 200 mg/kg bw male and no females, and the severities of these lesions in all affected groups were minimal to mild. Below 200 mg/kg bw, the incidences of skin lesions decreased markedly with a minor difference in response between 50 and 100 mg/kg bw. Therefore, 200 mg/kg bw was selected as the high dose and 100 mg/kg bw as the low dose for this 2-yr study.
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical findings were recorded initially, at 4 wk intervals during the study, and at the end of the study

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed initially, weekly during wk 1 through 13, at 4 wk intervals thereafter, and at the end of the studies







Sacrifice and pathology:
SACRIFICE: Carbon dioxide asphyxiation

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes, Complete histopathology was performed on all mice. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone and marrow, brain, clitoral gland, esophagus, gallbladder, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, 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, spleen, stomach (forestomach and glandular), testis (and epididymis and seminal vesicle), thymus, thyroid gland, trachea, urinary bladder, and uterus.
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 Nonneoplastic 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 pairwise 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.

Analysis of Continuous Variables: Organ and body weight data, which historically have approximately normal distributions, were analyzed with the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972). Jonckheere's test (Jonckheere, 1954) was used to assess the significance of the dose-related trends. Average severity values were analyzed for significance with the Mann-Whitney U test. Treatment effects were investigated by applying a multivariate analysis of variance (Morrison, 1976) to the transformed data to test for simultaneous equality of measurements across dose levels.

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The only treatment-related clinical finding was irritation of the skin at the site of application in males that received 200 mg/kg bw.
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
The only treatment-related clinical finding was irritation of the skin at the site of application in males that received 200 mg/kg bw.
Mortality:
mortality observed, treatment-related
Description (incidence):
The survival of dosed males and 100 mg/kg bw females was similar to that of the vehicle controls. Survival of the 200 mg/kg bw group of female mice was reduced compared to the vehicle control group, but the difference was not significant.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights of dosed males were similar to those of the vehicle controls throughout most of the study; those of 100 and 200 mg/kg bw females were less than those of the vehicle controls from wk 93 and 77, respectively.
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Skin: Several nonneoplastic lesions of the skin at the site of application were determined to be chemical related. Incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and hyperkeratosis in all dosed groups of males and females were significantly greater than those in the vehicle control groups. The incidences of ulceration in 200 mg/kg bw males and inflammation and parakeratosis in 200 mg/kg bw females were increased.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver: Dosed male and female mice had significantly greater incidences of hepatic neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma (males) than the vehicle controls. There was a morphologic continuum from adenoma to carcinoma, with less differentiation and typical trabecular formations in the carcinomas. Carcinomas were often a centimeter or more in diameter, whereas adenomas were generally smaller and more discrete. Carcinomas metastasized to the lung in a few males and females. Adenomas, carcinomas, and hepatoblastomas displaced normal liver parenchyma, and none contained normal lobular architecture. Hepatoblastomas were characterized by well-demarcated focal areas composed of bundles of deeply basophilic, spindle-shaped cells.

Kidney: The incidences of renal tubule adenoma (1/50, 1/50, 7/50) and of renal tubule adenoma or carcinoma (combined) (1/50, 1/50, 9/50) in 200 mg/kg bw males were significantly greater than those in the vehicle controls. Renal tubule hyperplasia, adenoma, and carcinoma formed a morphological continuum. Adenomas were focal, compressive masses approximately five or more tubules in diameter; carcinomas were morphologically similar to adenomas but were larger and often showed cellular debris and/or mineralization. Renal tubule neoplasms were located in the cortex or outer medulla. Focal proliferative masses less than five tubules in diameter were classified as focal hyperplasia.

Thyroid Gland: The incidences of follicular cell hyperplasia in all dosed groups of males (vehicle control, 11/50; 100 mg/kg bw, 20/50; 200 mg/kg bw, 23/50) and females (27/50, 36/50, 33/50) were significantly greater than those in the vehicle controls. Follicular cell hyperplasia consisted of focal areas of thyroid gland follicles lined with increased numbers of epithelial cells, which formed papillary projections in some instances.
Relevance of carcinogenic effects / potential:
Yes
Key result
Dose descriptor:
NOAEL
Based on:
other:
Sex:
male/female
Remarks on result:
not determinable
Remarks:
No NOAEL identified as hepatic tumours seen in mice and the proposed mode of non-genotoxic mechanism for renal/liver tumours are not relevant to humans/primates.

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

Conclusions:
Under the study conditions, there was clear evidence of carcinogenic activity in male B6C3F1 mice based on increased incidences of hepatic and renal tubule neoplasms and in female B6C3F1 mice based on increased incidences of hepatic neoplasms. These increases were associated with the the concentration of free diethanolamine present as a contaminant in the diethanolamine condensate. However, recent evidences suggest that DEA should not be classified as a carcinogen, as the hepatic tumours seen in mice and the proposed mode of non-genotoxic mechanism for renal/liver tumours are not relevant to humans/primates.
Executive summary:

A study was conducted to evaluate the long term repeated dose dermal carcinogenicity of the test substance, C8-18 and C18-unsatd. DEA, in compliance with GLP. The doses studied included 0, 100 and 200 mg/kg bw/day of test substance (corresponding to 0, 50, or 100 mg/mL in ethanol). Fifty male/female test animals were used in each group. Five exposures per week were administered for 104 to 105 weeks. The animals were observed twice daily, and body weights and clinical findings were recorded periodically. All animals were necropsied and complete histopathology was performed. Survival of dosed male and female mice was generally similar to that of the vehicle controls. The mean bodyweights of the 100 mg/kg bw/day females from week 93 and of the 200 mg/kg bw/day females from week 77 were lower than those of the vehicle controls. The only clinical finding attributed to treatment was an irritation of the skin at the site of application in males administered 200 mg/kg bw/day. The incidences of hepatic neoplasms (hepatocellular adenoma, hepatocellular carcinoma and hepatoblastoma) were significantly increased in male and/or female mice. The number of eosinophilic foci in dosed groups of male mice was higher than in the vehicle controls. The occurrences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) were significantly increased in 200 mg/kg bw/day 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 than in the vehicle controls and the number of thyroid gland follicular cell hyperplasia in all dosed groups was also significantly greater than those in the vehicle control groups. There was clear evidence of carcinogenic activity in male B6C3F1 mice based on increased incidences of hepatic and renal tubule neoplasms and in female B6C3F1 mice based on increased incidences of hepatic neoplasms. These increases were associated with the concentration of free diethanolamine present as a contaminant in the test substance. However, recent evidences suggest that DEA should not be classified as a carcinogen, as the hepatic tumours seen in mice and the proposed mode of non-genotoxic mechanism for renal/liver tumours are not relevant to humans/primates (NTP, 2001).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic

Additional information

A study was conducted to evaluate the long-term repeated dose dermal carcinogenicity of the test substance, C8-18 and C18-unsatd. DEA, in B6C3F1 mice, in compliance with GLP. The doses studied included 0, 100 and 200 mg/kg bw/day of test substance (corresponding to 0, 50, or 100 mg/mL in ethanol). Fifty male/female test animals were used in each group. Five exposures per week were administered for 104 to 105 weeks. The animals were observed twice daily, and body weights and clinical findings were recorded periodically. All animals were necropsied and complete histopathology was performed. Survival of dosed male and female mice was generally similar to that of the vehicle controls. The mean bodyweights of the 100 mg/kg bw/day females from week 93 and of the 200 mg/kg bw/day females from week 77 were lower than those of the vehicle controls. The only clinical finding attributed to treatment was an irritation of the skin at the site of application in males administered 200 mg/kg bw/day. The incidences of hepatic neoplasms (hepatocellular adenoma, hepatocellular carcinoma and hepatoblastoma) were significantly increased in male and/or female mice. The number of eosinophilic foci in dosed groups of male mice was higher than in the vehicle controls. The occurrences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) were significantly increased in 200 mg/kg bw/day 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 than in the vehicle controls and the number of thyroid gland follicular cell hyperplasia in all dosed groups was also significantly greater than those in the vehicle control groups. There was clear evidence of carcinogenic activity in male B6C3F1 mice based on increased incidences of hepatic and renal tubule neoplasms and in female B6C3F1 mice based on increased incidences of hepatic neoplasms. These increases were associated with the concentration of free diethanolamine present as a contaminant in the test substance. However, recent evidences suggest that DEA should not be classified as a carcinogen, as the hepatic tumours seen in mice and the proposed mode of non-genotoxic mechanism for renal/liver tumours are not relevant to humans/primates (NTP, 2001).

A study was conducted to evaluate the long-term repeated dose dermal carcinogenicity of the test substance, C8-18 and C18-unsatd. DEA, in Fischer 344 rats, in compliance with GLP. Groups of 50 male and 50 female rats were exposed to 0, 50 or 100 mg/kg bw/day of the substance in ethanol by dermal application, 5 times per week, for 104 weeks. Mortality, clinical signs and bodyweight were recorded throughout the study. At necropsy, a gross macroscopic examination and complete histopathology were carried out. The survival rates of treated male and female rats were similar to those of controls. There were no significant differences in bodyweight throughout the groups. The only treatment-related clinical finding was irritation of the skin at the site of application in 100 mg/kg bw/day females. 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. There were marginal increases in the incidences of renal tubule adenoma or carcinoma (combined) in 50 mg/kg bw/day females. The severity of nephropathy increased with increasing dose in female rats. 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/day group. Under the study conditions, there was no evidence of carcinogenic activity of the test substance in male rats at any dose. There was an equivocal evidence of carcinogenic activity in female rats based on a marginal increase in the incidences of renal tubule neoplasms. However, the absence of an increase in neoplasms in the 100 mg/kg bw/day group in the presence of increased hyperplasia makes the association with treatment uncertain (NTP, 2001).

Justification for classification or non-classification

The available data suggests that the test substance is not carcinogenic to humans. Although studies provided evidence of carcinogenicity in mice, it was concluded that this was due to the presence of a contaminant - free diethanolamine (DEA, EC no. 203-868-0, CAS no. 111-42-2) - in the test substance. DEA has been shown to be a non-genotoxic carcinogen in mice. However, the proposed mode of action indicates a rodent-specific phenomenon involving choline depletion which is unlikely to be relevant in humans. This evaluation is supported by a decision of a scientific board by National Toxicology Program (NTP) after a public hearing at which it was decided that DEA should not be listed as a carcinogen under the RoC (Report on Carcinogens) process. DEA has also recently been reviewed in the EU under the REACH regulation and no classification for carcinogenicity has been proposed (https://echa.europa.eu/registration-dossier/-/registered-dossier/15770/2/1/?documentUUID=b015c4bf-61f0-4b7b-b858-cfe6f686f088). Therefore, based on the overall weight of evidence of the available information, C8-18 and C18-unsatd. DEA does not require classification for carcinogenicity according to CLP (EC 1272/2008) criteria.