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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Not available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for data waiving:
other:
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
secondary source
Title:
Unnamed
Year:
2001

Materials and methods

Principles of method if other than guideline:
The test substance was applied daily to the skin in graduated doses to several groups of mice, one dose per group, for a period of 14 wk. During the period of application the animals are observed daily to detect signs of toxicity. Animals which die during the test are necropsied, and at the conclusion of the test the surviving animals were sacrificed and necropsied.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Coconut oil acid diethanolamine condensate
- Physical state: Viscous yellow liquid
- Composition of test material, percentage of components: Composed primarily of diethanolamides of coconut oil acids, with unreacted diethanolamine, alkanolamides of unsaturated acids, and amine salts of the acids. The polar nitrosamine, N-nitrosodiethanolamine, was detected at a concentration of 219 ppb
- Lot/batch No.: 1G01742286
- Stability: Instable when stored in glass tubes for 2 wk at 60°C
- Storage condition of test material: At room temperature, protected from light, in amber glass bottles sealed with Teflon- lined caps

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, 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 (P.J. 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: 16 to 17 d

ENVIRONMENTAL CONDITIONS
- Temperature : 20.6 -22.8 °C
- Humidity : 41-58 %
- Air changes : 10/h
- Photoperiod : 12 h dark/12 h light

IN-LIFE DATES: From: Feb. 12, 1992 To: May 15, 1992

Administration / exposure

Type of coverage:
open
Vehicle:
ethanol
Details on exposure:
The test material formulations were applied on shaved skin of the test animals.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of the dose formulations of test material were conducted at the study laboratory using HPLC. Dose formulations from the beginning, middle, and end of the studies were analyzed
Duration of treatment / exposure:
14 wk
Frequency of treatment:
5 exposures/wk
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 50, 100, 200, 400 and 800 mg/kg bw (0, 20, 40, 80, 160, or 320 mg/mL ethanol)
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10/sex/dose group
Control animals:
yes, concurrent vehicle
Details on study design:
No information
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly once


BODY WEIGHT: Yes
- Time schedule for examinations: Weighed initially, weekly, and at the end of the studies


OTHER: Organs weighed were heart, right kidney, liver, lung, right testis, and thymus
Sacrifice and pathology:
SACRIFICE: Yes (Carbon dioxide asphyxiation)
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes. Complete histopathology was performed on 0 and 800 mg/kg bw 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, spleen, stomach (forestomach and glandular), testis (and epididymis and seminal vesicle), thymus, thyroid gland, trachea, urinary bladder, and uterus.
Other examinations:
Sperm motility and vaginal cytology: At the end of the studies, samples were collected for sperm motility or vaginal cytology from mice of 200, 400 and 800 mg/kg bw groups. The following sperm motility parameters were evaluated: spermatid heads per gram of testis, spermatid heads per testis, spermatid count, and epididymal spermatozoal motility and concentration. The left cauda epididymis, epididymis, and testis were weighed. Vaginal samples for cytology evaluations were collected for 12 consecutive days prior to the end of the studies from all female mice. The length of the estrous cycle and the length of time spent in each stage of the cycle were evaluated.
Statistics:
Not reported

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
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:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: The only treatment related clinical finding was irritation of the skin at the site of application in males and females administered 800 mg/kg bw. All mice survived until the end of the study.


BODY WEIGHT AND WEIGHT GAIN: Final mean body weights and body weight gains of dosed males and females were similar to those of the vehicle controls


ORGAN WEIGHTS: The absolute and relative liver and right kidney weights of 800 mg/kg bw males and females and the absolute and relative liver weights of 400 mg/kg bw females were significantly greater than those of the vehicle controls. The absolute and relative lung weights of 800 mg/kg bw females were also significantly greater than those of the vehicle controls.



HISTOPATHOLOGY: Histopathologic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, chronic active inflammation, parakeratosis, and ulcer. The incidences and severities of these skin lesions generally increased with increasing dose in males and females


OTHER: Epididymal spermatozoal concentration was significantly increased in 800 mg/kg bw males. Estrous cycle lengths of dosed females were similar to that of the vehicle controls

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 50 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of amides, C8 -18 and C18 -unsatd., N, N-bis(hydroxyethyl) was considered to be 50 mg/kg bw in mice.
Executive summary:

A study was conducted to evaluate the subchronic toxic effects of amides, C8 -18 and C18 -unsatd., N, N-bis(hydroxyethyl) when administered by dermal route in B6C3F1 mice. The study was performed in compliance with FDA GLP.

Groups of 10 male and 10 female mice were administered 0, 25, 50, 100, 200, 400, or 800 mg/kg bw by dermal application for 14 wk.

 

All mice survived until the end of the study. There were no treatment related effects on body weight. The only treatment related clinical finding was irritation of the skin at the site of application in males and females administered 800 mg/kg bw. Weights of the liver and kidney of 800 mg/kg bw males and females, liver of 400 mg/kg bw females, and lung of 800 mg/kg bw females were significantly increased compared to the vehicle controls. Epididymal spermatozoal concentration was significantly increased in 800 mg/kg bw males. Histopathologic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, chronic active inflammation, parakeratosis, and ulcer. The incidences and severities of these skin lesions generally increased with increasing dose in males and females.

 

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of amides, C8 -18 and C18 -unsatd., N, N-bis(hydroxyethyl) was considered to be 50 mg/kg bw in mice.