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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: 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:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other 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 is applied daily to the skin in graduated doses to several groups of experimental animals, 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: Unstable 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:
rat
Strain:
Fischer 344
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: 14 to 15 d

ENVIRONMENTAL CONDITIONS
- Temperature : 22.2 -23.9°C
- Humidity : 38-55 %
- Air changes : 10/hr
- Photoperiod : 12 h dark/12 h light

IN-LIFE DATES: From: Feb. 10, 1992 To: May 13, 1992

Administration / exposure

Type of coverage:
open
Vehicle:
ethanol
Details on exposure:
Not reported


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 analysed.
Duration of treatment / exposure:
14 wk
Frequency of treatment:
5 exposures/wk
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 50, 100, 200, or 400 mg/kg bw (0, 30, 61, 121, 243, or 485 mg/mL in ethanol)
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10/sex/dose in the core study, 10/sex/dose for clinical pathology groups
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


HAEMATOLOGY: Yes
- Time schedule for collection of blood: On Days 4 and 24 (blood was collected from the retroorbital sinus of clinical pathology study male and
female rats from each dose group)
- Anaesthetic used for blood collection: Yes (carbon dioxide/oxygen mixture)
- How many animals: All animals
- Parameters checked in table [No.?] were examined.: Hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, nucleated erythrocyte, and platelet counts; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On Days 4 and 24 (blood was collected from the retroorbital sinus of clinical pathology study male and
female rats from each dose group)
- How many animals: All animals
- Parameters checked in table [No.?] were examined: Urea nitrogen, creatinine, total protein, albumin, cholesterol, triglycerides, alanine aminotransferase, alkaline phosphatase, sorbitol dehydrogenase, and total bile acids


OTHER: Organs weighed were heart, right kidney, liver, lung, right testis, and thymus
Sacrifice and pathology:
SACRIFICE: At the end of the 14 wk studies, blood was collected from the retroorbital sinus of all core study rats for hematology and clinical chemistry analyses. Thereafter the test animals were anesthetised with a carbon dioxide/oxygen mixture.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes. Complete histopathology was performed on 0 and 400 mg/kg bw. In addition to gross lesions and tissue masses, the following tissues were examined: 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. In addition, the skin (site of application) was examined in all core study animals, and the kidney was examined in core study male and female rats.
Other examinations:
Sperm motility and vaginal cytology: At the end of the studies, samples were collected for sperm motility or vaginal cytology from all rats receiving 100, 200 and 400 mg/kg bw of test material. 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 rats. 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:
effects observed, treatment-related
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:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
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: Clinical findings included irritation of the skin at the site of application in 100, 200, and 400 mg/kg bw males and females.


BODY WEIGHT AND WEIGHT GAIN: Final mean body weights and body weight gains of 200 and 400 mg/kg bw males and females were significantly less than those of the vehicle controls.



HAEMATOLOGY: At week 14, a minimal microcytic, normochromic, nonresponsive anemia occurred in the 100 and 200 mg/kg bw females and 400 mg/kg bw males and females. The anemia also occurred in the 400 mg/kg bw males and females on Day 24. Increased segmented neutrophil counts occurred in 400 mg/kg bw males and females at week 14 and in 400 mg/kg bw females on Day 24.


CLINICAL CHEMISTRY: Cholesterol concentrations were significantly decreased in 200 and 400 mg/kg bw males and in females administered 100 mg/kg bw or greater; triglyceride concentrations were also decreased in 200 and 400 mg/kg bw males. At week 14, there was a minimal concentration-related increase of serum albumin concentration in all treated groups of females and in 100 mg/kg bw or greater male rats; on Day 24, increased albumin concentration occurred in the 400 mg/kg bw females. There were minimal increases of urea nitrogen concentration that occurred in the 200 and 400 mg/kg bw female rats on Day 24 and at week 14. At week 14, an increase in alanine aminotransferase activity occurred in 50 mg/kg bw or greater male rats. Additionally, alkaline phosphatase activity was increased in 400 mg/kg bw males.



ORGAN WEIGHTS: Kidney weights of females administered 50 mg/kg bw or greater were significantly greater than those of the vehicle control group. Left epididymis weights of 200 and 400 mg/kg bw males were significantly less than those of the vehicle controls, but this was most likely secondary to decreased mean body weights in these groups



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. The incidences of renal tubule regeneration in 100, 200, and 400 mg/kg bw females were significantly greater than the vehicle control incidence, and the severities in 200 and 400 mg/kg bw females were increased.


OTHER: Estrous cycle lengths of dosed females were similar to those 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 the test material was considered to be 50 mg/kg bw .
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 F344/N rats. The study was performed in compliance with Food and Drug Administration Good Laboratory Practice Regulations (21 CFR, Part 58).

Groups of 10 male and 10 female rats were administered 0, 25, 50, 100, 200, or 400 mg/kg bw of amides, C8 -18 and C18 -unsatd., N, N-bis(hydroxyethyl) in ethanol by dermal application for 14 wk.

 

All rats survived until the end of the study. Final mean body weights and body weight gains of 200 and 400 mg/kg bw males and females were significantly less than those of the vehicle controls. Clinical findings included irritation of the skin at the site of application in 100, 200, and 400 mg/kg bw males and females. Hematological changes include minimal microcytic anemia at the end of the treatment period. Decreases in cholesterol and triglyceride concentrations were observed in the higher group rats.

Histopathological lesions of the skin at the site of application included epidermalhyperplasia, 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. The incidences of renal tubule regeneration in 100, 200, and 400 mg/kg bw females were significantly greater than the vehicle control incidence, and the severities in 200 and 400 mg/kg bwfemales were increased.

 

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 body weight.