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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August 2000-October 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Reliability 1a - OECD Guideline No. 407 GLP-compliant study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA Guideline 799, 9620-62-158
Deviations:
no
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): 11-AMINOUNDECANOIC ACID
- Physical state: Solid (powder)
- Lot/batch No.: USA000523365
- Expiration date of the lot/batch: May 2001
- Storage condition of test material: At room temperature, protected from light and humidity, under nitrogen atmosphere

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK, Margate, UK
- Age at study initiation: 6 weeks
- Weight at study initiation: 146-260 g
- Fasting period before study: No
- Housing: 2 rats of same sex and group in suspended wire-mesh cages (43x21.5x18 cm)
- Diet : ad libitum
- Water : ad libitum
- Acclimation period: 9 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2
- Humidity (%): 50 +/- 20
- Air changes (per hr): 12 cycles
- Photoperiod (hrs dark / hrs light): 12/12 (7.00am-7.00pm)


IN-LIFE DATES: From: 22 August 2000 To: 29 September 2000

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Powder maintenance diet UAR A04C P 2.5
- Storage temperature of food: At room temperature
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity and stability of the dietary admixtures were checked in a previous rat study in the same test facility (CIT 20436 RSR - see section 7.8.2) at 2000 ppm and 30000 ppm. Homogeneity and stability were also checked at 1250 ppm in the present study.
Stability was checked on samples taken from dietary admixtures after 0 and 10 days of storage in closed bags and 0, 5 and 9 days of storage in open feeder.
Concentrations were determined for a sample taken from each dietary admixture including controls in weeks 1 and 4.
The analytical data indicated that the variance between nominal and actual dosage was acceptable.
The concentrations of 1250, 5000 or 20000 ppm corresponded to achieved dosages of 118, 472 or 1644 mg/kg/day for the males and 129, 507 or 1828 mg/kg/day for the females.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Dietary exposure at constant concentrations
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1250, 5000 and 20000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
118, 472 and 1644 mg/kg/day
Basis:
other: Based on analytical verification
No. of animals per sex per dose:
6
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: No data
- Post-exposure recovery period in satellite groups: Not applicable
Positive control:
Not included

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly


BODY WEIGHT: Yes
- Time schedule for examinations: once weekly


FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 28
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5 per sex and per dose
- Standard toxicity study parameters were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 28
- Animals fasted: Yes
- How many animals: 5 per sex and per dose
- Standard toxicity study parameters were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: day 28
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Standard toxicity study parameters were examined.


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: end of week 4
- Dose groups that were examined: all (5 rats per sex)
- Battery of functions tested: sensory activity / grip strength / motor activity / other: vision, audition, reflexes


OTHER: rectal temperature at the end of week 4
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
A complete macroscopic post-mortem examination was performed on all study animals, including examination of external surfaces, all orifices, cranial cavity, external surface of bain and spinal cord, thoracic, abdominal and pelvic cavities with the associated organs and tissues, and neck with the associated organs and tissues.

HISTOPATHOLOGY: Yes
Microscopic examination was performed for the first 5 animals on :
- all the following tissues for control and high-dose groups: macroscopic lesions, adrenals, brain, cecum, colon, duodenum, epididymides, esophagus, heart, ileum, jejunum, kidneys, liver, lungs with bronchi, lymph nodes, ovaries, sciatic nerve, seminal vesicles, spinal cord, spleen, stomach with forestomach, testes, thymus, thyroids with parathyroids, trachea, urinary bladder, uterus, vagina,
- kidneys for low- and intermediate-dose groups,
- sternum with bone marrow for males of control and high-dose groups.
Other examinations:
Not included
Statistics:
Statistical analysis was perfomed on bodyweight, food consumption, hematology, blood chemistry, urinalysis and organ weight data, using a statistical decision tree to select the most appropriate test for each parameter.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
BODY WEIGHT AND WEIGHT GAIN
At 5000 ppm, a slight and transitory decrease (not statistically significant) in body weight gain in males during weeks 2 and 3 was noted and was not considered as an adverse effect.
At 20000 ppm, a decrease in body weight gain in both males and females was noted during weeks 1, 2 and 3.
These dose-related decreases in body weight gain correlated with lower food consumption values.

HAEMATOLOGY
At 20000 ppm, decrease in hemoglobin concentration, packed cell volume, mean cell volume and mean cell hemoglobin, decrease in Activated Partial Thromboplasmin (APTT) and increase in fibrinogen level were noted in males.
Treated females at 20000 ppm showed also a tendency to lower hemoglobin concentration, lower packed cell volume, decreased APTT values and increased fibrinogen level.
These differences in red blood cell or coagulation parameters observed in the 20000 ppm group were considered to be related to treatment with the test substance.

CLINICAL CHEMISTRY
At 20000 ppm, a decrease in inorganic phosphorus levels, an increase in urea and triglyceride levels and a decrease in alkaline phosphatase or alanine aminotransferase activities were noted in treated males.
Increased urea levels were noted among treated females at 20000 ppm.
The above-mentioned differences noted in the 20000 ppm group were considered to be the consequence of treatment with the test substance.

ORGAN WEIGHTS
At 5000 or 20000 ppm, the absolute and relative kidney weights were higher when compared to controls, as follows:

Concentration (ppm) 5000 20000
-----------------------------------------------------
Males +15 (+21) +23 (+41**)
Females +10 (+7) +52** (+64**)
-----------------------------------------------------
relative weight in brackets; **: p<0.01

At 20000 ppm, these differences correlated with macroscopic and microscopic findings in the kidneys and were attributed to treatment with the test substance.

GROSS PATHOLOGY
At 5000 ppm, grey/green color of the kidneys was observed in 1/6 males.
At 20000 ppm, grey/green color of the kidneys was observed in 3/6 males (associated with enlargement or irregular color in one male); greyish/whitish or yellowish areas were noted in 5/6 females.
These abnormalities observed among the 5000 or 20000 ppm groups correlated with higher kidney weights and were considered to be treatment-related.

HISTOPATHOLOGY: NON-NEOPLASTIC
At 20000 ppm, lesions of the renal papilla were seen in 5/5 females (e.g. acute inflammatory cells infiltration, hyperplasia of the epithelium, dilatation of collecting ducts) and both sexes showed cortical tubular dilatation.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
5 000 ppm
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
20 000 ppm
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The dose level of 5000 ppm of 11-aminoundecanoic acid (corresponding to 472 mg/kg/day for the males and 507 mg/kg/day for the females) was established as a NOAEL in this 28-day study in rats by dietary administration.
At this dose-level, there was only a slight decrease in body weight gain (not statistically significant), correlating with lower food consumption in males.
Executive summary:

In a repeated-dose toxicity study (G. Chevalier, CIT, 2001) complying with OECD Guideline 407 (Repeated Dose 28-day Oral Toxicity Study in

Rodents), Sprague-Dawley rats (6 per dose and per sex) received plain diet (controls) or 11-AMINOUNDECANOIC ACID (batch No.

USA000523365) mixed in the diet at constant concentrations of 1250, 5000 or 20000 ppm for 4 weeks.

Examinations and measurements included mortality, clinical signs, functional observation battery (for potential signs of neurotoxicity), bodyweight,

food consumption, hematology, blood biochemistry, urinalysis, gross examination at necropsy, and histopathology.

Based on analytical verifications, the achieved dosages were 118, 472 and 1644 mg/kg/day for the males and 129, 507and 1828 mg/kg/day for the

females, for the 1250, 5000 and 20000 ppm concentrations, respectively.

At 5000 ppm, a slight and transitory decrease in bodyweight gain was noted for males in weeks 2 and 3 was but was not considered significant. At

20000 ppm, decreased bodyweight gain was observed for both genders in weeks 1, 2 and 3, correlating with a lower food consumption.

Decreased hemoglobin concentration, packed cell volume, mean cell volume and mean cell hemoglobin, activated partial thromboplastin time and

increased fibrinogen level were obserevd in males given 20000 ppm. Females given 20000 ppm also showed a tendency to lower hemoglobin

concentration, packed cell volume, activated partial thromboplasmin and increased fibrinogen level. Decreased inorganic phosphorus plasma

concentrations, increased urea and triglyceride plasma concentrations, and decreased alkaline phosphatase and alanine aminotransferase

activities were also observed for males given 20000 ppm. Increased urea plasma concentrations were noted among females given 20000 ppm. All

these clinical chemistry changes at the high dose were attributed to 11-AMINOUNDECANOIC ACID.

At 5000 or 20000 ppm, the absolute and relative kidney weights were higher (up to +52% and +64%, respectively) than in controls. This correlated with 
grey/green color of the kidneys in some males given 5000 or 20000 ppm, and greyish/whitish or yellowish areas in most females given 20000 ppm. 
Microscopic examination showed lesions of the renal papilla (e.g. acute inflammatory cell infiltration, epithelium hyperplasia, dilatation of collecting
 ducts) in all females given 20000 ppm. Cortical tubular dilation was noted for both genders at the high dose. All these pathology changes were 
attributed to 11-AMINOUNDECANOIC ACID.Consequently, under the conditions of this study, 5000 ppm of 11 -AMINOUNDECANOIC ACID in diet 
(equivalent to 472 and 507 mg/kg/day for males and females, respectively) was established as a No Observed Adverse Effect Level (NOAEL) following 
4 weeks of administration.