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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From: February 1, 1989 To: March 2, 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
2c: Comparable to guideline study with acceptable restriction. Justification for read-across : a read across approach is proposed with heptanoic acid for the 28 day toxicity study as it was shown from pharmacokinetic study (Jaillet, 2013, see section 7.1.1 and document for read across justification attached in section 13 ) that Heptanal oral administration to rats allows rapid generation of significant heptanal plasma levels which confirmed that heptanoic acid is a metabolite of Heptanal. Furthermore, it is known from the litterature that aldehydes are rapidly oxidized to the corresponding carboxylic acids that is subsequently completely oxidized to carbon dioxide and water in the fatty acid pathway and tricarboxylic acid cycle.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Heptanoic acid
EC Number:
203-838-7
EC Name:
Heptanoic acid
Cas Number:
111-14-8
Molecular formula:
C7H14O2
IUPAC Name:
heptanoic acid
Details on test material:
- Name of test material (as cited in study report): heptanoic acid
- Substance type: carboxylic acid
- Physical state: clear colorless liquid
- Lot/batch No.: 00809TE
- Storage condition of test material: amber jars under refrigeration

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 45 days old
- Weight at study initiation: 209.5 -251.5 g for the males, 149.4-189.1 g for the females
- Fasting period before study:
- Housing: individually in hanging, stainless-steel wire cages
- Diet : ad libitum (Purina certified rodent chow 5002)
- Water : ad libitum (tap water)
- Acclimation period: yes (14-day quarantine period)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 (19-26)
- Humidity (%): 50 +/6 20
- Air changes (per hr): no data
- Photoperiod : 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: February 1, 1989 To: March 2, 1989

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: A calculated amount of test material was placed in the desiccator for 20 minutes. The test material was placed in the desiccator for 20 minutes. The test material was weighed into a volumetric flask of appropriate size and using an analytical balance (corn oil) was added to achieve the appropriate volume. The container was mixed by inversion and agitation for approximately two minutes until a solution was achieved.


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the dosing and vehicle control solutions from the first day and last day of dosing (except for 3500 mg/kg/day group) were retained and sent to sponsor for verification of concentration.
Duration of treatment / exposure:
27 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 875, 1750 and 3500 mg/kg/day
Basis:
nominal in diet
No. of animals per sex per dose:
20 (10 females and 10 males)
Control animals:
yes, concurrent vehicle
Positive control:
No

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to initiation (10 animals) and at termination (all surviving animals)
- Anaesthetic used for blood collection: Yes (ketamine)
- Animals fasted: Yes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to initiation (10 animals) and at termination (all surviving animals)
- Animals fasted: Yes

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
ANOVA, then Dunnett's Comparison.

Results and discussion

Results of examinations

Clinical signs:
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:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Six animals (one male and five females) died prior to study termination. A variety of histopathologic changes were present in five of the six unscheduled deaths. The cause of death for these five animals was considered related to gavage administration. In one low-dose female marked pyelonephritis and inflammation throughout the lower urinary tract with an associated urinary calculus were present. The most noted observation was wheezing in the high-dose males and mid- and high-dose females. The findings was considered treatment related. Sporadic observations including hunched posture, thin, soft, few or no feces, excretion from penis, dyspnea, polypnea, urine stains, alopecia, rough haircoat, sores and squinted eyes were also noted through out the groups.


BODY WEIGHT AND WEIGHT GAIN
Statistical analysis revealed a significant decrease between the control and high-dose males for mean body weight gain. The findings were considered treatment related. The findings for females did not reveal a significant difference for treated compared to control animals.

FOOD EFFICIENCY
Statistical analysis revealed a significant decrease between the control and high-dose males for total food consumption. The findings were considered treatment related. The findings for females did not reveal a significant difference for treated compared to control animals.

OPHTHALMOSCOPIC EXAMINATION
not performed

HAEMATOLOGY
The mean hemoglobin and hematocrit values were significantly decreased for high-dose males. The finding was considered to be incidental and of no apparent toxicological significance.

CLINICAL CHEMISTRY
No significant findings were noted in the clinical chemistry data.

URINALYSIS
not performed

NEUROBEHAVIOUR
not performed

ORGAN WEIGHTS
Statistically significant findings for the absolute and relative organ weight (adrenal, heart, brain w/stem, testis/epidid) were sometimes observed. As this findings were not associated with a morphological change, they were not considered to be toxicologically significant.

GROSS PATHOLOGY
In the animals sacrificed at study termination, the most notable gross pathology findings were exhibited by the stomach and consisted of thickened or rough mucosa. These findings were observed only in the high-dose animals of both sexes and were considered treatment related. One low dose female exhibited signs of urinary tract inflammation and/or renal failure. The finding was not associated with treatment. Other findings were considered incidental.

HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment-related changes consisting of hyperkeratosis were present in the non-glandular region of the stomach of almost all of the high-dose male and female terminally sacrificed animals. This change correlates with the rough and thickened mucosa noted in the non-glandular region of the stomach at necropsy. Hyperkeratosis was generally diffuse and was graded minimal to moderate. The presence of this change suggests a mild local irritating effect associated with the gavage administration of heptanoic acid. There was however no evidence of degeneration/necrosis or inflammation. Microscopic examination of the non-glandular region of the stomach in the 850 and 1750 mg/kg/day groups showed no evidence of hyperkeratosis. Histopathologic changes present in the animals that died prior to study termination nearly all appeared to be gavage related or considered typical spontaneous lesions for this age and strain of test animal and occured in all groups with similar incidence and severity. The cause of death for five of the six animals dying during the study were considered to be gavage administration. The other animal died due to renal failure or urinary tract inflammation.



OTHER FINDINGS

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 750 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Based on few signs exhibited by the animals at this dosage.
Dose descriptor:
LOAEL
Effect level:
3 500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Based on decreased body weights and food consumption, gross lesions of the stomach, microscopic lesions of the non-glandular region of the stomach and mortality.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this test, the high-dose animals (3500 mg/kg/day of heptanoic acid) exhibited wheezing; decrease in body weight change and total food consumption (males only); gross lesions of the stomach and microscopic lesions in the non-glandular region of the stomach. The few signs exhibited by the animals receiving 1750 mg/Kg/day, or less, suggested that these animals were unaffected by treatment.
Executive summary:

Under a repeated toxicity test (Hazleton, 1990), the test material, heptanoic acid, was administered to male and female Sprague-Dawley rats by oral gavage for 27 consecutive days in order to evaluate the subchronic toxicity. Animals were necropsied on test day 30. Corn oil was used as the vehicle. Dose levels were 0, 875, 1750 and 3500 mg/kg/day. Criteria evaluated included mortality, cageside and detailed clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, organ-to-body weight ratios, gross pathology, and histopathology. Six animals (3 low-dose females, two high-dose females and one high-dose male) died during the study. The cause of death for five of the six unscheduled deaths was considered related to gavage administration. In one low-dose females marked pyelonephritis and inflammation throughout the lower urinary tract with an associated urinary calculus were present which was considered as a typical spontaneous lesions for this age and strain of test animal. Treatment-related findings included physical signs such as salivation, languid behavior, polypnea, dyspnea, tremors, wheezing, thin appearance, ataxia and hunch posture; these findings were observed, predominately in the high-dose animals, approximately one hour post-dosing. At the weekly observations which were performed prior to dosing only respiratory distress (wheezing) was exhibited by the high-dose males and mid- and high-dose females. The mean body weight change and mean total food consumption in high-dose males was significantly decreased compared to control males. Pathology findings included hyperkeratosis that was present in the non-glandular region of the stomach of almost all of the high-dose male and female animals sacrificed at termination. Hyperkeratosis was generally diffuse and was graded minimal to moderate. This change correlates with the rough and thickened mucosa noted in the non-glandular region of the stomach at necropsy. The presence of this change suggests a mild local irritating effect associated with the gavage administration of heptanoic acid. There was however no evidence of degeneration/necrosis or inflammation. Microscopic examination of the non-glandular region of the stomach in the low- and mid-dose groups showed no evidence of hyperkeratosis.

In conclusion the high-dose animals (3500 mg/kg/day of heptanoic acid) exhibited wheezing; decrease in body weight change and total food consumption (males only); gross lesions of the stomach and microscopic lesions in the non-glandular region of the stomach. The few signs exhibited by the animals receiving 1750 mg/kg/day, or less, suggested that these animals were unaffected by treatment.

Based on decreased body weights and food consumption, gross lesions of the stomach, and microscopic lesions of the non-glandular region of the stomach at 3500 mg/kg/day, the lowest observable adverse effect level (LOAEL) and the no observable adverse effect level (NOAEL) for heptanoic acid were concluded to be 3500 and 1750 mg/kg/day, respectively.

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