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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 11 APR 1996 to 02 MAY 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
[Describe why the read-across can be performed (e.g. common functional group(s), common precursor(s)/breakdown product(s) or common mechanism(s) of action]

It is hypothesized that the target chemical and the following chemical as source chemicals should exhibit comparable toxicity profiles:
• 6-(isononanoylamino)hexanoic acid


It is proposed to use the toxicity data of the mentioned source chemicals to fulfill the data requirement for the target chemical on the human health endpoint. The chemical is the corresponding acid of the target chemical.

The underlying scientific rationale for the use of corresponding acid as source chemical is apparent. The target chemical is the 2,2`,2``-nitrilotriethanol (TEA) salt of the source chemical. The source chemical is a weak acid due to the terminal carboxylic acid moiety and can be neutralized/dissolved in aqueous system by reaction with base such as TEA. The target chemical can be formally described as carboxylate of the source chemical. As the carboxylate and carboxylic acid are inter-convertible, it is apparent that source and target chemicals are inter-convertible and should exhibit comparable toxicity profile. The base 2,2`,2``-nitrilotriethanol is a well-investigated substance and is considered to be less relevant for the toxicological assessment.

The proposed approach applies for all exposure routes (oral/dermal/inhalation), because both the target chemical and source chemicals are expected to be bioavailable by all exposure routes and the systemic release of the presumed metabolite is less dependent on exposure route.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
[Provide here, if relevant, additional information to that included in the Test material section of the source and target records]

Target chemical:
6-(isononanoylamino)hexanoic acid, compound with 2,2`,2``-nitrilotriethanol; CAS: 85702-79-0

Source chemicals:
6-(Isononanoylamino)hexanoic acid; CAS: 71902-23-3


The target chemical is a mono-substituent substance, the analytical purity being >99%. The source chemical is the raw materials (6-(isononanoylamino) hexanoic acid) of the target chemical. A toxicity difference due to different impurity profiles is not likely to occur.

3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]

Justification for the use of 6-(isononanoylamino)hexanoic acid as source chemical:

- The target chemical is an ionic compound that results from the neutralization reaction of the given source chemical and 2,2`,2``-nitrilotriethanol. When it is dissolved in an aqueous system or in a biological fluid, an immediate dissociation occurs to give the source chemical and the base, thereby explaining the expected comparable toxicity profile to that of target chemical.
A significant toxicity contribution of 2,2`,2``-nitrilotriethanol is not expected. 2,2`,2``-nitrilotriethanol is a well investigated substance. It is of low toxicity and the available kinetic data are demonstrative of efficient elimination mechanisms in animal models.

- In order to verify the expected toxicity comparability, the given source and the target chemicals were investigated under identical testing conditions. Both substances exhibited comparable findings after 7-day oral application to rat:
liver and kidney enlargement
decrease of eosinophil counts
peroxisome proliferation in the liver
The decrease of eosinophil counts is possibly a transient effect, associated with the peroxisome proliferation stimulating effect of test compounds. No such findings were present after 28-day treatment of the target chemical.

- Comparable findings were obtained in the 28-day oral toxicity study for the target chemical and in the above mentioned two 7-day repeated oral toxicity studies with the source and the target substance. Further special histopathological investigation revealed the alpha-2u-globulin accumulation in male kidneys and the peroxisome proliferation in liver.


4. DATA MATRIX

Data matrix and other information see the attached read-across justification in chapter 13

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Remarks:
according to Principles of Good Laboratory Practice, annex of paragraph 19a, section 1 of the chemical law of July 25, 1994
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst Aktiengesellschaft, Kastengrund, SPF breeding colony, Germany
- Age at study initiation: male animals approximately 7 weeks; female animals approximately 8 weeks
- Weight at study initiation: males mean: 182 g; females mean: 172 g
- Fasting period before study: from about 16 hours before to 3 - 4 hours after treatment
- Housing: in fully air-conditioned rooms in macrolon cages (type 4) on soft wood granulate in groups of 5 animals
- Diet: ssniff R/M-H (V 1534), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least one day (breeding at identical conditions)

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): fully air conditioned rooms
- Photoperiod (hrs dark / hrs light):12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: starch mucilage (potato starch in deionised water)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20% suspension in 2% starch mucilage
- Amount of vehicle (if gavage): 10 mL/kg bw
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: symptoms were recorded twice every day (in the morning and in the afternoon), on weekends and public holidays only once.
- Frequency of and weighing: weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no animal died during the 14-day observation period
Mortality:
No deaths occurred during the whole study.
Clinical signs:
The following clinical signs were observed after the application of the test material:
sunken flanks, squatting posture, decreased spontaneous activity, irregular respiration, stilted and uncoordinated gait. The clinical symptoms had reversed 6 to 8 hours after application.
Body weight:
Development of body weight was not impaired.
Gross pathology:
The animals killed at the end of the observation period showed no macroscopically visible changes.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Single oral application of 2000 mg test substance per kg body weight via gavage did not cause lethality in male and female Wistar-rats during the 14 day observation period, resulting in a LD50 > 2000 mg/kg bw.
Executive summary:

10 Wistar-rats (5 males and 5 females) were subjected to test acute oral toxicity. The test substance was administered by gavage at a dose of 2000 mg/kg body weight (vehicle starch mucilage). Body weight development was not impaired, general clinical signs observed were reversible within 8 hours after substance application and there were no macroscopically visible changes found. No animal died during the 14 day observation period, resulting in a LD50 > 2000 mg/kg bw.