Registration Dossier

Toxicological information

Acute Toxicity: oral

Currently viewing:

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 17 APR 1996 to 07 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 chemical should exhibit comparable toxicity profiles:
-6-(isononanoylamino)hexanoic acid, compound with 2,2`,2``-nitrilotriethanol

It is proposed to use the toxicity data of the mentioned source chemical to fulfill the data requirement for the target chemical.

The underlying scientific rationale for the use of corresponding salt as source chemical is apparent. The target 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 2,2`,2``-nitrilotriethanol. The proposed source chemical can be formally described as carboxylate of the target 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 proposed read-across consideration.

The proposed approach applies for all exposure routes (oral/dermal/inhalation), because both the target chemical and source chemical are expected to be bioavailable by all exposure routes: the inter-conversion between carboxylic acid and carboxylate is likely to occur prior to resorption; 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; CAS: 71902-23-3
Source chemicals:
6-(isononanoylamino)hexanoic acid, compound with 2,2`,2``-nitrilotriethanol; CAS: 85702-79-0


The target chemical is a mono-substituent substance, the analytical purity being >99%. The source chemical is the further chemically processed products (dissolved in water with 2,2`,2``-nitrilotriethanol) 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, compound with 2,2`,2``-nitrilotriethanol as source chemical:

- The given source chemical is an ionic compound that results from the neutralization reaction of the target 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 target 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 source chemical.
- Comparable findings were obtained in the 28-day oral toxicity study for the given source chemical and in the above mentioned two 7-day repeated oral toxicity studies. Further special histopathological investigation revealed the alpha-2µ-globulin accumulation in male kidneys and the peroxisome proliferation in liver.
- In the available skin sensitization data the given source chemical was applied using water as vehicle. The dissociation into the target chemical and 2,2`,2``-nitrilotriethanol is expected to have occurred prior to resorption, so that the animals must have been exposed to the target chemical.

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:
other: fluid

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: 188 g; females mean: 162 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:
water
Remarks:
deionised
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20% suspension
- 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:
squatting posture, decreased spontaneous activity, stilted gait. The clinical symptoms had reversed 4 to 6 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 deionised water). Body weight development was not impaired, general clinical signs observed were reversible within 6 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.