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Description of key information

The NOAEL of 300 mg/kg bw/d obtained from the sub-chronic oral repeated dose toxicity study, with the read-across substance partially unsaturated TEA-Esterquat was used to evaluate repeated dose toxicity of Fatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternized.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The hypothesis for this analogue approach is that target and source substances, being different compounds, have similar (eco) toxicological properties based on structural similarity with common functional groups; a quaternized ethanolamine moiety, one to three ester groups with a typical UVCB distribution with long-chain fatty acids of natural origin.
Furthermore identical precursors (triethanolamine, long-chain fatty acids, dimethyl sulphate) are used for manufacturing. Therefore common breakdown products via physical and biological processes, which result in structurally similar chemicals, are evident.
For further information refer to general justification for read-across attached to chapter 13 of this IUCLID file.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See general justification for read-across attached to chapter 13 of this IUCLID file.

3. ANALOGUE APPROACH JUSTIFICATION
See general justification for read-across attached to chapter 13 of this IUCLID file.

4. DATA MATRIX
See general justification for read-across attached to chapter 13 of this IUCLID file.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Species:
rat
Route of administration:
oral: gavage
Key result
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No substance related effects in this dose group
Remarks on result:
other: 90 day study
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: highest tested dose, no treatment related effects et all
Remarks on result:
other: 28 day study
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
System:
urinary
Organ:
bladder
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
System:
gastrointestinal tract
Organ:
other: forestomach
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
no
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No experimental data are available for the assessment of repeated dose toxicity of the target substanceFatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternized. However, reliable relevant data are available for the closely related source substance partially unsaturated TEA-Esterquat. 

In a subchronic toxicity study according to OECD guideline 407 (1995) and EU method B7 (1996) the test substance partially unsaturated TEA-Esterquat, was administered to 5 CD rats/sex/dose by gavage at dose levels of 0,100, 300 and 1000 mg/kg bw/day for 28 days. A satellite group of 5 males and 5 female for the control and high dose group was included to assess the reversibility of any effects after a 2-week recovery period.

No mortality and no influence on behavior, external appearance, body weight, food and drinking water consumption, the eyes or optic region, the haematological and clinical-biochemical parameter and the relative or absolute organ weights at any of the tested dose levels was noted. No test item-related changes were revealed during neuropharmacological functional observations in any of the dosed groups.

Macroscopic post mortem examination and histopathology including the reproductive organs (epididymis, ovary, prostate, testicle and uterus) revealed no test item related changes in treated animals. There is no evidence for a specific target organ toxicity in this study.

Under test conditions, the NOAEL was above 1000 mg/kg bw /day in this 4- week subchronic toxicity study.

The analytical verification of dosing solutions demonstrated agreement of actual initial concentrations with nominal test concentrations.

 

In a subchronic toxicity study comparable to OECD guideline 408 (1981) partially unsaturated TEA-Esterquat was administered to 10 Sprague-Dawley rats/sex/dose by gavage at dose levels of 0, 100, 300 and 1000 mg/kg bw/day. The animals were treated 5 days/week and received in total 68 or 69 applications (depending on section date). Study performed according to the OECD guideline 408 of 1981, which allowed for exposure during working days, only, and stalling exposure at weekends. A satellite group of 5 males and 5 female for the control and high dose group was included to assess the reversibility of effects after a 35 day recovery period.

In the experimental animals no clinical effects and no impairment of body weight gain, food and water consumption, hematological parameters, organ or body weights related to the test substance administration were seen. The examination of the eyes with a slit lamp microscope showed no test substance related effects. The interpretation of this study is somewhat hampered due the occurrence of a bacterial infection (Tyzzer´s Disease induced by Clostridium piliforme) in all dose groups, including control and recovery group. Macroscopic or microscopic findings in the mandibular lymph node and the liver in all dose groups including the control were judged as directly related to this infection. Bacterial foci were detected in the liver.

Apart from these effects, animals of the high dose groups displayed potentially substance related increases of the activity of the alanine transaminase (ALT) in blood serum, signs of forestomach irritation and regressive epithelial changes in the urine bladder. However, an interaction with the bacterial infection cannot be entirely excluded. The significant increase of the ALT-values in the male and female animals of the high dose group was considered by the study author to be indicative for substance related liver effects. However, a confounding effect by the infection with Clostridium piliforme is likely. Beside the intestines and the myocardium, the liver is a common target organ of an infection by Clostridium piliforme (Tyzzer´s Disease). Typical degenerative histopathologic findings associated with the infection were seen in all dose groups and the control.

An induction of the enzyme alanine aminotransferase as a marker of liver damage in addition to these histopathologic alterations was evident. The histopathologic liver findings as well as the induction of the enzyme ALT - commonly associated with pathological liver alterations – are most likely due to the infection with Clostridium piliforme might have been intensified by the substance application. The observed edema of the forestomach mucosa in 2/9 male and 3/10 female animals of the highest dose group were considered to be a reaction due to irritating properties of the test substance observed in some (but not all) skin and eye irritation studies. The animals of the high dose recovery group were free of any forestomach findings, 35 days after termination of the treatment. Forestomach findings related to an irritant activity of the test item are common findings in rat gavage studies. They are attributable to the specific anatomy of the test species and the non-physiological bolus application by gavage and therefore judged as not relevant in view of a potential serious health risk for humans.

In 6/9 male animals of the high dose group the urinary bladder showed increased desquamation and localized regressive changes of the epithelium. The effects on the urinary bladder epithelium were considered by the study author to be a result of local physiological accumulation of the test compound or possible metabolites. A complete reversibility of the urinary bladder effects has been seen in the high dose recovery 35 days group. Therefore, the effects on the urinary bladder epithelium seen only in the high dose male animals can be judged as transient and do not pose a severe adverse health risk relevant to humans.

The histological examination of the reproductive organs (testes, epididymis, prostata, seminal vesicle, ovary and uterus) did not reveal any treatment related abnormalities.

On the basis of this study, a NOEL of 300 mg/kg bw/day for partially unsaturated TEA-Esterquat (90 % a.i.) can be derived.

 

There are no data gaps for the endpoint repeated dose toxicity. No human data are available. However, there is no reason to believe that these results from rat and rabbits would not be applicable to humans.

Justification for read-across

The read-across is built on the hypothesis that target and source substances, being different compounds, have similartoxicologicalproperties based on structural similaritywith common functional groups.

A detailed justification for read-across is attached to chapter 13 of the IUCLID file.

 

Conclusion

Based on structural similarities of the target and source substance as presented in the justification for read across, it can be concluded that the available data from the source substance partially unsaturated TEA-Esterquat are also valid for the target substanceFatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternized.

The repeated dose toxicity of the target substance is expected to be low. Variability in the fatty acid moiety is not expected to be relevant to the intrinsic systemic toxicity of the substances. The dose descriptor obtained from the subchronic repeated dose toxicity study conducted with the source substance partially unsaturated TEA-Esterquat is considered as an appropriate starting point for deriving a DNEL.

Justification for classification or non-classification

Based on the available data,Fatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternizeddoes not need to be classified for repeated dose toxicity according to regulation (EC) 1272/2008. Thus, no labelling is required.