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Description of key information

One sub-acute toxicity study according to OECD Guideline 407 and one sub-chronic toxicity study according to OECD Guideline 408 with the 
partially unsaturated TEA-Esterquat are available for the oral route of administration.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

One sub-acute toxicity study according to OECD Guideline 407 and one sub-chronic toxicity study according to OECD Guideline 408 with the partially unsaturated TEA-Esterquat are available for the oral route of administration.

In a subacute toxicity study according to OECD guideline 407the partially unsaturated TEA-Esterquat, was administered to 5 CD rats/sex/dose by gavage atdose 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 reversibility of any potential effect after a 2-week recovery period.

No mortality, morbidity or significant changes of any of the investigated parameters were noted in any of the dose groups, including neurotoxicological functional observations (FOB). Macroscopic post mortem examination and histopathology including the reproductive organs revealed no test item related changes in the partially unsaturated TEA-Esterquat treated animals. There was no evidence for specific target organ toxicity in this study.

Under the test conditions used, the NOAEL was above 1000 mg/kg bw /day in this 28-day subacute toxicity study.

 

In a subchronic toxicity study comparable to OECD guideline 408 (1981) the 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 test substance related clinical signs, effects on body weight gain, food and water consumption, hematological parameters, organ or body weights and eyes were observed.

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 the partially unsaturated TEA-Esterquat (90 % a.i.) can be derived.

Discussion:

As discussed in the HERA RAR Esterquats (2009) it is indicated that after oral ingestion a rapid metabolism of free fatty acid moieties following de-esterification can be assumed. The methyltriethanol-ammonium-ion remaining after splitting of the esterbonds is the same for all TEA-Esterquats. Therefore, read-across from both, the sub-acute and the sub-chronic toxicity study, is justified without restrictions for the whole TEA-Esterquat group.

The NOAEL of the sub-acute (oral) study was determined to be 1000 mg/kg bw/day and the NOEL of the sub-chronic (oral) study was determined to be 300 mg/kg bw/day. However, the interpretation of the sub-chronic study is somewhat hampered due to the detection of a bacterial infection in all dose groups. An overlying substance related systemic effect cannot be entirely excluded and therefore the systemic NOEL of 300 mg/kg bw/day has to be used for risk assessment purposes. But apart from this, there is no evidence for a potential serious health risk for humans. A local NOEL of 300 mg/kg bw/day has to be established due to common forestomach findings observed in studies with irritating substances. 

Justification for classification or non-classification

In conclusion, results of both studies indicate that none of the TEA-Esterquats needs to be classified for repeated dose toxicity according to Directive 67/548/EEC as well as GHS Regulation EC No 1272/2008 and therefore labelling is not necessary.