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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

In the repeated dose toxicity studies, Charles River CD rats (Sprague-Dawley) were treated with the test substance by oral gavage for 28 days (5 animals/sex/dose) or for 95 or 96 days (10 animals/sex/dose, recovery groups 1 (control) and 4 (high dose group) additional 5 males and females each) at dose levels of 0, 100, 300, or 1000 mg/kg bw/day (for a detailed study description see section 5.6.1.1). In both studies, no adverse test substance-related effects were found for any reproduction parameter measured, especially regarding organ weights of ovary and testes and histopathology of gonads, uterus, mammary gland, prostate and seminal vesicle.

Further testing for effects concerning fertility is considered not to be necessary because up to 1000 mg/kg bw/day there were no indications for substance-related effects regarding reproduction organ weights (ovary and testis) and histopathology of gonads, uterus, epididymis, prostate and seminal vesicles from the repeated dose toxicity studies. In addition this is substantiated by the absence of effects on maternal reproduction, embryo lethality or embryotoxicity in the developmental toxicity study in rats with doses of up to 1000 mg/kg bw/day.

From a risk assessment standpoint, as demonstrated already in HERA RAR (HERA Esterquats Risk Assessment Report; Human Health section: 2009) the human consumer exposure to Esterquats (a class of structurally similar substances, including MDEA- and TEA-Esterquats) under normal and foreseeable conditions of use is very low (0.04 mg/kg bw/day worst case total exposure from different consumer scenarios) resulting in substantial margin of exposure.

An alternative approach to addressing the lack of specific fertility data from a risk assessment perspective could be the application of the concept of the Toxicological Threshold of Concern (TTC) (Kroes R. et. al., 2004). In context of this approach, Esterquats would fall into the Cramer class I which are substances that have efficient modes of metabolism and are generally considered to be of low toxicity (Cramer et al., 1978). For Class I chemicals, the respective TTC level reflecting a daily exposure below there is a low probability of an appreciable risk to human health amounts to 1800 µg/person/day (Kroes R. et al., 2004). Considering a body weight of 60 kg, the estimated human exposure to Esterquats as derived in the HERA RAR is with 2.4 mg/person/day in the same range of the TTC level.

An effect, which may only become evident at such high exposure levels compared to the substantial margin of exposure does not warrant further animal testing.


Short description of key information:
In the repeated dose toxicity studies, Charles River CD rats (Sprague-Dawley) were treated with the test substance by oral gavage for 28 days (5 animals/sex/dose) or for 91 days (10 animals/sex/dose) at dose levels of 0, 100, 300, or 1000 mg/kg bw/day (for a detailed study description see section 5.6.1.1). In both studies, no adverse test substance-related effects were found for any fertility parameter measured, especially regarding organ weights of ovary and testes and histopathology of gonads, uterus, mammary gland, prostate and seminal vesicle.

Effects on developmental toxicity

Description of key information
The results of the prenatal developmental toxicity study do not indicate a substance-related effect on the fetus up to the limit dose of 1000 mg/kg bw/day.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

Data from a structural similar substance MDEA-Esterquat (methyl-diethanol-ester-amine) are available. MDEA-Esterquat (CAS-no 67846-68-8) is based on diethanolamine whereas the TEA-Esterquats are based on triethanolamine. The structure of MDEA-Esterquat is very similar to the main component (TEA-Esterquat Diester, Compound I) of the TEA-Esterquat (see Figure 3 given in CSR). The TEA-Esterquat represent a mixture containing mono-, di-, and triesters of triethanolamine with C16-C18 saturated, and C18 unsaturated fatty acids.

Due to the structural similarity and the absence of any effect regarding organ weights (ovary and testis) and the histological examination of the reproductive organs (testes, epididymis, prostata, seminal vesicle, ovary and uterus) up to 1000 mg/kg bw/day in the 90-day repeated dose toxicity study and the absence of any effect from another substance of the esterquat family this read across is justified.

In the developmental toxicity study, groups of 25 mated female Wistar rats were treated with the test substance orally by gavage once daily from day 6 through 15 post coitum, at dose levels of 0, 50, 250 and 1000 mg/kg bw/day. Females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section.

At 50, 250, and 1000 mg/kg, for the dams no test substance-related deaths or clinical signs as were noted as reaction to treatment. Up to and including the highest dose level of 1000 mg/kg, food consumption and body weight development of the dams were not affected by treatment with the test substance. At necropsy, no test substance-related abnormal findings in the dams were noted in any group.

A slight (statistically non significant) decrease in the number of corpora lutea and a slight (statistically non significant) increase in pre-implantation losses were observed in the high dose group (17.4 %) as compared to the controls (12.8 %); however, this is not a substance-related effect, since exposure started at gestation day 6, the day of implantation.

The slightly but statistically significant increased post-implantation losses at the high dose of (8.7 %) as compared to the controls (4.8 %) resulted in a slightly reduced portion of total fetuses per implantation site (91.3%) and in a reduced mean litter size (10.5 fetuses/litter) as compared to the controls (95.2 %; 11.2 fetuses/litter). The values were within the range of historical control values (3.9 % to 11.6 % for post-implantation losses and 10.2 to 12.2 fetuses/litter).

At 1000 mg/kg, two females with total post-implantation losses were noted. One of the two females had bleeding from the vagina on days 15-16 post coitum. However these two animals had only two and one corpora lutea, respectively, and were obviously not fit for reproduction. A small but significant increase in post-implantation losses was noted for the remaining females; however, the increase was within the historical data of the laboratory. These findings were considered by the authors to be a potentially effect of the test substance. At 50 and 250 mg/kg, no test substance-related effects were noted on the maternal reproductive parameters, assessed by the mean number per dam of corpora lutea and implantation sites, pre- or post-implantation losses, and by the mean number of fetuses per dam.

Up to and including the highest dose level of 1000 mg/kg, no adverse effects on the fetal parameters were recorded. No external, skeletal or soft tissue malformations and no external variations were found. Mean fetal body weights and the sex ratios of the fetuses were comparable in all groups.

There are indications that the slightly increased incidences of post-implantation losses at 1000 mg/kg bw/day are due to some maternal (toxic) effects, which could not be further evaluated because this dose level has not been tested in the repeated dose toxicity studies.

The slightly increased post-implantation losses at the high dose compared to the controls could be caused by some maternal toxicity, incidentally and therefore not treatment related or through a direct toxic effect on the fetus. Since two females of the high dose had total post-implantation losses (implantation-sites only) and one of these females showed vaginal bleeding, this may indicate that the post-implantation losses are due to (some) maternal toxicity effects. Other long-term studies with this high dose level are not available to further evaluate substance-related toxicity. Therefore, the impact of the maternal effects cannot be evaluated in depth. As the values were well within the range of the historical control values recorded at the same laboratory, it is likely that the effects observed are incidental and therefore not treatment related. Since there was no effect on fetal body weight and no increased incidences of abnormal fetuses, it is assumed that the post-implantation losses are not due to a direct effect on the fetus.

The results of the prenatal developmental toxicity study do not indicate a substance-related effect on the fetus up to the limit dose of 1000 mg/kg bw/day. Therefore, the aspect of prenatal developmental toxicity is sufficiently covered.

Additional data from another substance of the esterquat family (HEQ-based esterquat, CAS-no 19467-38-0) are described in the HERA RAR Esterquats (2009). There was no increased embryolethality, foetotoxicity, nor any specific defect in the foetuses which could be attributable to maternal exposure to the HEQ-based esterquat up to 1000 mg/kg bw/day in the rat.

Justification for classification or non-classification

Results of the prenatal developmental toxicity study do not indicate a substance-related effect on the fetus up to the limit dose of 1000 mg/kg bw/day. The slightly increased incidences of post-implantation losses at 1000 mg/kg bw/day are within the range of historical control data and might therefore be accidental and not treatment related. Vaginal bleeding observed in one animal with total post-implantation losses might be due to some maternal (toxic) effects which cannot be further evaluated. Therefore, the aspect of prenatal developmental toxicity is sufficiently covered and the substance does not require to be labelled for developmental toxicity.

Results of the repeated dose toxicity tests do not indicate a substance-related effect on reproduction (fertility) up to the dose of 1000 mg/kg bw/day, which was the highest dose tested.

In conclusion, results of existing studies indicate that the TEA-Esterquat, needs not be classified for effects on toxicity to reproduction according to Directive 67/548/EEC as well as on toxicity to reproduction (fertility and development) according to GHS Regulation EC No 1272/2008 and therefore labelling is not necessary.