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Key value for chemical safety assessment

Effects on fertility

Description of key information

Data obtained from a sub-acute and a sub-chronic oral repeated dose toxicity study, both with the read-across substance partially unsaturated TEA-Esterquat were used to evaluate effects on fertility ofFatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternized.

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.

Link to relevant study records
Reference
Endpoint:
fertility, other
Remarks:
repeated dose toxicity study (28 d, 90 d)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting 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
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: from 28 d study
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: from 90 d study
Critical effects observed:
no
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No experimental data are available for the assessment of reproductive toxicity of the target substance Fatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternized.

However, for the assessment of effects to fertility, reliable relevant data from repeated dose toxicity studies are available for the closely related source substance partially unsaturated TEA-Esterquat. 

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 “Repeated dose toxicity”). 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.

Furthermore it has to be emphasized that there is no consumer exposure of the substance. The use is very specific and takes place at industrial sites only. 

 

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

There are no data gaps for effects on fertility. No human data are available. However, there is no reason to believe that these results from rat would not be applicable to humans.

Based on structural similarities of the target and source substance as presented in the justification for read-across, it can be concluded that the absence of effects to fertility observed in the repeated dose toxicity studies conducted with the source substance partially unsaturated TEA-Esterquat is also valid for the target substance C18 and C18 unsatd. TEA-Esterquat.

The dose descriptor for effects to fertility 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.

Effects on developmental toxicity

Description of key information

The NOEL of 1000 mg/kg bw/d from a prenatal developmental toxicity study in rats according to OECD Guideline 414 with the read-across substance MDEA-Esterquat C16-18 and C18 unsatd. were used to evaluate effects on developmental toxicity ofFatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternized.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
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
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: overall effects
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Abnormalities:
no effects observed
Developmental effects observed:
no
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No experimental data are available for the assessment of reproductive toxicity of the target substance Fatty acids, C18 unsatd., mono and diester with triethanolamine , di-Me sulfate-quaternized.

However, for the assessment of developmental toxicity effects, reliable relevant data from repeated dose toxicity study are available for the closely related source substance MDEA-Esterquat C16-18 and C18 unsatd. 

 

In the developmental toxicity study, groups of 25 mated female Wistar rats were treated with MDEA-Esterquat C16-18 and C18 unsatd. 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.

 

Performance of a prenatal developmental toxicity study in a second species is not necessary as no substance-related effect on the fetus was observed up to the limit dose of 1000 mg/kg bw/day.

 

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

There are no data gaps for effects on development. No human data are available. However, there is no reason to believe that these results from rat would not be applicable to humans.

Furthermore, it has to be emphasised that there is no consumer use for this substance.

The absence of prenatal developmental toxicity for the source substance MDEA-Esterquat C16-18 and C18 unsatd. is also relevant for the target substance C18 and C18 unsatd. TEA-Esterquat based on the close structural similarities.

Justification for classification or non-classification

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