1-Propanaminium, 2-hydroxy-N-(2-hydroxypropyl)-N,N-dimethyl-, esters with fatty acids, C16-18 (even numbered) and C18 unsatd., Me sulfates (salts)

Endpoint summary

Description of key information

- Subacute (28 day) study; oral (gavage), rat (Charles River CD; 25/sex/dose), OECD guideline 407, GLP; NOAEL = 500 mg/kg bw/d (highest dose level tested); read across from MDEA-Esterquat C16-18 and C18 unsatd.

- Subchronic (91 day) study; oral (gavage), rat (Crl CD BR; 15/sex/dose), OECD guideline 408, GLP; NOAEL = 500 mg/kg bw/d (highest dose level tested); read across from MDEA-Esterquat C16-18 and C18 unsatd.

- EOGRTS; oral (gavage), rat (Sprague-Dawley; 25/sex/dose), OECD guideline 443, GLP; NOAEL = 1000 mg/kg bw/d (highest dose level tested); read across from MDEA-Esterquat C16-18 and C18 unsatd.

- Subacute (28 day) study; oral (gavage), rat (Crl:WI(Han); 3/sex/dose), similar to OECD guideline 407, GLP, bridging study; NOAEL 1000 mg/kg bw/day; read-across from MDIPA Esterquat C18 unsatd.

- Subchronic (91 day) study; oral (drinking water), rat (Fischer 344/DuCrl; 10/sex/dose), equivalent to OECD guideline 408, GLP; NOAEL = 500 mg/kg bw/d (as DIPA), corresponding to 2850 mg/kg bw/d (as MDIPA-Esterquat C16-18 and C18 unsatd.); read-across from Diisopropanolamine (DIPA)

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

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
This read-across is based on the hypothesis that source and target substances have similar toxicological and ecotoxicological properties because they share structural similarities with common functional groups: quaternary amines, esters, and fatty acid chains varying in their length and degree of (un)saturation. Moreover, the fatty acid chains are chemically simple structures which have no structural alerts for toxicity, and which are closely related to substances of known low toxicity (i.e. stearic acid, oleic acid, linoleic acid, linolenic acid). Furthermore, the substances can be expected to have comparable breakdown products (MDEA or MDIPA and long chain fatty acids).

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance MDIPA-Esterquat C16-18 and C18 unsatd. are predicted to be similar to those of the source substances MDEA-Esterquat C16-18 and C18 unsatd. and MDIPA Esterquat C18 unsatd.

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

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

4. DATA MATRIX
See justification for read-across attached to chapter 13 of this IUCLID file.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: no toxicologically relevant adverse effects observed

Critical effects observed:

no

Conclusions:

In conclusion, the dosage of 1000 mg/kg/day was considered the NOAEL for general toxicity in this extended one generation reproduction toxicity study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 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

Repeated dose toxicity data on the target substance MDIPA-Esterquat C16-18 and C18 unsatd. is not available. For the assessment of repeated dose toxicity of MDIPA-Esterquat C16-18 and C18 unsatd. a subacute 28 day oral toxicity study, a subchronic 91 day oral toxicity study, and an EOGRTS conducted with the source substance MDEA-Esterquat C16-18 and C18 unsatd., as well as a 28 day bridging study with the source substance MDIPA Esterquat C18 unsatd. are available. Further support is given by subchronic toxicity data on Diisopropanolamine. A justification for read-across is attached to Iuclid section 13.

 

One 28 day repeated dose study comparable to OECD Guideline 407 and one sub-chronic toxicity study comparable to OECD Guideline 408 are available for the oral route of administration for the source substance MDEA-Esterquat C16-18 and C18 unsatd.

 

Studies with MDEA-Esterquat C16-18 and C18 unsatd. 

MDEA-Esterquat C16-18 and C18 unsatd. (10 % a. i. aqueous dispersion) was administered by oral gavage to Charles River CD rats, groups of 25 male and female at dose levels of 1, 10 and 500 mg/kg bw/day for 28 days and to15 rats/sex/dose at dose levels of 1, 10 and 500 mg/kg bw/day for a period of 13-weeks. In both studies, limit doses of 1000 mg/kg bw/day as required by the OECD guidelines were not examined. Furthermore, in both studies there were two control groups, animals received either deionised water (water control group) or pH 2.5 adjusted deionised water (pH-water control group).

In both studies all animals survived until study termination and no significant test substance-related adverse findings were detected or observed for any parameter measured.

In the 28 day study three animals exhibited focal scarring or retinal loss. This finding was not considered to be substance-related and no other test article-related ophthalmoscopic abnormalities were detected. All observations noted were pathologies that would be expected for this group of rats considering their age, sex and strain.

A slight but statistically significant decrease in the MCH index was observed in the male high dose group (500 mg/kg bw/day). However, since no corresponding changes were detected in any other haematologic parameter, this change in the MCH was not considered to be test article related.

In the 90 day study a statistically significantly lower mean MCV value was observed in male rates in the water control group and in the 10 and 500 mg/kg bw/day test groups than in the pH-water control group. However, even these lower mean MCV values were within ± 2 standard deviations of laboratory´s historical control mean value for this parameter for rats of this stain, age and sex. Furthermore, they also fall within the ranges of published reference data. Since changes in MCV values were not present in both sexes and since they occurred also in the water control group, they were considered not to be toxicologically significant nor test article-related.

In male rats the blood urea nitrogen values of the 500 mg/kg bw/day group were significantly lower than those of the pH-water control group. These differences were not considered to be test substance-related as there were within the laboratory’s historical control mean values for rats of this strain, age and sex. Individual male and female animals of all groups, including the controls, had elevated values for aspartate aminotransferase (ASAT) activity. These findings in clinical chemistry had no statistical relevance, did not show a dose-response correlation and were without histopathological correlates and therefore they were considered not to be test article-related.

In the 90 day study there were no statistically significant changes in the mean relative ovary/body or ovary/brain weight ratio when compared to both control groups with the exception of a statistically significant decrease in the mean relative ovary/body weight ratio observed in the 500 mg/kg bw/day group when compared to the pH-water control group. The mean body weight of the pH-water control group was the lowest of all female groups in contrast to that of the 500 mg/kg bw/day group, which was the highest. In addition, there were no statistically significant changes in the mean absolute ovary weights. The mean absolute ovary weight of the 500 mg/kg bw/day group falls within the range of the mean absolute ovarian weight for 13-week CD rat studies at the contract laboratory. Therefore, the observed decreased mean ovary/body weight ratio was considered not to be biologically relevant and not test article-related. Individual male and female animals of the 10 mg/kg bw/day group groups, and the control groups, had elevated values for aspartate aminotransferase (ASAT) activity. Also higher alanine aminotransferase (ALAT) activity was seen in individual male and female animals in the 10 mg/kg bw/day group in males and females. These findings in clinical chemistry had no statistical relevance, did not show a dose-response correlation and were without histopathological correlates and therefore they were considered not to be test article-related.

 

In an extended one generation reproduction toxicity study in accordance with OECD TG 443 (adopted on 25 June 2018) the pre- and post-natal effects of MDEA-Esterquat C16-18 and C18 unsatd. on development, as well as a thorough evaluation of systemic toxicity were investigated in male and female rats of the parental generation treated for 10 weeks before pairing and during gestation and lactation period.

In this Iuclid section only the results with the parental generation are considered. The parameters relevant for reproduction are discussed in Iuclid section 7.8.1. Toxicity to reproduction.

The dose levels of 100, 300 and 1000 mg/kg/day were selected for parental animals and were administered orally by gavage. The control group received softened water.

Males were treated for 10 weeks prior to pairing, through the mating period and thereafter until the day before necropsy, for a total of 96-100 days.

Females were treated for 10 weeks prior to pairing, during mating, gestation and post partum periods until Day 21 post partum, for at least 85 days.

The number of females with live pups on Days 21/22 post partum was: 21 in the control, 22 in the low dose (100 mg/kg/day), 24 in the mid-dose (300 mg/kg/day) and 22 in the high dose (1000 mg/kg/day) groups.

At the daily and weekly clinical observation, no signs considered adverse and no effect in the neurotoxicity assessment were observed.

Body weight, body weight gain and food consumption were unaffected by treatment.

No changes that could be considered adverse were seen in haematology, coagulation and clinical chemistry parameters of treated animals compared to controls.

Exposure to Core 134 (metabolite used to monitor the presence of the test item in plasma) was demonstrated in all treated dams on Day 18post coitum and Day 21post partum at 1 and 4 hours after treatment and in pups of Groups 3 and 4 on Day 21post partum, after approximately 24 hours of treatment of the respective dams. No exposure to Core 134 was detected in pups of Group 2.

No treatment-related anomalies were noted in the oestrous cycle of the treated females, when compared to controls. Copulatory and fertility indices did not show any treatment related differences among treated and control groups. Implantation, pre-natal loss, litter data and sex ratio did not show any changes of toxicological relevance. No significant differences in the anogenital distance were seen between control and treated groups both for male and female pups. No nipples were observed in male pups. Clinical signs and findings at necropsy and organs weight did not reveal any treatment-related or adverse effect.

Sperm analyses performed in all treated males was comparable to controls. Enumeration of ovarian follicles performed in control and high dose females did not show any treatment related effects. No relevant changes were seen in bone marrow evaluation.

No treatment-related changes were noted in animals sacrificed at the end of treatment at organ weight, macroscopic and microscopic examination.

The NOAEL is the highest dose examined, i. e. 1000 mg/kg bw/day.

 

Study with MDIPA Esterquat C18 unsatd.

In a subacute toxicity study similar to OECD guideline 407 (2008) and EU method B.7 (2008) MDIPA Esterquat C18 unsatd. (100%) was administered to 3 Crl: WI(Han) rats/sex/dose in propylene glycol by gavage at dose levels of 0, 150, 500, 1000 mg/kg bw/day for 28 consecutive days. As this study was mainly intended for justification of read-across to a structurally comparable substance, the guidelines are not fully applicable. Additional male reproductive parameters have been evaluated.

No toxicologically relevant changes were noted in any of the following parameters investigated in this study: clinical appearance, body weight, food consumption, haematology parameters, macroscopic examination, organ weights, and microscopic examination. The spermatogenic staging profiles were normal in the high dose group males.

Changes were confined to higher alanine aminotransferase activity in two males and one female at 1000 mg/kg and in one male at 500 mg/kg, and higher aspartate aminotransferase activity in one male each at 500 and 1000 mg/kg. These increases did not show a dose-related trend and were not seen among all animals of the same group. Liver weights and macroscopic observations were normal for all animals, including those showing increased alanine/aspartate aminotransferase activity. No further changes in clinical biochemistry parameters (such as increased alkaline phosphatase activity, changes in glucose, total protein/albumin, total bilirubin and cholesterol) were noted that could be indicative of altered liver function. Therefore, the increased ASAT/ ALAT activity is considered of no toxicological relevance and considered indicative of a commonly observed adaptive (hepatic enzyme induction) type of response. Elevated levels of aminotransferases, though neither dose-related nor statistically significant, were also observed in individual animals in the 91-day and 28-day studies with the source substance MDEA-Esterquat C16-18 and C18 unsatd. In those animals with elevated levels of aminotransferases, these findings in clinical chemistry were without histopathological correlates, supporting the presumption of being an adaptive response.

The NOEL in this study based on clinical chemistry was determined to be 500 mg/kg bw/d, the NOAEL was determined to be 1000 mg/kg bw/d.

 

Study with Diisopropanolamine

A subchronic toxicity study similar to OECD guideline 408 with Diisopropanolamine (DIPA) is presented as supporting data.

DIPA (98.8 to 99.6%) was administered to 10 Fischer 344/DuCrl rats/sex/dose in drinking water at dose levels of 0, 100, 500, or 1000 mg/kg bw/d daily for 13 weeks. Additional 10 animals in the control and highest dose groups were maintained on untreated drinking water for 4 weeks as recovery group.

No mortality occurred in any group; no treatment related clinical signs were observed. No relevant effects on body weight, ophthalmoscopic examinations, haematological parameters, prothrombin times, gross or histopathology were detected. The water consumption in the high dose group males and females was slightly reduced compared to control animals. Consistent with this, rats of the 1000 mg/kg bw/day dose group had increased urine specific gravity and females had decreased urine volume, which were also considered secondary adaptive effects.

There were minimal, but statistically identified, differences noted for cholesterol (increased), albumin (decreased) and phosphorus (decreased) for males given 1000 mg/kg bw/day. There were no effects upon clinical chemistry parameters for males given 100 or 500 mg/kg bw/day or for females at any dose level. Increased relative kidney weights for males and females of the 500 or 1000 mg/kg bw/day dose group were observed without any treatment-related gross or histopathologic correlate.

In the recovery group, water consumption in the treated group was below control by app. the same degree as at the end of the dosing period; all other affected endpoints showed reversibility. The absolute and relative kidney weights of the treated rats were still above the controls, but the differences were about one-half of those immediately following 13 weeks dosing. No treatment-related renal histopathological changes were observed

The NOAEL in this study was therefore 500 mg/kg bw/d based on minor changes in clinical chemistry in males of the 1000 mg/kg bw/d dose group. The LOAEL was 1000 mg/kg bw/d.

Based on the molecular weights of DIPA (133.19 g/mol) and MDIPA-Esterquat C16-18 and C18 unsatd. (approx. 760 g/mol), the NOAEL of 500 mg/kg bw/d in terms of DIPA has been extrapolated to 2850 mg/kg bw/d in terms of MDIPA-Esterquat C16-18 and C18 unsatd.

 

Conclusion

No adverse effects were observed in any of the available studies. The 90 d repeated dose toxicity study was not conducted up to the limit dose; the highest tested dose level was 500 mg/kg bw/d in this study. However, the EOGRTS, which was conducted up to the limit dose of 1000 mg/kg bw/d, contains a thorough examination of systemic toxicity covering all relevant parameters of a subchronic repeated dose toxicity study. Therefore, the NOAEL of 1000 mg/kg bw/d obtained in the EOGRTS is considered as the key value for hazard assessment.

 

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 would not be applicable to humans.

Justification for classification or non-classification

Based on the available data, MDIPA Esterquat C16 -16 and C18 unsatd. does not need to be classified for repeated dose toxicity according to the criteria given in regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.