Reaction mass of stearoyl sarcosine and palmitoyl sarcosine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive/Developmental Toxicity Screening Test (OECD 421), rat: NOAEL = 1000 mg/kg bw/day

RA from analogue substance N-methyl-N-[C18-(unsaturated)alkanoyl]glycine (EC 701-177-3)

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to analogue justification report provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

reproduction

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: observed effects were considered secondary effects due to parental toxicity

Remarks on result:

other: Source: EC 701-177-3, vivo science, 2010

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reduction of mean relative food consumption and strong increase of mean relative water consumption, reduced mean body weight and body weight gain

Remarks on result:

other: Source: EC 701-177-3, vivo science, 2010

Key result

Dose descriptor:

NOAEL

Remarks:

reproduction

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: observed effects are considered to be secondary effects due to parental toxicity

Remarks on result:

other: Source: EC 701-177-3, vivo science, 2010

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 1) study from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and similar physico-chemical, ecotoxicological and toxicological properties of the source and the target substances. Taken together, the information from this independent source is sufficient for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No. 1907/2006 (REACH). Therefore, the available information is sufficient to fulfil the standard information requirements set out in Annex VIII - IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006 (REACH).

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 data on toxicity to reproduction are available with Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7). Therefore, read across from the analogue substance N-methyl-N-[C18-(unsaturated)alkanoyl]glycine (EC 701-177-3) was applied.

Toxicity to reproduction (Reproduction/Developmental Toxicity Screening Test)

N-methyl-N-[C18-(unsaturated)alkanoyl]glycine (EC 701-177-3) was tested for toxicity to reproduction in a Reproduction/Developmental Toxicity Screening Test performed according to OECD TG 421 and in compliance with GLP (vivo Science, 2010). Dose selection was based on the results of a 28-day dose range finding study, performed with 3 animals of each sex per dose which were administered the test material at dose levels of 50, 250 and 1000 mg/kg bw/day via oral gavage. In the main study, groups of 12 Wistar rats of each sex were administered 50, 250 and 1000 mg/kg bw/day of the test material via oral gavage. Male animals were treated with the test material two weeks before mating, throughout the mating period until the study termination. The female animals were administered the test material during 2 weeks before mating, up to 14 days until mating, an average of 21 days of gestation, and a minimum of 4 days of lactation. A concurrent negative control group receiving the vehicle (1% sodium carboxymethyl cellulose + 0,1% Polysorbate 80 (Tween 80), diluted in water) only was included in the study. Examination of the parental animals revealed laboured breathing and vocalisations in animals from all test groups probably due to the high surface activity of the test item. Small amounts of test item solution reached the respiratory tract, some leading to fatalities by acute exogenous lipid pneumonia. Eight animals died spontaneously or were killed during the course of the study. Their premature death of most of these animals is considered to be most likely due to an inadvertent deposition of a small amount of the test item at the laryngeal orifice that was inhaled during inspiration. One rat was euthanised due to an application error. In high dose males, body weight and relative body weight gain were prominently reduced throughout the study with a net mean body mass loss in the first two weeks of application. In females of the high dose group, a significantly lowered relative body weight gain during gestation and lactation was observed. A reduction in the mean relative food consumption and an increase in the mean relative water consumption were observed in all animals from the high dose groups during the first two weeks of application. No effects on the organ mass of the sexual organs and no histomorphological effects on the genital system were observed. In addition, no test item related abnormalities were found during gross necropsy. Regarding the reproductive performance, animals of the high dose groups showed a slightly but statistically significantly reduced mean number per dam of corpora lutea. Furthermore, in the medium and high dose groups a weak evidence for a delayed conception was apparent. In the high dose group significantly reduced mean numbers of live pups at Day 4 were observed. However, the numbers of abnormal pups born and the pre-implantation and pre-natal loss were normal for rats of this strain and age. A statistically highly significant reduction of mean pup body mass and mean litter mass in the high dose group at day four of lactation was apparent. A mild and statistically significant reduced mean pup body mass (males) was found at day of birth in the high dose group when compared to the vehicle control as well. Considering the fact that no abnormalities were found by a gross necropsy and in the following histopathological examination of the reproductive organs of the parental animals, the authors concluded that the negative effects of the high dose of the test item on reproduction were not caused by its toxic properties on those organs directly, but rather on other secondary local or systemic factors affecting parental animal health. Thus, a systemic NOAEL for the parental animals of 250 mg/kg bw/day and a NOAEL for reproduction of 1000 mg/kg bw/day was derived in the study.

In summary, a Reproduction/Developmental Toxicity Screening Test with the source substance N-methyl-N-[C18-(unsaturated)alkanoyl]glycine (EC 701-177-3)resulted in a systemic NOAEL for the parental animals of 250 mg/kg bw/day and a NOAEL for reproduction of 1000 mg/kg bw/day. Based on the read-across approach, these NOAELs are concluded also for Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7).

Effects on developmental toxicity

Description of key information

Developmental toxicity NOAEL >= 250 mg/kg bw/day (OECD 414, rats, GLP)

Developmental toxicity NOAEL >= 500 mg/kg bw/day (OECD 414, rabbits, GLP)

RA from source substances Sodium N-lauroylsarcosinate (CAS 137-16-6)

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to analogue justification report provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: Source: CAS 137-16-6, Harlan, 2014

Key result

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: No adverse effect on developmental toxicity observed at the highest tested dose level.

Remarks on result:

other: Source: CAS 137-16-6, Harlan, 2014

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Additional study on pre-natal developmental toxixicity (in rabbits) also taken into account in the Weight-of-Evidence approach:

CAS 137-16-6, Envigo, 2017: NOAEL (maternal) = 500 mg/kg bw/day; NOAEL (development) = 500 mg/kg bw/day

Conclusions:

Under the conditions of the study the test substance did not induce any treatment-related biologically relevant malformations in the developing unborn organism in the presence of maternal toxicity. Therefore, the test substance does not meet the criteria for classification for prenatal developmental toxicity according to Regulation (EC) No 1272/2008. The available data is thus conclusive but not sufficient for classification.

Executive summary:

As explained in the category/analogue justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences with respect to toxicity to reproduction.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 1) studies from a source substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and similar physico-chemical, ecotoxicological and toxicological properties of the source and the target substances. Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No. 1907/2006 (REACH). Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII - IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006 (REACH).

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

Developmental toxicity/teratogenicity

No data on developmental toxicity / teratogenicity are available for Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7). Therefore, read across from the analogue substance Sodium N-lauroylsarcosinate (CAS 137-16-6) was applied.

Study in rats

The test item Sodium N-lauroylsarcosinate (CAS 137-16-6) was administered by gavage to three groups of time-mated pregnant Sprague-Dawley rats, between Days 5 and 19 of gestation, at dose levels of 30, 100, and 250 mg/kg bw/day in a study performed according to OECD TG 414 and observing GLP provisions (Harlan, 2014). A further group of time-mated pregnant females was exposed to the vehicle only (control). Clinical signs, body weight change, food and water consumptions were monitored during the duration of the study. At sacrifice (at Day 20 of gestation) all females were subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weight, foetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination. With regard to maternal toxicity one female treated with 250 mg/kg bw/day was found dead on day 10 of gestation. Another female from this treatment group was found dead on Day 18 of gestation. There were no further unscheduled deaths. Surviving females treated with 250 mg/kg bw/day showed incidences of increased salivation and noisy respiration during the treatment period. One female treated with 100 mg/kg bw/day also showed increased salivation on Day 18 of gestation and a further female showed noisy respiration on Day 13. No such effects were detected in females treated with 30 mg/kg bw/day. The female found dead on Day 10 did not show any clinical signs prior to Day 10. The female found dead on Day 18 had noisy respiration, increased salivation and pilo-erection. Females treated with 250 mg/kg bw/day and to a lesser extent females treated with 100 mg/kg bw/day showed a reduction in body weight development throughout the treatment period. Body weight gain adjusted for gravid uterus weight between Days 5 and 20 was also redued in these females. No such effects were detected in females treated with 30 mg/kg bw/day. Correspondingly, females treated with 250 mg/kg bw/day also showed a reduction in food consumption throughout the treatment period. No such effects were detected in females treated with 100 or 30 mg/kg bw/day.

With regard to developmental toxicity no toxicologically significant effects were detected in the uterine parameters examined, in foetal viability or in growth and development. In addition, no treatment-related effects were detected on foetal external findings. No treatment-related effects were detected on skeletal development or in the type and incidence of skeletal or visceral findings in foetuses from females treated with 250, 100 or 30 mg/kg bw/day. Furthermore there were no findings considered to represent any known malformations. In conclusion, as the oral administration of the test item to pregnant rats by gavage during gestation at dose levels of 30, 100 and 250 mg/kg bw/day resulted in substance-related effects in females treated with 250 and 100 mg/kg bw/day, the NOAEL for maternal toxicity was therefore considered to be 30 mg/kg bw/day. No toxicological significant changes were detected in the offspring parameters measured. The NOAEL for reproductive and developmental toxicity was therefore considered to be 250 mg/kg bw/day, corresponding to the hightest dose tested.

Study in rabbits

In another pre-natal developmental toxicity study performed with rabbits according to OECD TG 414 and GLP conditions, three groups of 22 females received the test item Sodium N-lauroylsarcosinate (CAS 137-16-6) at doses of 125, 250 or 500 mg/kg/day by oral gavage administration, from Day 6 to 28 after mating (Envigo, 2017). A similarly constituted control group received the vehicle, purified water at the same volume dose as treated groups. Animals were killed on Day 29 after mating for reproductive assessment and fetal examination. Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 29 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination of the head or skeletal examination.

With regard to maternal toxicity one female of the control group and one female each of the mid- and high-dose group died during the study period. However, the deaths were not considered to be treatment-related, since no treatment-related clinical signs were observed after treatment with the test substance at 125, 250 or 500 mg/kg bw/day. In addition, there was no clear effect of treatment on the body weight or food consumption performance of females receiving the test substance at 125 or 250 mg/kg bw/day when compared with that of the control group. The mean body weight loss of females exposed to 500 mg/kg bw/day was slightly greater than that of the control group after the start of treatment (between Days 6 and 8 after mating), and body weight gain was slightly lower than that of the controls from Days 8 - 29 after mating. The food consumption of females treated with 500 mg/kg bw/day was slightly lower than that of the control from the start of treatment (Day 6 after mating), resulting in a lower overall (Day 6 - 28 after mating) food consumption. When mean values of body weight and body weight gain were adjusted for the contributions of the gravid uterus, overall maternal mean body weight loss during Days 6 - 29 of gestation was greater than in controls at 500 mg/kg bw/day. There were no test item-related macroscopic abnormalities detected among the females at scheduled termination on Day 29 after mating.

Embryo-fetal survival was unaffected by treatment at 125, 250 or 500 mg/kg bw/day with mean numbers of implantations, resorptions, live young and percentages of sex ratio and pre and post-implantation loss being similar to control values. Mean placental, litter and fetal weights at 500 mg/kg bw/day were marginally lower (ca 10%) than controls. Mean placental, litter, and male, female and overall fetal weights at 125 or 250 mg/kg bw/day were similar to the control group and unaffected by treatment. At 500 mg/kg bw/day there was a slightly higher incidence of the minor fetal abnormality additional cranial sutures, which was outside Historical Control Data (HCD). An increase was also seen in the incidence of 20 thoracolumbar vertebrae. However, this was within HCD. At 500 mg/kg bw/day there was also a slightly higher incidence of delayed ossification of the cervical vertebrae but this was considered to be related to the lower mean fetal weights seen in this group.

In conclusion, at 500 mg/kg bw/day, maternal body weight performance and food consumption and mean fetal weights were slightly reduced. Embryo-fetal survival was unaffected by treatment and fetal development was not adversely affected in rabbits. The No-Observed-Adverse-Effect-Level (NOAEL) for maternal and embryo-fetal toxicity was concluded to be 500 mg/kg bw/day, corresponding to the highest dose tested.

Conclusion

Based on the reliable and adequate studies with the structural analogue substance Sodium N-lauroylsarcosinate (CAS 137-16-6) in two species, no effects on maternal and embryo-fetal toxicity are anticipated for Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7).

Justification for classification or non-classification

The available data obtained from analogue substances for toxicity to reproduction and developmental toxicity / teratogenicity do not meet the criteria for classification according to Regulation (EC) No. 1272/2008 (CLP). Therefore, applying the read-across approach, Reaction mass of N-(1-oxooctadecyl)sarcosine and N-hexadecanoyl-N-methylglycine (EC 947-850-7) is also considered not to meet the criteria for classification for toxicity for reproduction.