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

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Screening study: No adverse effects were observed up to the limit dose of 1000 mg/kg bw/day. (read across from MDEA-Esterquat C16-18 and C18 unsatd.)

 

EOGRTS: No adverse effects were observed in an EOGRTS with basic test design up to the limit dose of 1000 mg/kg bw/day (read across from MDEA-Esterquat C16-18 and C18 unsatd.).

Link to relevant study records

Reference

Reference 1

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

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

Species:

rat

Sex:

male/female

Route of administration:

oral: gavage

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no toxicologically relevant adverse effects observed

Key result

Critical effects observed:

no

Dose descriptor:

NOAEL

Generation:

F1 (cohort 1A)

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no toxicologically relevant adverse effects observed

Dose descriptor:

NOAEL

Generation:

F1 (cohort 1B)

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no toxicologically relevant adverse effects observed

Key result

Reproductive effects observed:

no

Conclusions:

In conclusion, the dosage of 1000 mg/kg/day was considered the NOAEL for general and reproductive toxicity and pups development in Parental generation and for general and reproductive toxicity in Cohort 1A and 1B.

Reference 2

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:

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 source

Reason / purpose for cross-reference:

read-across: supporting information

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Frequency of treatment:

daily

Details on study schedule:

- F1 parental animals not mated (screenign study)

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

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

No. of animals per sex per dose:

10

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Salivation was the treatment-related clinical sign recorded during the study. This sign was occasionally noticed in all males and females treated at 1000mg/kg/day, starting from the pre-mating phase until sacrifice (end of mating for males and post partum phase for females). Males treated at 300mg/kg/day also showed salivation, but this sign appeared later in the study, mostly at the end of the mating was considered not adverse.
Other signs, such as scabs, damaged eye, hairloss and isolation in cage, were sporadically recorded during the study. These findings were considered as incidental or related to in-life procedures and were, thus, deemed as minor clinical signs, not related to treatment with the test item.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No differences in body weight were observed in treated animals of both sexes, when compared to controls.
Statistically significant differences in body weight gain were observed:
– decrease in low and high dose groups of males on Day 8 of treatment
– decrease in low dose group of females on Day 1 of treatment
– increase in high dose females on Day 7 post partum
These differences were occasional and with no dose relationship, therefore considered unrelated to treatment.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

no effects observed

Description (incidence and severity):

Thyroid hormones: No changes were recorded between control and treated groups.

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related changes were noted during the microscopic organ exminations.
The sporadic lesions, reported in control and treated animals, were considered to be an expression of spontaneous/or incidental pathology, seen in this species and age in this kind of studies and under the test site's experimental conditions.

Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted.

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Fate of females
All females mated.
The number of females with live pups on Day 13/14 post partum was 10 in the control group and 10 in all treated groups, dosed at 100, 300 and 1000 mg/kg/day.

Oestrous cycle, reproductive parameters, pairing combination and mating
performance
No anomalies were noted in the oestrous cycle and pre-coital interval of the treated females, when compared to controls.
All females mated, all gave birth and all conceivings were within 5 days of mating.

The copulatory indices were 100% for controls and treated animals. The fertility indices were 100% for control animals and 100% for all treated groups.

Implantation sites, pre-implantation loss data, pre-natal loss dataandgestation
length of females
Implantations and pre-implantation loss, total litter size and pre-natal loss (as percentage) did not show dose-related or treatment-related differences.
Gestation periods were comparable between control and treated groups. All dams gave birth between Days 21 and 23 post coitum.

Key result

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: no signs of treatment-related toxicity

Key result

Critical effects observed:

no

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Small size, cold to touch, pallor, apparently no food intake (milk) and small appearance were in general the clinical signs noted in the pups of control and treated groups.

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

No significant differences in total litter size, live litter size, mean pup loss (percentage), and sex ratio of pups were observed among the treated and the control dams at birth and on Days 1, 4, 13 and 14 post partum.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant differences in mean pup weights (percentage) were observed among the treated and the control dams at birth and on Days 1, 4, 13 and 14 post partum.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

effects observed, non-treatment-related

Description (incidence and severity):

Statistically significant decreases in the anogenital distances were noted in male pups (up to 14%) and female pups (up to 32%) of treated groups in respect to the controls. However, the above results were considered incidental and unrelated to treatment, considering the following:

- all values were within the range of ERBC historical control data (0.55 - 3.14mm/g1⁄3 for males and 0.48 - 2.09mm/g1⁄3 for females). What are the control group means of the historical data? Compare mean litter values with mean litter values of historical control data. To might be able to show that It Is some individual litter causing the decrease, and not a decrease in all litters.
- there was no relation to the dose. (Compound identified as endocrine disruptors show marked effects on AGD in a dose-dependent manner. Camilla Lindgren Schwartz, et al., Archives of Toxicology volume 93, pages253–272(2019)) – Absence of other correlated findings considered androgen-mediated endpoints (such as areola/nipple retention, cryptorchidism, decreased reproductive organ weights, and malformation incidence)
- the testing was performed at high doses, not representing real live exposure ("For these evaluations, there should be stronger emphasis on effect doses and to what extend supra-high test reliably recapitulate what occurs at more human relevant doses." Camilla Lindgren Schwartz, et al., Archives of Toxicology volume 93, pages253–272(2019)).

Nipple retention in male pups:

no effects observed

Description (incidence and severity):

No nipples were observed in male pups on Day 13/14 post partum.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No significant differences were noted in thyroid weight between controls and pups of treated groups (1 pup/sex/litter).

Gross pathological findings:

no effects observed

Description (incidence and severity):

The majority of decedent pups from all groups were found autolysed or cannibalised without any possibility for a macroscopic examination of internal organs. However, at external examination, performed in pups not extremely cannibalised, no findings were noted.
Culled pups sacrificed on Day 4 post partum and those sacrificed onDays 13/14 post partum did not show any abnormalities.

Histopathological findings:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Thyroid hormones in Pups - Day 13/14 post partum
No changes were recorded between control and treated groups.

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no signs of treatment-related toxicity

Key result

Reproductive effects observed:

no

Conclusions:

Based on read-across, the NOAEL for reproductive toxicity is 1000 mg/kg bw/d.

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 target substance MDIPA-Esterquat C16-18 and C18 unsatd. However, a Reproduction / Developmental Toxicity Screening Test in accordance with OECD TG 421 as well as an extended one generation reproduction toxicity study in accordance with OECD TG 443 is available for the source substance MDEA-Esterquat C16-18 and C18 unsatd. A justification for aread-across is attached to Iuclid section 13.

 

Screening study

The toxic effects on Sprague Dawley rats of both sexes were investigated after repeated dosing with MDEA-Esterquat C16-18 and C18 unsatd. in accordance with OECD TG 421 (adopted on 29 July 2016). Furthermore, effects of the test item on male and female reproductive performance were examined, i.e. gonadal function, mating behaviour, conception, development of conceptus, parturition and early lactation of the offspring.

Groups of 10 males and 10 females received the test item, by gavage, at dosages of 0, 100, 300 and 1000 mg/kg body weight/day. An additional group of 10 males and 10 females received the vehicle alone (softened water) at the dose volume of 10 mL/kg and acted as control.

No effects were observed in the in vivo parameters of parental animals: no relevant clinical signs and no effects on body weight, body weight gain and food consumption were noted at any dose level investigated. Thyroid hormones (T3, T4 and TSH) evaluated in parental males did not show any changes of toxicological relevance. No remarkable differences were noted at post mortem examination including organ weights and no treatment-related macroscopic and microscopic changes were observed in treated animals, when compared to controls. Futhermore, no effects on the spermatogenic cycle were described. No intergroup differences were seen in oestrous cycle, pre-coital intervals, copulatory and fertility indices.

No significant differences were observed in the number of corpora lutea, implantations, total litter size, pre-implantation loss, pre-birth loss and gestation length between control and treated females. Litter data at birth and on Days 1, 4 and 13 post partum and sex ratios were also comparable between treated and control females.

There were neither treatment-related signs at clinical observation of pups, nor at necropsy of deceased pups or those sacrificed after culling or at term. The statistically significant decrease noted in the ano-genital distance of female pups on Day 1 of age in all treated groups cannot be considered as adverse, since it had a positive trend (feminisation effect).

No nipples were observed on Day 13 of age, in male pups at all dose levels. Increases of circulating T3 levels were found in mid- and high dose male pups sacrificed at Day 14 of age. However, no clear consistency of hormones variations, dose and/or sex relation were noted to finally address an adverse effect of the test compound on thyroid function.

Analysis of plasma samples showed that after oral administration of the test item, females were exposed to the test item (detected as Core 134) both on Day 18 post coitum and Day 13 post partum, as well as, via milk, in pups on Day 13 post partum. The exposure increased with the dose and the duration of treatment (Day 18 post coitum corresponds to approximately 33 days of treatment; Day 13 post partum corresponds to approximately 50 days of treatment.

Based on the results obtained in this study, the NOAEL (No Observed Adverse Effect Level) for both general toxicity and reproduction/developmental toxicity was considered to be 1000 mg/kg/day for both males and females.

These results were used to set the dose levels for the subsequent EOGRTS.

 

Extended One Generation Reproduction Toxicity Study

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.

40 male and 40 female pups/group, from different litters, were selected and assigned to Cohort 1 A and Cohort 1 B in order to follow the toxicity effect in the second generation administered from weaning (Day 21 of age) up to 13 weeks.

In addition, the study provided and/or confirmed information about the effects of the test item on the integrity and performance of the adult male and female reproductive systems. The following parameters were considered: gonadal function, oestrous cycle, epididymal sperm maturation, mating behaviour conception, pregnancy, parturition and lactation.

 

Parental generation (F0)

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 196-100 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.

Changes noted in thyroid hormone levels of treated males and high dose females were considered to be unrelated to treatment since the simultaneous changes of two or three hormones (conditions which could represent a pathological significance) were sporadic and not dose-related, and no histopathological changes were recorded.

Exposure to Core 134 (metabolite used to monitor the presence of the test item in plasma) was demonstrated in all treated dams on Day 18 post coitum and Day 21 post partum at 1 and 4 hours after treatment and in pups of Groups 3 and 4 on Day 21 post 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 analysis 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.

 

Cohorts 1A and 1B

No mortality occurred in Cohort 1A and Cohort 1B animals.

At the daily and weekly clinical observation, no signs of toxicological relevance and no effect in the neurotoxicity assessment were observed in treated males and females of both Cohorts.

Body weight, body weight gain and food consumption of both sexes of both Cohorts were unaffected by treatment.

Oestrous cycle, vaginal opening and balano-preputial skin folds separation did not reveal differences considered adverse in Cohort 1A and Cohort 1B animals.

No changes were recorded in the haematology, coagulation, clinical chemistry and urinalysis parameters between treated and control animals of Cohort 1A.

The increase in Triiodothyronine level noted in low dose males was considered unrelated to treatment, in the absence of a of dose-relation.

No sign of alteration in the immune cell distribution was observed in splenocytes of treated animals of Cohort 1A.

No treatment-related changes were noted at sperm analysis (in Cohort 1 A), organ weights, gross pathology and the histopathological examination (in Cohort 1 A). Enumeration of ovarian follicles enumeration and the staging of spermatogenic cycle performed did not show any treatment-related effects in Cohort 1A and Cohort 1B.

In conclusion, the dosage of 1000 mg/kg/day was considered the NOAEL for general and reproductive toxicity and pups development in Parental generation and for general toxicity in Cohort 1A and 1B.

 

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.

 

Effects on developmental toxicity

Description of key information

NOEL=1000 mg/kg bw/d, prenatal developmental toxicity study; oral (gavage); rat (Wistar, 25/group, dosed from day 6 through 15 post coitum); OECD Guideline 414; GLP; read-across from MDEA-Esterquat C16-18 and C18 unsatd.

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
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

Species:

rat

Route of administration:

oral: gavage

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Dose / conc.:

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

No. of animals per sex per dose:

25/group.

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: embryotoxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: fetotoxicity

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: teratogenicity

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

NOAEL = 1000 mg/kg bw/day (general tolerability in the females and for the fetal organism).
NOAEL = 1000 mg/kg bw/day (maternal reproduction).
NOAEL = 1000 mg/kg/day (teratologic effects)

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 target substance MDIPA-Esterquat C16-18 and C18 unsatd. However, a prenatal developmental toxicity study is available for the source substance MDEA-Esterquat C16-18 and C18 unsatd. A justification for aread-across is attached to Iuclid section 13.

 

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 relatedor 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. 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.

 

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.

 

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 extended one generation reproduction toxicity study do not indicate a substance-related effect to reproduction up to the limit dose of 1000 mg/kg bw/day

In conclusion, results of existing studies indicate that the substance does not need to be classified for effects on toxicity to reproduction according to GHS Regulation EC No 1272/2008 and therefore labelling is not necessary.