N'-[3-(dimethylamino)propyl]-N,N-dimethylpropane-1,3-diamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Data generated with the related substances DMAPA and DEAPA is used for endpoint coverage. 

In a key, reliable study, DMAPA was administered to rats for a period of up to 56 consecutive days at dose levels up to 200 mg/kg bw/day, in a screening test for reproduction/developmental toxicity performed according to OECD guideline 421 (BASF, 1999). The NOAEL for systemic toxicity was established at 50 mg/kg bw/day, for reproductive toxicity at 200 mg/kg bw/day.

An extended one-generation reproductive toxicity sutdy with DEAPA is currently ongoing. Data will be considered when available. 

Link to relevant study records

Reference

Reference 1

Endpoint:

extended one-generation reproductive toxicity – with F2 generation and both developmental neuro- and immunotoxicity (Cohorts 1A, 1B with extension, 2A, 2B, and 3)

Type of information:

experimental study planned (based on read-across)

Justification for type of information:

An extended one-generation reproductive toxicity study with the related substance DEAPA is currently ongoing (ECHA decision number CCH-D-2114457570-49-01/F). The data of this study will be included in the test substance dossier when available.

Read-across hypothesis:
The rationale for the read-across is based on the “analogue approach” described in described in ECHA’s (2017) Read-Across Assessment Framework (RAAF). This read-across is based on the hypothesis that the source and the target substances have similar toxicological and ecotoxicological properties because they are structurally closely related and have similar general mechanistic properties. This prediction is supported by the existing experimental data available on the substances themselves which confirm their similar physicochemical and (eco)toxicological characteristics. In this case, an ‘analogue approach’ has been chosen as the data from the analogue DEAPA will be used to fulfill the information requirement. Scenario 2 of the RAAF guidance is selected.

The full read-across justification document for this endpoint will be included when the study becomes available.

Qualifier:

according to guideline

Guideline:

OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)

Justification for study design:

SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS:

Extended one-generation reproductive toxicity study OECD TG 443 in rats, oral route with the read across source substance as specified in the decision number CCH-D-2 1 1 4457 57 O-49-OU F:
At least two weeks premating exposure duration for the parental (PO)
generation;
- Dose level setting shall aim to induce systemic toxicity at the highest
dose level;
- Cohort 1A (Reproductive toxicity);
- Cohort 18 (Reproductive toxicity) with extension to mate the Cohort 18
animals to produce the F2 generation;
- Cohorts 2A and 28 (Developmental neurotoxicity); and
- Cohort 3 (Developmental immunotoxicity).

The rationale for the study design are included in the above mentioned decision and further details on the study design will be included at a later date with the full study summary

Species:

rat

Reproductive effects observed:

not specified

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

read-across from related substance

Justification for type of information:

Data from the related substance DMAPA is used to cover this endpoint. Justification for the read-across approach is included in section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

200 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

reproductive performance

other: fertility

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

50 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Generation:

F1

Effect level:

200 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

No reliable screening for reproductive/developmental toxicity study with the test substance is available. Data generated with the related substance DMAPA is used for endpoint coverage.
Under the conditions of the study, the oral administration of DMAPA by gavage to rats had no adverse effects on reproductive performance or fertility of the F0 parental animals of all substance-treated groups. Signs of general, systemic toxicity in the F0 parental animals were confined to the male rats of the 200 mg/kg bw/day group.
NOAEL reproductive performance and fertility = 200 mg/kg bw/day (male/female),
NOAEL developmental toxicity = 200 mg/kg bw/day (male/female),
NOAEL systemic toxicity = 50 mg/kg bw/day (male).

The same is assumed to be correct for the test substance.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP-compliant, according to OECD guideline

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Data generated with the related substances DMAPA and DEAPA is used for endpoint coverage. Justification of the read-across approach is included in section 13.

Screening study (OECD421)

A Reproduction/Development Toxicity Screening Test of the related substance DMAPA by oral administration to Sprague-Dawley Rats according OECD method 421 was carried out with four groups of 10 male and 10 female rats each. The rats received 0 (control), 10, 50 or 200 mg/kg bw/day; males: 14 days prior to mating and during the 14-day mating period, females: 14 days prior to mating and during the mating period, pregnancy and lactation period. Examinations were carried out on mortality, clinical signs, body weight, food consumption, reproduction, macroscopic post mortem findings/organ weights of parent animals and histopathology.

Under the conditions of the above-mentioned study, the oral administration of DMAPA by gavage to rats had no adverse effects on reproductive performance or fertility of the F0 parenteral animals of all substance-treated groups. Mating behavior, conception, gestation, parturition and lactation as well as the sexual organ weights, gross and histopathological findings of these organs were similar between the treated animals and the controls. With the exception of one male F0 and one female F0 in the control group and in the mid-dose group, all F0 rats proved to be fertile. Thus, the observable difference was regarded to be incidental in nature and not of toxicological or biological relevance.

 

Signs of general, systemic toxicity in the F0 animals were confined to the male rats of the 200 mg/kg bw/day group. Toxicity was characterized by decreased food consumption. No compound-related adverse effects were observed in female rats up to the highest dose level of 200 mg/kg bw/day. There were no signs of developmental toxicity in the progeny of the F0 parents up to and including the high dose group (200 mg/kg bw/day). Observed differences did not show any biological relevance between the substance-treated groups and the control group. Thus, the NOAEL (no observed adverse effect level) for reproductive performance and fertility was 200 mg/kg bw/day for the F0 parental rats. The NOAEL for general, systemic toxicity of the test substance was 200 mg/kg bw/day for the F0 parental females, while it was 50 mg/kg bw/day for the F0 parental males. The NOAEL for developmental toxicity could be fixed at 200 mg/kg bw/day for the F1 progeny. The same is assumed to be correct for the test substance.

 

Extended one-generation reproductive toxicity study (OECD 443)

An EOGRTS according to guideline 443 is currently ongoing with DEAPA. Data will be considered when available. 

Effects on developmental toxicity

Description of key information

Data generated with the related substance DEAPA is used for endpoint coverage. 

In a key PNDT study in rat, the NOAEL for maternal parameters was considered to be 50 mg/kg bw/day based on clinical signs, food consumption, body weight, net body weight change and/or gravid uterus weight from 250 mg/kg bw/day and mortality at 750 mg/kg bw/day. THe NOAEL for embryo-fetal toxicity and teratogenicity was considered to be 50 and 250 mg/kg bw/day, respectively (in a context of marked to severe maternal toxicity).

In a key PNDT study in rabbit, the NOEL for maternal parameters was considered to be 15 mg/kg bw/day, based on the absence of any test item-related findings at this dose level. The NOAEL was considered to be 130 mg/kg bw/day, based on the transient and statistically significant but non adverse lower mean body weight gain and food consumption at this dose level. The NOAEL for embryo-fetal development was considered to be 130 mg/kg bw/day, based on the absence of adverse effects at this dose level. 

The same is assumed to be correct for the test substance. 

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Data from the related substance DEAPA is used to cover this endpoint. Justification for the read-across approach is included in section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Key result

Dose descriptor:

NOAEL

Remarks:

General toxicity

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: Based on absence of adverse effects

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on absence of adverse effects

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

No reliable developmental toxicity study was performed with the test substance. Data generated with the related substance DEAPA is used for endpoint coverage.
In a preliminary study in rabbits, it was established that the high dose level in the main study (study 47474 RSL) should be between 100 and 300 mg/kg bw/day.
In the key prenatal developmental toxicity study in rabbits (OECD guideline 414), the NOEL for maternal parameters was considered to be 15 mg/kg bw/day, based on the absence of any test item-related findings at this dose level. The NOAEL was considered to be 130 mg/kg bw/day, based on the transient and statistically significant but non adverse lower mean body weight gain and food consumption at this dose level. The NOAEL for embryo-fetal development was considered to be 130 mg/kg bw/day, based on the absence of adverse effects at this dose level.
The same is assumed to be correct for the test substance.

Reference 2

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

read-across from related substance

Justification for type of information:

Data from the related substance DEAPA is used to cover this endpoint. Justification for the read-across approach is included in section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

early or late resorptions

food consumption and compound intake

mortality

organ weights and organ / body weight ratios

pre and post implantation loss

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

uterus

Description (incidence and severity):

lower mean gravid uterus - weight

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

changes in litter size and weights

other: post-implantation losses

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

external malformations

Key result

Abnormalities:

not specified

Localisation:

other: not specified

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

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

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

No reliable developmental toxicity study was performed with the test substance. Data generated with the related substance DEAPA is used for endpoint coverage.
In a preliminary study in rats, 750 mg/kg bw/day was established as suitable high dose-level for the main study phase.
In the key prenatal developmental toxicity study in rats (OECD guideline 414), the NOAEL for maternal parameters was considered to be 50 mg/kg bw/day based on clinical signs, food consumption, body weight, net body weight change and/or gravid uterus weight from 250 mg/kg bw/day and mortality at 750 mg/kg bw/day. The NOAEL for embryo-fetal toxicity and teratogenicity was considered to be 50 and 250 mg/kg bw/day, respectively (in a context of marked (250 mg/kg bw/day) to severe (750 mg/kg bw/day) maternal toxicity).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP-compliant, according to OECD guideline

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 developmental toxicity/teratogenicity study with the test substance was performed. Data generated with the related substance DEAPA is used for endpoint coverage. Justification of the read-across approach is included in section 13. 

Prenatal developmental toxicity study in rat 

Preliminary study: The potential toxic effects of the test item, DEAPA, on the pregnant female and on embryonic and fetal development was evaluated in a range-finding study following daily oral administration (gavage) to pregnant female rats from implantation to the day prior to the scheduled hysterectomy (Day 6 to Day 20 post-coitum inclusive), in order to select dose-levels for a further main study. Three groups of eight time-mated female Sprague-Dawley rats were given the test item at 100, 300 or 1000 mg/kg/day by oral gavage once daily from Days 6 to 20 p.c.. Another group of eight time-mated rats received the vehicle,drinking water treated by reverse osmosis,under the same experimental conditions and acted as a control. All animals were checked daily for mortality and clinical signs. Body weight and food consumption were recorded regularly. After sacrifice, a macroscopic post-mortem examination was performed on the females on Day 21 p.c.. Hysterectomy was performed and the numbers and distribution of corpora lutea, implantation sites, early and late resorptions, uterine scars, and live and dead fetuses were recorded. The fetuses were sexed, weighed and examined for oral cavity and external abnormalities.

On Day 21 p.c., all control females and females given 100 or 300 mg/kg/day and 6/8 females given 1000 mg/kg/day were pregnant with live concepti. Unscheduled mortality occurred in 1/8 females at 1000 mg/kg/day. At final sacrifice, transient ptyalism was observed in all females given 1000 mg/kg/day associated with piloerection in 1/7 females. Reflux at dosing was noted on rare occasions in 2/8 and 1/7 females given the test item at 300 or 1000 mg/kg/day, respectively. 

A body weight loss was observed in females given 1000 mg/kg/day at the beginning of the treatment period (-13 g) whereas slight lower body weight gain was recorded in females given 300 mg/kg/day (+9 g vs. +13 g in controls); this was followed with lower body weight gain until Day 15p.c.at 1000 mg/kg/day leading to a statistically significantly lower body weight gain throughout the whole study period (+105 g vs. +140 g in controls). Body weight gain of females given 300 mg/kg/day returned to control values from Day 9 p.c..

These differences were accompanied with reduced food consumption (-11% at 300 mg/kg/day over the first 3 days of the treatment period and -13 to -52% at 1000 mg/kg/day between Days 6 and 15 p.c., compared to controls).

There were no effects of treatment with the test item at 100 mg/kg/day.

At necropsy on terminal sacrifice,there were no test item-related gross findings.

When compared with the control group, dams given 1000 mg/kg/day had a lower gravid uterus weight observed in high-dose dams (-9% compared to controls). Lower net weight change (+16 g vs. +41 g in controls) was considered to be a consequence of the lower body weight gain in these females.

Gestation parameters were not impacted by the test item treatment at any dose-levels.

There was no effect on the fetal body weight and on the percentage of male fetuses (sex ratio).

There were no treatment-related fetal external malformations or variations in any groups.

The test item was administered by gavage once daily from Days 6 to 20 p.c., inclusive, to pregnant Sprague-Dawley rats at the dose-levels of 100, 300 or 1000 mg/kg/day. The control group received the vehicle, drinking water treated by reverse osmosis, under the same experimental conditions.

The dose-level of 1000 mg/kg/day was associated with one death and therefore considered to exceed the Maximum Tolerated Dose. Treatment-related effects were also observed (i.e. ptyalism, piloerection and reflux at dosing, marked body weight loss followed by slight body weight gain associated with reduced food consumption resulted in lower net weight change).

The dose-level of 300 mg/kg/day was associated with isolated reflux at dosing and moderate effects at initiation of the study (i.e. moderate body weight gain associated with reduced food consumption). The dose-level of 100 mg/kg/day was not associated with any test item effects.

Based on these findings, 750 mg/kg/day could be considered as a suitable high dose-level for the main embryo-fetal developmental study with the test item.

 

Main study:

The potential toxic effects of the test item, DEAPA, on the pregnant female and on embryonic and fetal development was evaluated following daily oral administration (gavage) to pregnant female rats from implantation until the day before scheduled hysterectomy [Day 6 to Day 20 post-coitum (p.c.) inclusive]. This GLP study was carried out according to OECD test guideline No. 414 (22 January 2001). Three groups of 24 time-mated female Sprague-Dawley rats received the test item, DEAPA (as pH-neutralized dose formulations), by the oral route (gavage), at dose-levels of 50, 250 or 750 mg/kg/day, once daily from Day 6 until Day 20 p.c.. Another group of 24 time-mated rats received the vehicle only,drinking water treated by reverse osmosis, under the same experimental conditions and acted as a control group. A constant dosage volume of 5 mL/kg/day was used. The test item concentrations in the dose formulations were determined. The animals were checked daily for mortality and clinical signs. Body weight and food consumption were recorded at designated intervals. On Day 21 p.c., the females were sacrificed and submitted to a macroscopic post-mortem examination. Hysterectomy was performed and the numbers of corpora lutea, implantation sites, uterine scars, early and late resorptions, and live and dead fetuses were recorded. The fetuses were weighed, sexed and examined for external, soft tissue and skeletal abnormalities (including cartilage). The stomach of all dams was sampled andpreserved in 10% buffered formalin.

The concentrations of the test item in the dose formulations (-1% to +4%) remained within the acceptable range of variations (± 10%) when compared to the nominal concentrations. At study termination on Day 21p.c., there were 24, 21, 23 and 18 females with live fetuses in the groups given 0, 50, 250 or 750 mg/kg/day, respectively. On Day 20p.c., one pregnant female at 750 mg/kg/day was found dead. From 250 mg/kg/day, ptyalism, sneezing, chromorhinorrhea and/or dacryhorrheawere considered to be test item treatment-related but of minor toxicological importance. At 250 and 750 mg/kg/day, 4/24 and 19/23 dams, respectively, showed clinical signs (round back, emaciated appearance, piloerection, loud breathing and/or reddish vaginal discharge) which were considered to be test item treatment-related and adverse at 750 mg/kg/day. An adverse body weight loss was observed in females given 750 mg/kg/day at the beginning of the treatment period (-16 g on Day 6- 9 p.c., p<0.001), which resulted in a lower body weight gain until the end of the treatment period (+97 g vs.+149 g in controls, during the period of Days 6 to 21 p.c. p<0.001). Body weight gain was slightly lower in females given 250 mg/kg/day (+5 g vs. +15 g in controls, on Days 6 to 9 p.c., p<0.01), but returned towards control values from Day 9 p.c.. Therefore, toxicologically significant effects were observed on terminal body weight in females given 750 mg/kg/day (-12% versus controls on Day 21 p.c., p<0.001). Body weight changes correlated with lower mean food consumption (21% vs. controls between Days 6 and 9 p.c. at 250 mg/kg/day, and -9 to -63% vs. controls between Days 6 and 18 p.c. at 750 mg/kg/day). These findings were considered to be adverse at 750 mg/kg/day. Spleen enlargement, raised focus on the spleen and colored focus on the stomach wall were observed only in females given the high dose-level. Therefore, a relationship to the test item treatment cannot be excluded. At 750 mg/kg/day, statistically significantly lower mean net weight change (+8.5 g vs. +42.0 in controls, p<0.001) and lower carcass weight (-10% vs. controls, p<0.001) were noted. At 250 and 750 mg/kg/day, mean gravid uterus weights were 9% and 18% lower than controls, respectively. This correlated with a lower mean number of live fetuses at both dose levels (11.4 and 11.2 vs. 13.2 in Historical Control Data (HCD), respectively) and with a lower mean fetal body weight at 750 mg/kg/day. At 250 and 750 mg/kg/day, total resorption in one female at each dose level and higher mean post-implantation loss (15.5 and 20.0 vs. 3.8 in HCD, respectively) were also observed. At 750 mg/kg/day, higher mean number of early resorptions (2.1 vs. 0.6 in controls, p<0.001) was noted, as along with lower mean net weight change and lower carcass weight.

All these findings were considered to represent embryo toxicity from 250 mg/kg/day.

At 750 mg/kg/day and when compared with controls, the lower mean fetal body weights were statistically significant (p<0.05). This finding, which was considered to be of minor toxicological importance, was not of a similar amplitude in both sexes as differences were mainly due to the lower body weight of male fetuses (p<0.05). The sex ratio was unaffected by the test item treatment at any dose-level. There were no test item treatment-related variations at external/oral cavity examination of the fetuses. At 750 mg/kg/day, two fetuses, from two different litters had anasarca, cleft palate, short trunk, short tail and/or anal atresia together with acaudia, for which a relationship to the test item treatment could not be ruled out. There were no test item-related variations and malformations at soft tissue examination. At 750 mg/kg/day and when compared with controls, there were higher litter and fetal incidences of fetuses with incomplete ossification of cervical vertebra(e) centrum). From 250 mg/kg/day and taking into account the percentage of litter with fetuses of abnormalities of the axial skeleton, a test-item treatment related effect cannot be excluded.

On the basis of the results obtained in this study:

.         the No Observed Adverse Effect Level (NOAEL) for maternal parameters was considered to be 50 mg/kg/day (based on clinical signs, food consumption, body weight, net body weight change and/or gravid uterus weight from 250 mg/kg/day and mortality at 750 mg/kg/day),

.         the NOAEL for embryo-fetal toxicity and teratogenicity was considered to be 50 and 250 mg/kg/day, respectively (in a context of marked (250 mg/kg/day) to severe (750 mg/kg/day) maternal toxicity).

Prenatal developmental toxicity study in rabbit 

preliminary study: The objective of this preliminary study was to evaluate the potential toxic effects of the test item, DEAPA (as pH-neutralized dose formulations), on the pregnant female and on embryonic and fetal developments, following daily oral administration (gavage) to pregnant female rabbits from implantation to the day before scheduled hysterectomy [Day 6 to Day 28 post-coitum (p.c.) inclusive], in order to select dose levels for a further main study (study plan No. 47474 RSL).Three groups of eight timed-mated female New-Zealand White rabbits received the test item, DEAPA, as pH-neutralized dose formulations), by the oral route (gavage), once daily from Day 6 until Day 28 p.c., at dose levels of 100, 300 or 750 mg/kg/day. Another group of eight time-mated rabbits received the vehicle only, drinking water treated by reverse osmosis, under the same experimental conditions and acted as a control group. A constant dosage volume of 4 mL/kg/day was used. All animals were checked daily for mortality and clinical signs. Body weight and food consumption were recorded at designated intervals. On Day 29 p.c., the surviving females were euthanized and a macroscopic post-mortem examination was performed. Hysterectomies were performed and the numbers of corpora lutea, implantation sites, early and late resorptions, and live and dead fetuses were recorded. The fetuses were weighed and examined for external abnormalities. All fetuses were then discarded.

At hysterectomy, on Day 29 p.c., all surviving females were pregnant with live fetuses at termination.

At 300 and 750 mg/kg/day, 4/8 and 8/8 females were prematurely euthanized for ethical reasons between Days 15 and 23 p.c. and between Days 10 and 12 p.c., respectively. Prior to euthanasia, signs of poor clinical condition were observed (i.e. soft feces or absence of feces, soiled urogenital area, emaciated appearance, coldness to the touch, ventral decubitus, hypotonia, body weight loss and/or almost no food intake). The cause of these signs was probably related to gastrointestinal changes. No mortality was observed at 100 mg/kg/day. No test item-related clinical signs were reported in the 4/8 surviving females at 300 mg/kg/day or in females at 100 mg/kg/day. At 300 mg/kg/day, severe reduction in food intake (down to -82% vs. controls) was noted between Days 6 and 15 p.c. (p<0.01 or p<0.001) followed with a low food consumption in surviving females until the end of the treatment period (down to -54%). This correlated with body weight loss (-193 g in cumulative; p<0.05 or p<0.001) and low body weight gain the same intervals, leading to a low body weight gain over the treatment period (+70 g vs. +405 g in controls; p<0.01). Body weight was slightly affected from Day 12 p.c. (down to -10% vs. controls). At 100 mg/kg/day, no effects on body weight or food consumption were noted although a low body weight gain was observed over the whole treatment period (+298 g vs. +405 g in controls).

Test item-related macroscopic observations were noted at ≥ 100 mg/kg/day in the stomach, at ≥ 300 mg/kg/day in the kidneys and at 750 mg/kg/day in the intestines and liver.

At 300 and 100 mg/kg/day, low net body weight changes (-393.3 and -269.2 g vs. -187.2 g in controls, respectively) was noted. At 300 mg/kg/day, low gravid uterus weight (-22% vs. controls) and fetal weight (-11% vs. controls) were observed.

There were no effects on hysterectomy data at 100 or 300 mg/kg/day and no effects on fetal body weight at 100 mg/kg/day. At 300 mg/kg/day, when compared with controls and/or Historical Control Data, mean fetal body weight was lower (-11% vs. controls). This finding was attributed to the test item treatment
and correlated with the lower mean gravid uterus weight recorded at this dose level.

There were no external variations or malformations at fetal examination in the 100 and 300 mg/kg/day groups.

The test item, DEAPA (as pH-neutralized dose formulations), was administered from gestation Day 6 to Day 28 p.c. inclusive, at dose levels of 100, 300 or 750 mg/kg/day, by the oral route (gavage), to time-mated female New-Zealand White rabbits.

At 300 and 750 mg/kg/day, there was overt maternal toxicity, with excessively reduced food consumption leading to body weight loss and poor clinical condition. All females at 750 mg/kg/day and half of the females at 300 mg/kg/day, were prematurely euthanized between Days 10 and 23 p.c. Macroscopic post-mortem lesions were observed in the stomach, intestines, liver and kidneys. At 300 mg/kg/day, the other findings observed in surviving females consisted of low net body weight change, gravid uterus and fetal weight.

At 100 mg/kg/day, no clinical signs were noted. Findings consisted of low body weight gain over the treatment period and macroscopic post-mortem lesions in the stomach of two females.

There were no effects on hysterectomy data at 100 or 300 mg/kg/day and no effects on fetal body weight at 100 mg/kg/day. At 300 mg/kg/day, when compared with controls and/or Historical Control Data, mean fetal body weight was lower (-11% vs. controls). This finding was attributed to the test item treatment
and correlated with the lower mean gravid uterus weight recorded at this dose level.

There were no external variations or malformations at fetal examination in the 100 and 300 mg/kg/day groups.

Based on the results of this study, the high dose level in the main study (study plan No. 47474 RSL) should be between 100 and 300 mg/kg/day.

 

Main study: A prenatal developmental toxicity study via oral gavage was performed in rabbits with test substance diethylaminopropylamine. The study was carried out according to GLP and to OECD test guideline No. 414 (25 June 2018). Three groups of 24 time-mated female New-Zealand White rabbits received the test item Diethylaminopropylamine (as pH-neutralized dose formulations, once daily by the oral route (gavage) at dose levels of 15, 50 or 130 mg/kg bw/day from Day 6 to Day 28 p.c. inclusive. A control group of 24 time-mated females received the vehicle (drinking water treated by reverse osmosis) under the same experimental conditions. A constant dosage volume of 2 mL/kg bw/day was used.

Actual concentrations of the test item in the dose formulations analyzed during the study were within an acceptable range of variations (-4.5% to +5.2%) when compared with the nominal concentrations.

The relevant endpoints are summarised in Table 12 of section "Any other information on results incl. tables". At hysterectomy on Day 29 p.c., 23/24, 21/24, 22/24 and 23/24 females were pregnant with live fetuses in the groups treated at 0, 15, 50 and 130 mg/kg bw/day, respectively. No test item-related deaths or clinical signs were recorded. Lower body weight gain was recorded between Days 6 and 29 p.c. at 50 and 130 mg/kg bw/day (-12% and -19% vs. controls, respectively; not statistically significant). These differences, which were especially due to continuous (at 50 mg/kg bw/day) or transient (at 130 mg/kg bw/day with p<0.05 on 2 interval days) lower body weight gain, did not impact the body weight on Day 29 p.c. and were considered to be non-adverse. This finding was associated with transient, non-adverse, slightly lower food consumption between Days 6 and 9 p.c. (-19%; p<0.05) at 130 mg/kg bw/day when compared with controls. No effects were observed at 15 mg/kg bw/day on body weight and food consumption. No effects were noted on gravid uterus weight, carcass weight or net body weight changes at any dose level. There were no test item-related macroscopic or microscopic findings at any dose level.

A slight increased mean post-implantation loss was noted from 50 mg/kg bw/day (up to 9.3% at 130 mg/kg bw/day vs. 2.6% in controls). As these variations were not statistically significant and were within the range of the HCD (min: 7.3 - max: 13.2%), they were not considered to be adverse. No other effects on the hysterectomy parameters were noted at any dose level. A minimally, not statistically significant and non-adverse lower mean fetal body weight was recorded at 130 mg/kg bw/day (-7% vs. controls) that correlated with minor findings of delayed ossification. No effects were noted on sex ratio at any dose level. No test item-related variations or malformations were observed at external examination at any dose level. Although a minor visceral abnormality (i.e. absence of brachiocephalic trunk) was noted from 50 mg/kg bw/day and minor findings of delayed ossification were noted in fetuses with higher litter and/or fetal incidences from 50 mg/kg bw/day (i.e. incomplete ossification of the 1^st metacarpal) and at 130 mg/kg bw/day [i.e. unossification or incomplete ossification of the 6^th sternebra(e), the 1^st metacarpal and the 5^th forepaw median phalanx, and/or incomplete ossification of pubis], no test item-related soft tissue or skeletal malformations were observed at any dose level.

Based on the results obtained in this study:

• the No Observed Effect Level (NOEL) for maternal parameters was considered to be
  15 mg/kg bw/day, based on the absence of any test item-related findings at this dose level and the No Observed Adverse Effect Level (NOAEL) was considered to be 130 mg/kg bw/day, based on the transient and statistically significant but non adverse lower mean body weight gain and food consumption at this dose level,


• the No Observed Adverse Effect Level (NOAEL) for embryo-fetal development was considered to be 130 mg/kg bw/day, based on the absence of adverse effects at this dose level.

Toxicity to reproduction: other studies

Description of key information

No study available

Justification for classification or non-classification

Based on the criteria of the CLP Regulation (EC) 1272/2008, the substance should not be classified as reproductive toxicant.