Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no specific reproduction toxicity study available.

Available 28-day and 90-day sub-chronic studies does not indicate specific effects on reproductive organs.There were specifically no indications of possible reproductive toxicity based on the additional parameters determined in the 90-day study: All females showed a normal (regular) estrous cycle of 4 days during the period in which estrous cycle length was determined (Day 71 up to and including Day 91), and histopathological examination of the male and female reproductive organs did not show treatment-related lesions. An additionally performed Prenatal developmental toxicity has furthermore shown that N-[2-piperazin-1-yl)ethyl]C18-unsatured-alkylamide had no impact on any of the fetal developmental parameters up to the highest dose level of 220 mg/kg bw/day, over 4 times the 90-day NOAEL. In view of the lack of effects in on reproductive parameters in these available studies, further testing of for fertility is of low priority.

 

In combination with low exposures no further reproduction studies are considered necessary. Manufacture and use are highly controlled. Its use is limited to industrial and professional users wherefollowing its severe corrosive properties the applied protection measures will provide for sufficient protection to prevent exposure. Also exposures via inhalation are not likely taking into account the low vapour pressure (<3 x 10-7 Pa at 23 °C) and high boiling point (>300 °C) of the substance, as well as low possibility of exposure to aerosols or droplets of an inhalable size.

Short description of key information:

There is no specific reproduction toxicity study available. Repeated dose studies do not indicate any concerns for reproductive tissues. In combination with low exposures no further reproduction studies are considered necessary.

Justification for selection of Effect on fertility via oral route:

Lack of effects in repeated dose studies and developmental toxicity study combined with low exposures it is waiving is proposed for the 2-generation study in accordance with the Annex XI(3) of the REACH regulation setting the guidelines for substance-tailored exposure-driven testing.

Justification for selection of Effect on fertility via inhalation route:

Exposure of humans to N-[2- piperazin-1-yl)ethyl]C18-unsatured-alkylamide (Tall oil reaction products with aminoethylpiperazine) via inhalation is not likely taking into account the low vapour pressure (<3 x 10-7 Pa at 23 °C) and high boiling point (>300 °C) of the substance as well as low possibility of exposure to aerosols or droplets of an inhalable size.

Justification for selection of Effect on fertility via dermal route:

N-[2- piperazin-1-yl)ethyl]C18-unsatured-alkylamide (Tall oil reaction products with aminoethylpiperazine) is severely corrosive. Effects will be characterized by local corrosive effects that are related to duration, quantity and concentration, rather than by systemic toxicity and subsequent reproductive effects following dermal uptake. Because of the corrosive properties, exposures are likely to be limited

Effects on developmental toxicity

Description of key information

In an oral OECD 414 prenatal developmental toxicity study in rats, the maternal NOAEL for N-[2- piperazin-1-yl)ethyl]C18-unsatured-alkylamide (Tall oil reaction products with aminoethylpiperazine) was established as 110 mg/kg and the developmental NOAEL was established as 220 mg/kg, the highest dose tested.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28 January - 18 April 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study has been performed according to OECD and/or EC guidelines and according to GLP principles.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: Wistar (Han)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
Females were nulliparous, nonpregnant and untreated at initiation of the study.
Stock male rats Crl:WI(Han) (outbred, SPF-Quality) were used for mating with the females.
- Age at study initiation: Approximately 11 weeks.
- Weight at study initiation: mean weight range at start of treatment was 234 gr.
- Fasting period before study: no
- Housing:
Pre-mating: Females were housed in groups of 5 animals/sex/cage in Macrolon cages.
Mating: Females were caged together with stock males on a one-to-one-basis in Macrolon cages.
Post-mating: Females were individually housed in Macrolon cages.
General: Sterilised sawdust as bedding material and paper as cage enrichment were supplied.
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

IN-LIFE DATES
From: 28 January - 18 April 2013
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
- Method of formulation: Formulations (w/w) were prepared daily within 5 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and specific gravity/density of the test substance. No correction was made for the purity/composition of the test substance.
- Storage conditions of formulations: At ambient temperature.
- Justification for use and choice of vehicle: Based on trial formulations performed at WIL Research Europe B.V..
- Dose volume: 5 mL/kg body weight. Actual dose volumes were calculated according to the latest body weight.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The delegated phase was performed by the Principal Investigator for Formulation Analysis. Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 5 hours at room temperature under normal laboratory light conditions was also determined (highest and lowest concentration). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Formulations were considered stable if the relative difference before and after storage was maximally 10%.
Details on mating procedure:
- M/F ratio per cage: 1/1 (one female was cohabitated with one stock male)
- Age at mating of the animals in the study: Approximately 12 weeks.
- Proof of pregnancy: Detection of mating was confirmed by evidence of sperm in the vaginal lavage and/or by the appearance of an intravaginal copulatory plug. This day was designated Day 0 post-coitum. Once mating had occurred, the males and females were separated.
- After successful mating each pregnant female was caged individually in Macrolon cages (MIII type, height 18 cm).
Duration of treatment / exposure:
Females were dosed from Day 6 to Day 19 post-coitum, inclusive.
Frequency of treatment:
Once daily for 7 d/w.
Duration of test:
Duration of treatment: From Days 6 to 19 post-coitum, inclusive.
Remarks:
Doses / Concentrations:
0, 55, 110, 220 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
22 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on results of the dose range finding study (Project 501975)
- Rationale for animal assignment: Upon detection of mating (Day 0 post-coitum), the females were distributed in a random sequence over the test groups. Females which were mated on the same day were classified in the same subgroup.
Maternal examinations:
CAGE SIDE OBSERVATIONS
- Time schedule: At least twice daily. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints (ENV/JM/MONO/ 2000/7). The circumstance of any death was recorded in detail.
DETAILED CLINICAL OBSERVATIONS
- Time schedule: At least once daily from Day 0 post-coitum onwards. The time of onset, grade and duration of any observed sign was recorded. Signs were graded for severity.
BODY WEIGHT
- Time schedule for examinations: Days 0, 3 and 6-20 (daily) post-coitum.
FOOD CONSUMPTION
- Days 0-3, 3-6, 6-9, 9-12, 12-15, 15-17 and 17-20 post-coitum.
FOOD EFFICIENCY: yes
WATER CONSUMPTION
No. Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
OPHTHALMOSCOPIC EXAMINATION
No
HAEMATOLOGY
No
CLINICAL CHEMISTRY
No
URINALYSIS
No
NEUROBEHAVIOURAL EXAMINATION
No
GENERAL REPRODUCTION DATA
- Mating date and confirmation of pregnancy was recorded.
- Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of these females was examined to detect signs of abortion or premature birth.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight.
- Number of corpora lutea.
- The number and distribution of live and dead fetuses.
- The number and distribution of embryo-fetal deaths.
- The weight of each fetus.
- The sex of each fetus from the ano-genital distance (during necropsy) and also from gonadal inspections (during further fetal examination).
- Externally visible macroscopic fetal abnormalities.
Fetal examinations:
External, visceral and skeletal fetal findings were recorded as developmental variations or malformations.
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter of Groups 1 and 4
- Head examinations: Yes: half per litter of Groups 1 and 4
Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the compound-treated groups to the control group.

All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss. Dead fetuses, early and late resporptions and pre- and post-implantation loss were compared using the litter as the statistical unit.
Indices:
For each litter the following calculations were performed:
Pre-implantation loss (%) = (number of corpora lutea - number of implantation sites) / number of corpora lutea x 100
Post-implantation loss (%) = (number of implantation sites - number of live fetuses) / number of implantation sites x 100
The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a mean litter proportion on a total group basis, where: Viable fetuses affected / litter (%) = number of viable fetuses affected / litter x 100
Details on maternal toxic effects:
Details on maternal toxic effects:
MORTALITY:
No mortality occurred in the study.
CLINICAL SIGNS:
At 220 mg/kg, hunched posture, rales, piloerection, chromodacryorrhoea of the snout, pale and lean appearance were noted for some animals towards the end of the treatment period. All other clinical signs were incidental in nature and included alopecia, scabs on the neck, rales (noted
for one female at 55 mg/kg) and piloerection (one female at 110 mg/kg). At the limited incidence observed, these were not toxicologically relevant.
BODY WEIGHTS:
At 220 mg/kg, absolute body weights and body weight gains were significantly lower for females from post coitum Days 6-20 than controls. Body weight gain remained lower than controls when weight gain was corrected for uterine weight. Body weight gains were also lower for females at 110 mg/kg than controls from Days 12-15 post coitum. When corrected for uterine weight, females had significantly lower relative gain on the day of necropsy. This was not considered to be toxicologically relevant as the difference from controls was only slight, was transient and was partially attributable to one female at 110 mg/kg who had implantation sites only.
FOOD CONSUMPTION:
Absolute and relative food consumption was significantly lower for animals at 220 mg/kg than controls during the entire treatment period (Days 6-20 post coitum). At 110 mg/kg absolute food consumption was significantly lower during the entire treatment period and relative food consumption was also lower during this time (not always statistically significant). This was not considered to be toxicologically relevant at this dose level, however, as the differences from controls were only slight and the lower food consumption for one animal at 110 mg/kg with only implantation sites also contributed to this.
MACROSCOPIC EXAMINATION:
There were no toxicologically relevant findings up to 220 mg/kg. One female at 220 mg/kg had several macroscopic findings including emaciation, thickened stomach and irregular surface of the forestomach, hardened contents of the colon and rectum, accentuated lobular pattern on the liver, and thymus reduced in size. However, as these occurred for only a single animal, they were not considered indicative of treatment related toxicity. A scab on the back of the neck and alopecia were incidental findings noted for two control females. These had no relation to treatment.
MATERNAL PREGNANCY DATA
There were 20, 19, 20 and 22 pregnant females in the control, 55, 110 and 220 mg/kg groups, respectively with 20, 19, 19 and 22 litters available for evaluation. There was a single female at 110 mg/kg with implantation sites only. Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. There were no significant differences were observed between control and treated groups regarding the number of corpora lutea, implantation sites, viable or dead fetuses, early or late resorptions, or pre- and postimplantation loss.
Dose descriptor:
NOAEL
Effect level:
>= 110 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
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
LITTER SIZE
There were no treatment related effects on litter size seen up to 220 mg/kg. The mean number of viable fetuses per litter was 11.7, 11.9, 12.0 and 12.7 in the control, 55, 110 and 220 mg/kg groups, respectively.
SEX RATIO
There were no treatment-related effects on the fetal sex ratio in any group.
FETAL BODY WEIGHT
There were no treatment related effects on fetal body weight up to 220 mg/kg. Mean fetal body weights were slightly lower than controls at 220 mg/kg (not statistically significant) which was attributable to low fetal body weights from one female at 220 mg/kg who lost a considerable amount of weight during the gestation period.
FETAL MORPHOLOGICAL EXAMINATIONS
The numbers of fetuses (litters) available for external and visceral morphological evaluation were 234(20), 226(19), 240(19) and 280(22) in the control, 55, 110 and 220 mg/kg groups, respectively. Soft cephalic tissue examinations were done for approximately half of the fetuses in each group and skeletal examinations were performed for all fetuses of the control and 220 mg/kg group. Malformations were observed in 4(3), 3(2), 0(0) and 5(5) fetuses (litters) in the control, 55, 110 and 220 mg/kg groups, respectively.
EXTERNAL MALFORMATIONS AND VARIATIONS
There were no treatment related effects on fetal external morphology. In one litter at 110 mg/kg a late resorption was observed with generalized subcutaneous edema. This finding is recorded in the individual data and not included in the summary tables because it was only noted in a late resorption. Due to its single occurrence in the mid dose group, this finding was not considered to be treatment related.
No external malformations and developmental variations were observed in any of the fetuses, thus it was considered that test substance treatment at dose levels up to 220 mg/kg had no effect on fetal external morphology.
VISCERAL MALFORMATIONS
There were no treatment related effects on fetal visceral morphology. Visceral malformations were observed in 0(0), 3(2), 0(0) and 2(2) fetuses (litters) of the control, 55, 110 and 220 mg/kg groups, respectively.
At 220 mg/kg, the two malformations noted were a small eye in one fetus and an absent lung lobe in one fetus. The affected fetuses at 55 mg/kg had situs inversus, abnormal lung lobation, persistent truncus arteriosus, absent ductus arteriosus (all together in one fetus), malpositioned testis (one fetus) or internal hydrocephaly (one fetus). All malformations noted were observed once and the occurrence was not restricted to the high dose group; therefore they were not considered to be treatment related.
VISCERAL VARIATIONS
Of the visceral variations a statistically significant decrease in the mean litter proportion was observed for small supernumerary liver lobes at 55 and 110 mg/kg. The mean litter incidences for this finding were 8.4%, 2.8%, 3.3% and 9.0% per litter in the control, 55, 110 and 220 mg/kg groups, respectively. Because no dose relationship for small supernumerary liver lobes could be established and because the mean litter incidence for this finding in all dose groups remained within the historical control data range (1.6-18.6% per litter), this variation was considered not to be treatment related.
Other visceral developmental variations observed in the test substance treated groups were partially undescended thymus horn, dilated ureter, convoluted ureter, small renal papilla, liver appendix and pale spleen. These variations were not considered to be treatment related, because they occurred at similar frequencies in the control group, occurred infrequently, occurred without dose relationship and/or occurred at frequencies within the historical control range.
SKELETAL MALFORMATIONS
There were no treatment related effects on fetal skeletal morphology. Skeletal malformations were observed in 4(3) and 3(3) fetuses (litters) of the control and 220 mg/kg group, respectively. In the high dose group, all three affected fetuses had malpositioned metatarsals. These fetuses had metatarsals that were not aligned with the corresponding digits. The same finding was also noted in a control fetus. Mean litter proportions of this finding were 0.4% and 1.0% per litter in the control and high dose group, respectively. Because these figures were not statistically significantly different and were within the historical control data range, the malpositioned metatarsals were considered not to be treatment related.
Other skeletal malformations in this study only affected control fetuses. A vertebral centra anomaly in one fetus a rib anomaly in one fetus and bent limb bones in one fetus. Due to their occurrence in the control group, these malformations were not related to treatment.
SKELETAL VARIATIONS
Skeletal variations occurred in 86.4% and 77.4% of fetuses per litter in the control and 220 mg/kg group, respectively. Among the variations that describe fetal skeletal ossification in the high dose group, increased mean litter incidences (not statistically significant) were noted when compared to the control group, for reduced ossification of vertebral centra (7.2% versus 1.2%), unossified vertebral centra (4.2% versusus 0.0%), reduced ossification of vertebral arches (4.2% versus 0.8%), unossified or reduced ossification of ilium (2.7% versus 0.0%), unossified or reduced ossification of ischium (3.8% versus 0.0%), reduced ossification of ribs (1.5% versus 0.0%) and entire sternum unossified (1.5% versus 0.0%). All these findings, except for reduced ossification of vertebral centra, occurred solely in the litter of female A081. The mean fetal body weight of this litter was 2.3 grams, which was markedly below the group mean value (3.3 grams). Therefore, the signs of delayed ossification in the high dose group were attributed to the low fetal body weights of only one litter in this group. Moreover, the low fetal body weights of this litter were considered to be secondary to maternal toxicity observed for this female.
Other variations noted in the high dose group were 14th rudimentary rib, 14th full rib, 7th cervical rudimentary rib, bent ribs, unossified sternebrae nos. 5 and/or 6, unossified sternebrae nos. 1,2,3 and/or 4, slightly to moderately malaligned sternebrae, reduced ossification of the skull, unossified hyoid, ossified vertebral centrum no. 1, caudal shift of pelvic girdle, and unossified metacarpals and/or metatarsals. These variations were not considered to be treatment related, because they occurred at similar frequencies in the control group, occurred infrequently, occurred without dose relationship and/or occurred at frequencies within the historical control range.
Dose descriptor:
NOAEL
Effect level:
>= 220 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No effects observed at highest dose level
Abnormalities:
not specified
Developmental effects observed:
not specified

FORMULATION ANALYSIS

No test substance was detected in the Group 1 formulations. The concentrations analysed in the formulations of Group 2, 3 and 4 were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%). The formulations of Group 2 and 4 were homogeneous (i.e. coefficient of variation ≤ 10%). Formulations at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 5 hours (i.e. relative difference ≤ 10%). The long term storage samples were stable at ≤-70°C for at least 59 days.

Conclusions:
In an oral OECD 414 prenatal developmental toxicity study with female rats,the maternal No Observed Adverse Effect Level (NOAEL) for N-[2-piperazin-1-yl)ethyl]C18-unsatured-alkylamide was established as 110 mg/kg and the developmental NOAEL was established as being 220 mg/kg.
Executive summary:

Prenatal developmental toxicity of N-[2-piperazin-1-yl)ethyl]C18-unsatured-alkylamide was evaluated following oral gavage in rats.

 

The study procedures were based on the following guidelines:

1) OECD 414, Prenatal Developmental Toxicity Study, January 2001.

2) Commission regulation (EC) No 440/2008 B.31: "Prenatal Developmental Toxicity Study". May 2008.

3) EPA OPPTS 870.3700, Prenatal Developmental Toxicity Study, August 1998.

 

Rationale for dose levels

Dose levels were based on the results of the dose range finding study. For this range finding study the dose levels were based on a previous 28 Day study, where 50, 125 and 310/220 mg/kg were tested. 310 mg/kg was the initial high dose, but was lowered due to mortality to 220 mg/kg from Day 17 onwards. Treatment related effects were mainly limited to high dose females and included clinical signs, lower body weights and body weight gains and food consumption. No prenatal or developmental effects were noted during the dose range finding study.

 

Study outline

Eighty-eight mated female Wistar Han rats were assigned to four dose groups. The test item was administered once daily by oral gavage from Days 6 to 19 post-coitum at doses of 55, 110 and 220 mg/kg (Groups 2, 3 and 4 respectively). The rats of the control group received the vehicle, propylene glycol, alone. Females were checked daily for the presence of clinical signs. Food consumption of females was determined at periodic intervals; body weight was determined daily during treatment and at periodic intervals in the other periods. Formulations prepared on one day during treatment were analyzed for accuracy, homogeneity and stability.

All animals surviving to Day 20 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and corrected body weights (changes) were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanized. One half of the fetuses were decapitated and the heads were fixed in Bouin’s fixative, all fetuses were dissected and examined for visceral anomalies and subsequently fixed in 96% aqueous ethanol and stained with Alizarin Red S for skeletal examinations.

 

RESULTS

Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

Maternal findings

Lower body weights, body weight gains and food consumption were seen for females at 220 mg/kg. Clinical signs including hunched posture, piloerection, rales and other signs were noted for some animals at this dose level towards the end of the treatment period. There were no toxicologically relevant effects seen for females at 55 and 110 mg/kg.

Developmental findings

No developmental toxicity was observed up to 220 mg/kg.

 

CONCLUSION

Based on the results in this prenatal developmental toxicity study the maternal No Observed Adverse Effect Level (NOAEL) for N-[2-piperazin-1-yl)ethyl]C18-unsatured-alkylamide was established as 110 mg/kg and the developmental NOAEL was established as being 220 mg/kg

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
220 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Recent OECD 414 guideline study of high validity.
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

Prenatal developmental toxicity of N-[2-piperazin-1-yl)ethyl]C18-unsatured-alkylamide was evaluated following oral gavage in rats according to OECD 414 guideline.

Dose levels were based on the results of the dose range finding study. For this range finding study the dose levels were based on a previous 28 Day study, where 50, 125 and 310/220 mg/kg were tested. 310 mg/kg was the initial high dose, but was lowered due to mortality to 220 mg/kg from Day 17 onwards. Treatment related effects were mainly limited to high dose females and included clinical signs, lower body weights and body weight gains and food consumption. No prenatal or developmental effects were noted during the dose range finding study.

 

In the main study, the substance was administered once daily by oral gavage to groups of 22 pregnant females from Days 6 to 19 post-coitum at doses of 55, 110 and 220 mg/kg (Groups 2, 3 and 4 respectively). The rats of the control group received the vehicle, propylene glycol, alone.

 

Maternal findings: Lower body weights, body weight gains and food consumption were seen for females at 220 mg/kg. Clinical signs including hunched posture, piloerection, rales and other signs were noted for some animals at this dose level towards the end of the treatment period. There were no toxicologically relevant effects seen for females at 55 and 110 mg/kg.

Developmental findings: No developmental toxicity was observed up to 220 mg/kg.

Justification for selection of Effect on developmental toxicity: via oral route:

Only available study

Justification for selection of Effect on developmental toxicity: via inhalation route:

Exposure of humans to N-[2- piperazin-1-yl)ethyl]C18-unsatured-alkylamide (Tall oil reaction products with aminoethylpiperazine) via inhalation is not likely taking into account the low vapour pressure (<3 x 10-7 Pa at 23 °C) and high boiling point (>300 °C) of the substance as well as low possibility of exposure to aerosols or droplets of an inhalable size.

Justification for selection of Effect on developmental toxicity: via dermal route:

N-[2- piperazin-1-yl)ethyl]C18-unsatured-alkylamide (Tall oil reaction products with aminoethylpiperazine) is severely corrosive. Effects will be characterized by local corrosive effects that are related to duration, quantity and concentration, rather than by systemic toxicity and subsequent reproductive effects following dermal uptake. Because of the corrosive properties, exposures are likely to be limited

Justification for classification or non-classification

Available data on N-[2- piperazin-1-yl)ethyl]C18-unsatured-alkylamide (Tall oil reaction products with AEP) do not indicate a concern for fertility or developmental toxicity.

Developmental toxicity: Adequate study data is only available for developmental toxicity from a valid OECD 414 guideline compliant study, showing no specific concerns for developmental toxicity.

Fertility: Although there is no valid study available evaluating complete fertility, the available information from repeated dose studies including sub-chronic 90-days and developmental toxicity study in rats indicate no concerns of effects on reproductive tissues or reproduction parameters.

As a firm conclusion on fertility from an adequate study with this compound is lacking, no definite conclusion might be drawn for classification purposes. But based on limited exposures by dermal route (substance is severely corrosive) or by inhalation (very low vapour pressure), as well as lack of indication for concerns regarding reproductive toxicity from repeated dose studies and a developmental toxicity study there are no concerns and further testing is not indicated.

 

Lactation: no adequate information.

Additional information