Octadecanoic acid, reaction products with triethylenetetramine

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

A NOAEL for systemic toxicity of 1000 mg/kg bw/day was established for Octadecanoic Acid, reaction products with triethylenetetramine based on information from an OECD 422 guideline study.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017-08-09 to 2017-11-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

29 July 2016

GLP compliance:

yes

Limit test:

no

Justification for study design:

not applicable

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Envigo Netherlands, Kreuzelweg 53, 5961 NM Horst, Netherlands
- Females nulliparous and non-pregnant: yes
- Age at study initiation:
7 to 8 weeks old
- Weight at study initiation:
200 to 225 g for males and 175 to 200 g for females
- Fasting period before study: no
- Housing: From arrival to mating, animals were housed up to 5 of one sex to a cage, in polysulfone solid bottomed cages measuring 59.5×38×20 cm.
During mating, animals were housed one male to one female in clear polysulfone cages measuring 42.5×26.6×18.5 cm with a stainless steel mesh lid and floor.
After mating, the males were re-caged as they were before mating.
The femaleswere transferred to individual solid bottomed cages (measuring 42.5×26.6×18.5 cm) for the gestation period, birth and lactation.
- Diet (e.g. ad libitum):
ad libitum, A commercially available laboratory rodent diet (4 RF 21,Mucedola S.r.l., Via G. Galilei, 4, 20019, SettimoMilanese (MI), Italy)
- Water (e.g. ad libitum):
ad libitum to each cage via water bottles
- Acclimation period:
An acclimatisation period of approximately 3 weeks was allowed before the start of treatment, during which time the health status of the animals was assessed by thorough observations.


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
22°C ± 2°C
- Humidity (%):
55% ± 15%,
- Air changes (per hr):
15 to 20 air changes per hour
- Photoperiod (hrs dark / hrs light):
artificial light for 12 hours

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The required amount of Octadecanoic Acid, reaction products with triethylenetetramine was suspended in the vehicle. The formulations were prepared daily (concentrations of 10, 30 and 100 mg/mL). Concentrations were calculated and expressed in terms of test item as supplied.

VEHICLE
- Justification for use and choice of vehicle (if other than water): standard vehicle
- Concentration in vehicle:
The formulations were prepared daily (concentrations of 10, 30 and 100 mg/mL) in 0.5% aqueous solution of carboxymethylcellulose
- Amount of vehicle (if gavage): 10 mL/ kg

Details on mating procedure:

- M/F ratio per cage: 1:1 monogamous
- Length of cohabitation: 14 days
- Proof of pregnancy: spermidentification, vaginal plug in situ or copulation plug found in the cage tray
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individual solid bottomed cages (measuring 42.5×26.6×18.5 cm) for the gestation period, birth and lactation.
Nesting material was provided inside suitable bedding bags.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The proposed formulation procedure for the test item was checked in the range from 10 to 100 mg/mL by chemical analysis (concentration and homogeneity) to confirmthat the method was suitable.
Final results for all levels were within the acceptability limits for concentration (85-115%) and homogeneity (CV< 10%).

Duration of treatment / exposure:

Females of the main groups were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 13 post partum, for a total of 42 to 64 days.
Females of the recovery groups were treated for a total of 56 days.
Males of the main groups were treated for 2 weeks prior to pairing and during pairing with females until the day before necropsy, for a total of 30/31 days.
Males of the recovery group were treated for a total of 28 days.

Frequency of treatment:

once a day, 7 days a week

Details on study schedule:

- Age at mating of the mated animals in the study: 12 weeks

Dose / conc.:

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

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:

Each main group comprised 10 male and 10 female rats (Groups 1 to 4).
Control and high dose level included 5 additional animals per sex to be sacrificed after 4 weeks of recovery (Groups 5 and 6).

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
Dose levels have been selectedbased on information from a preliminary study.
- Fasting period before blood sampling for clinical biochemistry: under condition of food deprivation

Positive control:

not applicable

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were checked twice daily for mortality. Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical signs recorded.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Once before commencement of treatment and at least once a week thereafter, each animal was given a detailed clinical examination.


BODY WEIGHT: Yes
- Time schedule for examinations:
Males were weighed weekly from allocation to termination. Females were weighed weekly from allocation to positive identification of mating and on Days 0, 7, 14 and 20 post coitum.
Dams were also weighed on Days 1, 4, 7, 13 post partum and just before necropsy.
Recovery groups: Each animal was weighed on the day of allocation to treatment groups, on the day that treatment commenced, weekly thereafter and just prior to necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no feeding study
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: no feeding study

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): not applicable

Oestrous cyclicity (parental animals):

Oestrous cycle was monitored by vaginal smears.
Vaginal smears were taken in the morning from Day 1 of allocation and during treatment period, up to positive identification of mating including not less than 2 weeks before pairing.

The vaginal smear data were examined to determine the following:
1. anomalies of the oestrous cycle
2. the pre-coital interval (i.e., the number of nights paired prior to the detection of mating)

Vaginal smears were also taken from all females, before despatch to necropsy.

Sperm parameters (parental animals):

A detailed qualitative evaluation of testes was performed on 5 randomly selected control and high dose males. The evaluation took into account the tubular stages of the spermatogenic cycle, in order to identify treatment-related effects, such as: missing germ cell layers or types, retained spermatids, multinucleated or apoptotic germcells and sloughing of spermatogenic cells into the lumen. Identification of the stages of the spermatogenic cycle was carried out as described by Leblond and Clermont, 1952 and referred to the comprehensive reviews on the subject Russell, 1990; Creasy, 1997; Creasy, 2002. The PAS-H stained sections were used to identify the spermatogenic stages.
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.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
On Day 4 post partum, all pups were weighed and litters in excess of 8 offspring were culled to 8 (4 males and 4 females, where possible) by a random selection. Partial adjustment (for example, 5 males and 3 females) was performed when necessary.
At least two pups (males or females, selected for culling) were sacrificed for blood collection.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
As soon as possible after parturition was considered complete (Day 0 post partum), all pups (live and dead) were counted, sexed and only live pups were identified.
Live pups were individually weighed on Days 1, 4, 7 and 13 post partum.

The AGD of each pup was measured on Day 1 post partum. The AGD was normalized to the cube root of body weight collected on Day 1 post partum.
On Day 13 post partum, the presence of nipples/areolae in each male pup was checked and recorded.

On Day 4 post partum, blood samples (approximately 0.2 mL) were collected from two of the non selected pups (males ro females) of the main groups. Blood samples were withdrawn under light ether anaesthesia from the heart (by intracardiac puncture).
On Day 14 post partum, blood samples (approximately 0.5 mL) were withdrawn under light ether anaesthesia from the heart (by intracardiac puncture) from at least two pups (1 sample/sex where possible) per litter.

All pups found dead in the cage were examined for external and internal abnormalities.
All culled pups sacrificed on Days 4 and 14 post partum were subjected to an external examination.
Sex was determined by internal gonads inspection.

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
The clinical history of the adult animals was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices).
Changes were noted, the requisite organs weighed (Table 1)(excluding animals sacrificed for humane reasons or found dead) and the required tissue samples preserved in fixative and processed for histopathological examination.

HISTOPATHOLOGY: Yes
Samples of all the tissues listed table 1 were fixed and preserved in 10% neutral buffered formalin (except eyes, optic nerves and Harderian glands, testes and epididymides which were fixed in modified Davidson’s fluid and preserved in 70% ethyl alcohol).

Postmortem examinations (offspring):

SACRIFICE
Pups that had completed the scheduled test period (Day 4 or 14 post partum) were euthanised by intraperitoneal injection of Sodium Thiopenthal. Pups selected for blood collection for hormone determination were killed on the day of blood sampling

GROSS NECROPSY
All pups found dead in the cage were examined for external and internal abnormalities.
All culled pups sacrificed on Days 4 and 14 post partum were subjected to an external examination.
Sex was determined by internal gonads inspection.

Thyroid was weighed from one male and one female pups selected for blood collection of hormone determination and preserved in 10% neutral buffered formalin. The thyroid weights were determined after fixation.

Statistics:

Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data.
The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the non-parametric version of the Williams test.
The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off.
Statistical analysis of histopathological findings was carried out by means of the non-parametric Kolmogorov-Smirnov test if ‘n’ was more than 5.

Reproductive indices:

Copulation Index males (%) = (No. of males mated / No. of males paired) X 100
Fertility Index males (%) = (No. of males which induced pregnancy / No. of males paired) X 100
Copulation Index females (%) = (No. of females mated / No. of females paired) X 100
Fertility Index females (%) = (No. of pregnant females / No. of females paired) X 100

Offspring viability indices:

Pre-implantation loss % = (no. of corpora lutea − no. of visible implantations/no. of corpora lutea) x 100
Pre-natal loss on Day 0 post-partum %: = (no. of visible implantations – total litter size ate birth/ no. of visible implantations) x 100
Post-natal loss on Day 4 post-partum (before culling) %: = (total litter size at birth – live litter size at day 4, before culling/ total litter size at birth) x 100
Post-natal loss on Day 14 post-partum (after culling) %: = (live litter size on day 4(after culling) – live litter size on day 14/ live litter size on day 4 (after culling) x 100

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs of toxicological relevance were observed in males and females of main and recovery groups.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One low dose female was sacrificed for humane reasons on Day 23 post coitum for difficulty in parturition.
Pallor, decreased activity and piloerection were observed in this animal prior to sacrifice.
No treatment-related changes were observed after gross and histopathology evaluation.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No difference in body weights was recorded in animals of both sexes compared to the control group, throughout the study.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No effects on food consumption were observed in either males or females of main and recovery groups.

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Slight lymphopenia was recorded in some females dosed at 300 and 1000mg/kg/day. However, due to the absence of dose-relation, these findings cannot be conclusively attributed to treatment.
Recovery phase (recovery phase animals): Lymphopenia and monocytopenia were still observed in females dosed at 1000mg/kg/day.
Coagulation: Dosing phase; no changes of toxicological relevance were observed.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Dosing phase
Triglycerides were decreased in a number of animals of all treated groups, with no doserelation.
In addition, glucose was increased in males receiving 1000mg/kg/day and in some females from all treated groups, with no dose-relation.
Recovery phase
Triglycerides showed complete reversibility in animals of both sexes. In males, glucose was comparable with controls, even though data were similar to those recorded at the end of treatment.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Observation of animals at removal from the cage and in an open arena did not reveal changes attributable to the test item.
No treatment-related alterations in motor activity, grip strength and sensory reactivity to stimuli were observed in any treatment group at the examination performed at the end of treatment.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathology evaluation revealed no treatment-related changes. Inparticular, no treatmentrelated findings were noted in the thyroid gland of all males and females of all main groups, when compared to their controls.
In addition seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and no alterations were noted.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Histopathology evaluation revealed no treatment-related changes.

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Oestrous cycle, pre-coital intervals, copulatory index and fertility index did not show intergroup differences.

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and no alterations were noted.

Reproductive performance:

no effects observed

Description (incidence and severity):

Oestrous cycle, pre-coital intervals, copulatory index and fertility index did not show intergroup differences.

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 treatment related effects observed

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Description (incidence and severity):

There were no compound-related effects. Pre-weaning clinical signs were comparable between treated and control groups.

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Description (incidence and severity):

No significant differences in total litter size, live litter size, mean pup loss, sex ratio and mean pup weights were observed among the treated dams and the controls at birth and on Days 1, 4 and 14 post partum.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant differences in mean pup weights were observed among the treated dams and the controls at birth and on Days 1, 4 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:

effects observed, non-treatment-related

Description (incidence and severity):

Day 4 post partum
No changes of toxicological relevance were observed.

Day 14 post partum
No changes were recorded.

Urinalysis findings:

not examined

Sexual maturation:

no effects observed

Description (incidence and severity):

Anogenital distance in treated pups was comparable to control pups.
No treatment related effect on nipple counts was observed in male pups on Day 14 post partum.

Anogenital distance (AGD):

no effects observed

Description (incidence and severity):

No differences in the anogenital distance (normalised value), performed on Day 1 post partum, were seen between control and treated groups both for male and female pups.

Nipple retention in male pups:

effects observed, non-treatment-related

Description (incidence and severity):

Six nipples (3 left, 3 right) were observed on Day 13 post partum in a single male pup from a low dose female. This single event was considered to be incidental.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No significant differences were observed in the weight of thyroid in treated pups when compared to controls.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum did not reveal any treatment-related effect.

Histopathological findings:

not examined

Other effects:

no effects observed

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 treatment related effects

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

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

Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening study according to OECD guideline 422, Octadecanoic Acid, reaction products with triethylenetetramine was administered to 10 Sprague-Dawley rats /sex/ at dose levels of 0, 100, 300 and 1000 mg/kg bw/day by gavage.

Males of the main groups were treated for 2 weeks prior to pairing and during pairing with females until the day before necropsy, for a total of 30/31 days. Females of the main groups were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 13 post partum, for a total of 42 to 64 days.

Additionally a recovery group was included (5 rats/sex) for control and high dose with a 4 week treatment-free period in order to assess any delayed toxicity or recovery from any adverse effects observed during the dosing phase. Males of the recovery group were treated for a total of 28 days and killed after 4 weeks of recovery period. Females of the recovery groups were treated for a total of 56 days. The females were sacrificed after 4 weeks of recovery period.

Based on the results of the present study, the NOAEL for general toxicity was considered to be 1000 mg/kg/day for both males and females. Details are reported in section 7.5 of IUCLID dataset.

A slight decrease of Thyroid Stimulating Hormone was recorded in male pup of Groups 3 and 4 (31% and 19%, respectively) at day 4 post partum. Due to the low severity and the absence of other related changes, this finding was considered to be of no toxicological relevance. No changes were recorded at day 14 post partum. No significant differences were observed in the weight of thyroid in treated pups, when compared to controls.

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. 

Oestrous cycle, pre-coital intervals, copulatory index and fertility index did not show intergroup differences. No significant differences were observed for Implantation, pre-birth loss data and gestation length of females between the treated groups and the controls. All dams gave birth between Days 22 and 23 post coitum.

No significant differences in total litter size, live litter size, mean pup loss, sex ratio and mean pup weights were observed among the treated dams and the controls at birth and on Days 1, 4 and 14 post partum.

No differences in the anogenital distance (normalised value), performed on Day 1 post partum, were seen between control and treated groups both for male and female pups.

Six nipples (3 left, 3 right) were observed on Day 13 post partum in a single male pup from a low dose female. This single event was considered to be incidental.

There were no compound-related effects in clinical signs of pups. Pre-weaning clinical signs were comparable between treated and control groups. Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum did not reveal any treatment-related effect.

 

Conclusion:

No treatment-related effects indicating systemic toxicity were observed in male or female animals from main and recovery groups at any of the dose levels investigated (100, 300 and 1000mg/kg/day).

No effects on sexual function and fertility or in developmental parameters and lactation were observed at any of the dose levels investigated.

No changes of toxicological relevance in thyroid hormone levels were oberved in parental animals or in pups at Days 4 and 14 post partum determinations.

Based on the results of the present study, the NOAEL (No Observed Adverse Effect Level) for general toxicity, reproductive and developmental toxicity was considered to be 1000 mg/kg/day for males and females.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

OECD 422 Guideline with GLP

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening study according to OECD guideline 422, Octadecanoic Acid, reaction products with triethylenetetramine was administered to 10 Sprague-Dawley rats /sex/ at dose levels of 0, 100, 300 and 1000 mg/kg bw/day by gavage.

Males of the main groups were treated for 2 weeks prior to pairing and during pairing with females until the day before necropsy, for a total of 30/31 days. Females of the main groups were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 13 post partum, for a total of 42 to 64 days.

Additionally a recovery group was included (5 rats/sex) for control and high dose with a 4 week treatment-free period in order to assess any delayed toxicity or recovery from any adverse effects observed during the dosing phase. Males of the recovery group were treated for a total of 28 days and killed after 4 weeks of recovery period. Females of the recovery groups were treated for a total of 56 days. The females were sacrificed after 4 weeks of recovery period.

Based on the results of the present study, the NOAEL for general toxicity was considered to be 1000mg/kg/day for both males and females. Details are reported in section 7.5 of IUCLID dataset.

A slight decrease of Thyroid Stimulating Hormone was recorded in male pup of Groups 3 and 4 (31% and 19%, respectively) at day 4 post partum. Due to the low severity and the absence of other related changes, this finding was considered to be of no toxicological relevance. No changes were recorded at day 14 post partum. No significant differences were observed in the weight of thyroid in treated pups, when compared to controls.

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. 

Oestrous cycle, pre-coital intervals, copulatory index and fertility index did not show intergroup differences. No significant differences were observed for Implantation, pre-birth loss data and gestation length of females between the treated groups and the controls. All dams gave birth between Days 22 and 23 post coitum.

No significant differences in total litter size, live litter size, mean pup loss, sex ratio and mean pup weights were observed among the treated dams and the controls at birth and on Days 1, 4 and 14 post partum.

No differences in the anogenital distance (normalised value), performed on Day 1 post partum, were seen between control and treated groups both for male and female pups.

Six nipples (3 left, 3 right) were observed on Day 13 post partum in a single male pup from a low dose female. This single event was considered to be incidental.

There were no compound-related effects in clinical signs of pups. Pre-weaning clinical signs were comparable between treated and control groups. Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum did not reveal any treatment-related effect.

 

Conclusion:

No treatment-related effects indicating systemic toxicity were observed in male or female animals from main and recovery groups at any of the dose levels investigated (100, 300 and 1000mg/kg/day).

No effects on sexual function and fertility or in developmental parameters and lactation were observed at any of the dose levels investigated.

No changes of toxicological relevance in thyroid hormone levels were oberved in parental animals or in pups at Days 4 and 14 post partum determinations.

Based on the results of the present study, the NOAEL (No Observed Adverse Effect Level) for general toxicity, reproductive and developmental toxicity was considered to be 1000 mg/kg/day for males and females.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Reproductive toxicity of Octadecanoic Acid, reaction products with triethylenetetramine was assessed based on data from a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening study. The no-observed-adverse-effect-level (NOAEL) for systemic toxicity and also for reproductive/ developmental toxicity was considered to be 1000 mg/kg/day, the highest tested dose.

Considering the available data it can be concluded, that according to GHS Regulation EC No 1272/2008 classification for reproductive toxicity is not warranted for Octadecanoic Acid, reaction products with triethylenetetramine.