Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Effects on fertility and developmental toxicity were tested in a combined experimental study (OECD 422 screening study).

The statistical analysis revealed significantly lower number of implantation sites, number of live pups and significantly high rate of percent pre and post implantation in HD group when compared to corresponding control. The statistical deviation observed as above might be due to treatment. Statistically no deviation was recorded for number of corpora lutea when compared to control.

Statistically significant difference was observed for precoital interval and duration of gestation in the females of HD group when compared to corresponding controls. All pregnancies resulted in normal births except for one animal (animal no. 37) in HD group, which resulted in still births. Hence, the effects observed in HD group might be considered treatment related. Successful mating resulted in 10/10 pregnancies in control, 9/9 pregnancies in LD groups, 9/10 pregnancies in MD groups and 3/5 pregnancies in HD.

The fertility index (No. of pregnant females/No. of copulated females X 100) observed in control and treatment groups are as follows: Control- 100%; LD- 100%; MD groups (90%) and HD (60 %). The decreased fertility rate in HD group might be related to treatment despite of premature deaths in HD group.

As no effects on reproductive organs were noted on terminal sacrifice animals, the minor histopathological changes were not considered to be directly test item-related, but might rather be a consequence of a general stress situation in the animals concerned.

The statistical analysis revealed significantly lower total pups born, number of females, live pups (PND 0 and 4) and significantly high number of still births in HD group when compared to the corresponding controls. The statistical difference observed in HD group might be due to treatment.

Survival of the pups from PND 0 to PND 4 remained unaffected due to treatment in all treatment groups. One pup from female no. 22 (pup no. 9) was found dead on PND 1 and was a runt. Apart animal no. 37 of HD group resulted in complete still births. The finding of still births, although in individual animal of HD group, might be considered due to treatment.

Gross necropsy of dead pups revealed no treatment related findings.

The general effect seen mainly for the fertility end-point may be considered directly correlated to the maternal toxicity occurred in most of the females treated and not a direct toxic effects.

Based on effects for fertility and developmental end-points, NOAEL for reproduction is therefore set at 300 mg/kg/day.

On the basis of the study results no additional reproductive toxicity studies on the substance is evaluated as scientifically necessary.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 06 - August 26, 2010
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to guideline
Guideline:
other: OPPTS 870.3650, Combined repeated dose Toxicity study with the Reproduction/ developmental Toxicity screening
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
Previous names of the test substance: MK 195KSF; Naphthenic acids, reaction products with diethylenetriamine.
Batch No.: MK195K/BM/198/067/A/001
Physical state at RT: Hazy solid
Colour: orange/brown
Active Components (%): 100
Storage Conditions: at room temperature
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Young healthy male and nulliparous, non pregnant female rats [strain: Wistar Crl:WI] (Full-Barrier), were used in this study. The animals were derived from a controlled full barrier maintained breeding system (SPF) (Source: Charles River, 97633 Sulzfeld, Germany).
At the beginning of the study, the age of the animals was 8-9 weeks.
The range of the body weight was:
Females: 154 to 183 g, (mean: 167.93 g, ± 20%= 33.59 g)
Males: 213 to 233 g, (mean: 222.30 g, ± 20%= 44.46 g)
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animals were randomly assigned (using Microsoft Excel template) to the dose/control groups, each animal was assigned a unique identification number and caged individually. The animals were acclimatised for at least five days before the first dose administration.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
The test item was administered by gavage using a gavaging cannula. The maximum dose volume administered was 5 mL / kg body weight.



The test item was dissolved/ suspended in corn oil (Batch No.: 11KBC6753; Storage conditions: at room temperature).

The vehicle was chosen as suggested by the test item‟s solubility.
Before dose formulation preparation test item was heated up to 80º C. The test item was weighed and the required volume of vehicle was added for better and speedy dissolution.
The test item formulation was prepared freshly on each administration day before the administration procedure.
Based on the available information from other toxicity studies following doses were selected:
Control: 0 mg/kg bw
LD: 100 mg/kg bw
MD: 300 mg/kg bw
HD: 750 mg/kg bw
The highest dose level is chosen with the aim of inducing toxic effects but not death or severe suffering. Thereafter, a descending sequence of dose levels is selected with a view to demonstrate any dosage related response and no-observed-adverse effects at the lowest dose level (NOAEL).
The animals in the control group were handled in an identical manner to the test group subjects and received the vehicle in the volume same as treated groups.

Storage conditions: at room temperature (RT),
Safety precautions: Routine hygienic procedures were sufficient to assure personnel health and safety
Details on mating procedure:
Animals were paired in the ratio of 1:1 (male to female). The subsequent morning and the next morning there onwards the vaginal smear of female were checked to confirm the evidence of mating. The day of vaginal plug and/or sperm was considered as day 0 of gestation. Cages were arranged in such a way that possible effects due to cage placement was minimised.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Each dosing concentration was analysed for nominal concentration.
Homogeneity of the test item in the vehicle was analysed for the low and high dose concentrations.
Samples for the nominal concentration verification were taken in study week 1 (first week of pre mating period), 3 (first week of mating), 5 (gestation) and 7 (gestation/lactation).
Samples for homogeneity were taken from the top, middle and bottom of the high dose and low dose preparation in study week 1 and 5.
All formulation samples were analysed on the same day of collection.
The results of the concentration measurements revealed recoveries between 85.3 % and 98.5% in HD group, between 86.4 % and 97.2 % in MD group and between 87.6 % and 95.5 % in LD group. Homogeneous distribution of the test substance in the preparation was approved.
Results are given as concentration in mg/mL and as recovery referring to nominal concentration.
Duration of treatment / exposure:
The test substance was administered daily during 14 days pre mating and 14 days mating in both male and in female, during gestation period and up to post natal day 3 in females. Males were dosed for 28-30 days.
Frequency of treatment:
daily; the animals were dosed with the test item on 7 days per week basis.
Details on study schedule:
Four groups comprising 10 adult males and 10 non pregnant nulliparous female rats (Wistar Crl:WI) were dosed daily by oral gavage with 100, 300 and 750 mg/kg body weight per day.
The test item was formulated in corn oil with administration volume of 5 mL/kg body weight.
Control animals were handled identically as treated groups and received corn oil in similar volume as treated groups.
The test item formulation was prepared freshly and administered daily during 14 days pre mating and 14 days mating period in both male and in female, during gestation period and up to post natal day 3 in females. Males were dosed for 28-30 days. Dose volumes were adjusted weekly based on the body weight measurement.
After 14 days of treatment to both male and female, animals were paired (1:1) for maximum 14 days.
The subsequent morning onwards the vaginal smears of females were checked to confirm the evidence of mating.
After the confirmation of the mating, females were separated. Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, still births, live births, runts and the presence of gross abnormalities. Live pups were counted, sexed and litters weighed within 24 hours of parturition and on day 4 post-partum.
Males and females were sacrificed on treatment day 29-31, post natal day 4 respectively and subjected to necropsy. Non Pregnant females were sacrificed on their respective day 26 after the evidence of mating.
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
750 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
80 animals (10 females and 10 males/group) were included in the study
Control animals:
yes, concurrent vehicle
Details on study design:
The duration of gestation was recorded and is calculated from day 0 of pregnancy.
The test item formulation was administered daily during 14 days pre mating and 14 days mating period in both male and in female, during gestation period and up to post natal day 3 in females. Males were dosed for 28-30 days.
After 14 days of treatment to both male and female, animals were paired (1:1) for maximum 14 days.
The subsequent morning onwards the vaginal smears of females were checked to confirm the evidence of mating.
After the confirmation of the mating, females were separated. Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, still births, live births, runts and the presence of gross abnormalities. Live pups were counted, sexed and litters weighed within 24 hours of parturition and on day 4 post-partum.
Animals were examined for the daily clinical signs, mortality, weekly detailed clinical observations, pre treatment and at termination for functional observations. Body weight and food consumption was measured weekly except food consumption was not measured during the mating period (female) and mating/post mating period (male). Haematological and clinical biochemistry evaluations were performed on blood samples collected at terminal sacrifice from five males and five randomly selected females from each group. Urinalysis was performed on samples collected at terminal sacrifice from five randomly selected males from each group.
Reproductive organs from all animals were weighed (testes, epididymides, prostate, seminal vesicle with coagulating glands as whole, ovaries, uterus with cervix as applicable).
Testes, epididymides, ovaries, uterus with cervix, vagina, accessory sex organs (prostate, seminal vesicle with coagulating gland) and all organs showing gross lesions were examined in all animals. For testis, a detailed qualitative examination was made.
Live Pups were identified by writing actual numbers on the back with the help of permanent marker In addition to the observations on parent animals abnormal behaviour of the offspring, if any, was recorded.
The number of implantation sites and corpora lutea was recorded for each parental female at necropsy.
Dead pups and pups sacrificed at day 4 post-partum, or shortly thereafter were carefully examined for gross abnormalities.
Parental animals: Observations and examinations:
Detailed Clinical Observation/Functional observation battery:
General clinical observations were made twice a day except during weekend and holidays where observations were made only once.
Once before the first exposure, and once a week thereafter, detailed clinical observations were made in all animals.
Sensory reactivity to different modalities, grip strength and motor activity assessments and other behaviour observations were conducted on five randomly selected males and females from each group. Observation was occurred during the last week of treatment in males and on day 3 of the lactation in females.

Body Weight and Food Consumption:
The animals were weighed at randomisation, males weekly during the entire study period and at terminal sacrifice.
Food consumption was measured on corresponding day of body weight after beginning of the dose administration. Food consumption was not measured during mating period.

Haematology:
Haematological examinations were made in five males and five females randomly selected from each group.
Blood samples were taken from the abdominal aorta as a part of the procedure for killing the animals.

Clinical Biochemistry:
Clinical biochemistry determinations to investigate major toxic effects in tissues and, specifically, effects on kidney and liver were performed on blood samples obtained from the randomly selected five males and five females of each group.
Urinalysis was performed on the samples collected from five randomly selected males at the terminal sacrifice.

Gross Pathology:
At the time of sacrifice or death during the study, the adult animals were subjected to a full, detailed gross necropsy which includeed careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents.
The number of implantation sites and corpora lutea was recorded for each parental female at necropsy.

Organ Weight:
Reproductive organs from all animals were weighed.
Apart from the reproductive organs from all animals, from five adult males and females randomly selected from each group, the wet weight of the liver, kidneys, adrenals, thymus, spleen, brain and heart were taken as soon as possible. Paired organs were weighed separately and no organ weights will be taken for animals found dead.

Histopathology:
Full histopathology was carried out on the preserved organs and tissues of the five randomly selected animals (Male and Female) in the control and high dose groups.
Testes, epididymides, ovaries, uterus with cervix, vagina, accessory sex organs and all organs showing gross lesions were examined in all animals.
Sperm parameters (parental animals):
Testes, epididymides, accessory sex organs (prostate, seminal vesicle with coagulating gland) and all organs showing gross lesions were examined in all animals.
For testis, a detailed qualitative examination was made.
Litter observations:
Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, still births, live births, runts and the presence of gross abnormalities. Live pups were counted, sexed and litters weighed within 24 hours of parturition and on day 4 post-partum.
Postmortem examinations (parental animals):
Body weight determination; haematological examinations; clinical biochemistry determinations; urinalysis; gross necroscopy; organ weight determination; histopathological examinations.
Postmortem examinations (offspring):
Dead pups and pups sacrificed at day 4 post-partum, or shortly thereafter were carefully examined for gross abnormalities.
Statistics:
Parameters like body weight gain and food consumption were calculated for each animal as the difference in weight measured from one week to the next. The relative organ weights were calculated in relation to the body weight (measured at necropsy) and presented as percentage.
All results are reported in tabular form.
For statistical analysis one-way analysis of variance (ANOVA) followed by Dunnett‟s multiple comparison test was carried out to reveal any differences between control- and test groups. These statistics were performed with GraphPad Prism V.5 software (p<0.05 was considered as statistical significant).
In the evaluation of laboratory parameters all values within a range of the mean value the two fold standard deviation (x 2s) are considered to be „normal“ values within a „normal“ population.
Reproductive indices:
Fertility index and delivery index
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Test item related clinical findings namely piloerection, vocalization, pushing the bedding and salivation were recorded in most animals of treatment groups during the study. Occasionally findings like reduced spontaneous activity, weight loss, dyspnoea, diarrhoea, nasal discharge (bloody or plain) and dehydration were also observed.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
During the study twelve rats were found dead or sacrificed moribund. Out of these, 1 male from control, 1 male and 1 female from LD group and 3 males/ 6 females of HD group died or sacrficed.
The death of three females (animal no.s 34, 35, 39) could not be determined due to advanced autolysis and as a reason no pathological evaluation could be performed.
The histopathological evaluation has revealed that the intercurrent deaths observed might possibly be due to gavaging error.
In addition in most of the HD intercurrent dead animals similar findings in the mesenteric lymph node, small intestine and stomach were found corresponding to those seen in terminal kill animals of this group which may have accounted for the degraded health status observed before death in these animals.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In males, the statistical analysis revealed significantly lower body weight development during premating period in HD group when compared with the controls, which further recovered during mating/post mating period.
Significantly low weight development was also observed on first week of mating/post mating period in MD group, which further recovered during second week of mating/post mating period. Overall from premating day 1 to mating/post mating day 14, the body weight development was significantly lower in MD and HD group.
In females, the statistical analysis revealed significantly lower body weight development during second week of premating period in HD group. Significant low weight development was also recorded during GD 0-7 (MD and HD groups), GD 7-14 (HD group), GD 14-20 (MD and HD groups), GD 0-20 (MD and HD groups). There was also a consistent dose response pattern observed for all treatment groups when compared to the corresponding controls.
The low body weight development in MD or HD groups might be considered due to treatment.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In males and females, statistical analysis reavelaed significantly lower food consumption during premating period in HD group when compared to the corresponding controls.
In females, significantly lower food consumption was also recorded during GD 0-7 and 14-20 in MD and HD groups when compared to corresponding controls. During GD 7-14 the measurement of food consumption was inadvertently not measured. Hence, there is no data available.
The food intake and weight development are correlated to each other. Hence, the lower food intake in MD or HD group is considered to be due to treatment related.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant deviation was for few hematological parameters MD or HD groups when compared to corresponding control values and also some individual values were below or above the historical control range, which are presented as follows.
WBC: In male, 1 individual value in LD group was below the historical control range. In females, 2 individual values in Control and 2 individual values in LD group were below the historical control range. Statistical significance was observed for male HD group and female MD and HD group compared to corresponding controls.
RBC: In males, all individual and mean values were within the historical control range. In females, 1 individual value each in control, LD and MD were below thehistorical control range.
HGB: In males, all individual and mean values were within the historical control range. In females, 1 individual value each in control and LD, 2 individual values each in MD and HD groups were below the historical control range.
MCV: In males, all individual and mean values were within the historical control range. In females, 1 individual value each in Control, LD and MD groups were above the historical control range. Statistical significance was observed for female HD group when compared to the control.
MCH: All individual values in male and female control and treatment groups were with historical control range. The statistical evaluation revealed significantly low value in female HD group compared to control.
Platelet: All individual values in male and female control and treatment groups were with historical control range. The statistical evaluation revealed significantly high value in male HD and female MD group compared to corresponding control.
aPTT: In males, 1 individual value in control was above the historical control range, while 1 individual values each in LD and MD groups were below the historical control range. In females, 1 individual value each in LD, MD and HD groups were below the biological range. There was no statistical deviation observed between the treatment and control groups.
PT: The statistical evaluation revealed significantly high value in male and female HD group.
Neutrophils: In males, 2 individual values and a mean value in MD group, 3 individual values and a mean value in HD group were above the historical control range. In females, 1 individual value in LD group, 3 individual values and mean value in MD group and all individual values and a mean values in HD group were above the historical control range. The statisatical significance was observed for both male and female MD and HD groups when compared to corresponding controls.
Lymphocytes: In males, 2 individual values and a mean value in MD group, 3 individual values and mean value in HD group were below the historical control range. Statistical significance was observed for male and female MD and HD groups when compared to the controls.
Monocytes: All individual values in male and female control and treatment groups were with historical control range. Statistically significant high values were observed in male MD and HD groups and female HD group compared to corresponding controls.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant deviation was for few clinical biochemistry parameters in treatment groups when compared to corresponding control values and also some individual values were below or above the historical control range, which are presented as follows.
GLU: In males, 1 individual value in control, 4 individual values and a mean value in LD group, 2 individual values in MD group were above the historical control range. In females, 1 individual value in MD group was above the historical control range. There was no statistical deviation observed between treatment and control groups. The deviation from the normal historical range could be due to differential feeding as the animals were not starved overnight.
CHOL: In males, all individual and mean values in control, LD (except 1 individual value) and HD groups, 3 individual values and a mean value in MD group were below the historical control range. In females, all individual and mean values in control, MD and HD, 3 individual values and a mean value in LD were below the historical control range. But there was no statistical deviation observed between the treatment and control groups.
TP: In males, all in individual and mean values of treatment and control groups were below the historical control range. In females, 2 individual values in control, all individual values and a mean value in LD and MD groups, 2 individual values and a mean value in HD group were below the biological range. There was no statistical deviation observed between the treatment and control groups.
ALBB: in males, 2 individual values in HD group were below the historical control range. In females, all individual and mean values were with the historical control range. The statistical deviation was observed for females LD, MD and HD groups compared to control.
SGPT: In males and females, all individual and mean values were within the historical control range. The statistical evaluation revealed significantly high value in male HD group compared to controls.
Na: In males and females, all individual and mean values were within the historical control range. The statistical evaluation revealed significantly low value in female HD group compared to controls.
Urinalysis findings:
no effects observed
Description (incidence and severity):
The urinalysis revealed no significant differences in any of the treatment groups compared to corresponding control.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No relevant differences were observed concerning functional and behavioural examination in males and females.
No abnormalities were recorded concerning posture, gait, palpebral closure, lacrimation and arousal, except for piloerection and respiration observed in MD or HD group animal during the study.
No convulsions, tremors, stereotypy or bizarre behaviour were observed for the animals of any groups.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At terminal sacrifice, histopathological changes considered to be directly test item-related and toxicologically relevant were seen in the small intestine (jejunum and ileum), mesenteric lymph node, spleen, lung and adrenal gland.
In HD group, minor aggregations of foamy histiocytes were seen in the villi of small intestine. In all treatment groups, minimal to marked histiocytic infiltrates were observed in the mesenteric lymph node (draining lymph node of the small intestine). The effect on mesenteric lymph node was strongly dose-related and in many cases associated with foci of necrosis and/or abscessation as well as in some cases also with other secondary changes. Histiocytic infiltrates were also noted in the spleen or lung of isolated animals of MD or HD groups. In the female MD and HD group, there were also higher grades of alveolar macrophage aggregations in the lung. In the inner cortex of the adrenal gland, minor vacuolation was noted in isolated animals and/or minor mononuclear cell infiltrates were seen in a proportion of animals of MD or HD groups and in a single female of LD group.
Histopathological lesions of the tracheal epithelium (diffuse epithelial alteration) and gastric nonglandular mucosa of stomach (extensive or diffuse epithelial hyperplasia) were seen in occasional decedents and/or terminal kill animals, predominantly of the high dose group, and were considered to be likely due to a local irritant effect of the test item. Further histopathological organ changes in the spleen, lung, liver, bone marrow and thymus were considered secondary to a general inflammatory state caused by test item effects in treated animals, or to stress.
Among the decedents, two HD group females did not show physiological estrous cycle, and in two decedent HD group males, there was minor testicular degeneration and/or decreased secretion in the sexual glands. As no effects on reproductive organs were noted on terminal sacrifice animals, these minor changes were not considered to be directly test item-related, but might rather be a consequence of a general stress situation in the animals concerned.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, non-treatment-related
Description (incidence and severity):
In males, statistically significant low mean values were observed for absolute weight seminal vesicle + coagulating gland (HD group) when compared with the corresponding controls.
The relative organ weight was significantly deviated for testes (MD group), seminal vesicles + coagulating gland (HD group).
The deviation observed for the relative organ weight of reproductive organs (seminal vesicles+coagulating gland) could be due to histopathological changes considered not to be directly related to test item, but attributed to general stress situation.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Precoital Interval, Duration of gestation and fertility Index:
Statistically significant difference was observed for precoital interval and duration of gestation in the females of HD group when compared to corresponding controls. All pregnancies resulted in normal births except for one animal (animal no. 37) in HD group, which resulted in still births. Hence, the effects observed in HD group might be considered treatment related.
Successful mating resulted in 10/10 pregnancies in control, 9/9 pregnancies in LD groups, 9/10 pregnancies in MD groups and 3/5 pregnancies in HD.
The fertility index (No. of pregnant females/No. of copulated females X 100) observed in control and treatment groups are as follows; Control- 100%; LD- 100%; MD groups (90%) and HD (60 %). The decreased fertility rate in HD group might be related to treatment despite of premature deaths in HD group.

Pre and post natal data:
The statistical analysis revealed significantly lower number of implantation sites, number of live pups and significantly high rate of percent pre and post implantation in HD group when compared to corresponding control. The statistical deviation observed as above might be due to treatment.
Statistically no deviation was recorded for number of corpora lutea when compared to control.

Reproductive Indices:
Reduced fertility index and delivery index was recorded in HD group when compared to corresponding controls, which could be related to treatment despite of premature deaths in HD group.
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Clinical signs:
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The statistical analysis revealed significantly lower total pups born, number of females, live pups (PND 0 and 4) and significantly high number of still births in HD group when compared to the corresponding controls. The statistical difference observed in HD group might be due to treatment.
Survival of the pups from PND 0 to PND 4 remained unaffected due to treatment in all treatment groups. One pup from female no. 22 (pup no. 9) was found dead on PND 1 and was a runt. Apart animal no. 37 of HD group resulted in complete still births. The finding of still births, although in individual animal of HD group, might be considered due to treatment.
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Gross necropsy of dead pups revealed no treatment related findings.
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: still births, runts , presence of gross abnormalities.
Reproductive effects observed:
yes
Lowest effective dose / conc.:
750 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
Based on the data generated from this combined repeated dose toxicity and reproduction/ developmental toxicity screening test with Fatty acids, C10-20 neo, reaction product with diethylenetriamine, the NOAEL is believed to be 300 mg/kg bw for reproductive/ developmental toxicity.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat

Justification for classification or non-classification

Based on the data generated from this combined repeated dose toxicity and reproduction/ developmental toxicity screening test, the substance is not classified as toxic for reproduction according to CLP Regulation.

Additional information