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EC number: 806-510-7 | CAS number: 1393571-43-1
Based on the data generated from the combined repeated dose toxicity and reproduction/ developmental toxicity screening test with the analogue substance, no effects were reported on reproductive/ developmental toxicity parameters measured in this study. There were also no effects reported on general toxicity parameters except for the reported macroscopic/microscopic lung changes at all doses tested, 100, 300 and 1000 mg/kg bw. Due to the lack of clear dose-response relationship (solely restricted to histopathological lung changes) observed in this study, the suitable NOAEL (No observed adverse effect level) general toxicity could not be determined. However, for reproductive/ developmental toxicity, the NOAEL could be set at 1000 mg/kg bw.
In male and female, statistically no significant effect was observed for any of the hematological and clinical biochemistry parameters when compared to their corresponding control. However, there were some individual deviations observed from the historical control range for the respective parameters.
Urinalysis in five randomly selected males from each group revealed no test item related effect.
Necropsy revealed macroscopic changes associated with liver, lung and epididymides in most of the animals of all groups, but microscopically only in lungs, the histopathological changes were observed in the animals of LD, MD and HD groups. No test item related changes were observed in pups at necropsy or death during the study.
In males, statistically no significant differences in the absolute and relative organ weights of the treatment groups was observed when compared with the controls.
In females, statistically significant difference was observed for relative brain weight in LD and HD group compared to controls.
In the female and male reproductive organs, no histopathological lesions considered to be test item-related were noted. Three females were recorded non pregnant during the study, but in histopathology showed normal cycling activity.
Test item-related histopathological lung changes like multifocal subacute bronchopneumonia, characterized by peribronchial foci of prominent fibrosis, with re-epithelialization, infiltration with mononuclear cells, histiocytes and occasional multinucleated cells, was observed in a small proportion of treated males and females of all dose groups, without dose relationship. In addition, a mild amount of intrahistiocytic black material was seen in the lung of each one male in LD and HD group.
The test is performed with an analogue. No effects on fertility were reported at any of the doses tested (100, 300 and 1000 mg/kg bw).The rationale for the read-across can be found in chapter 13
In a developmental toxicity study according to OECD 414, no adverse effects were noted related to maternal and developmental toxicity at the highest dose tested 1000 mg/kg bw.
For detailed results and historical data see attached tables
Body weight (gain)
Body weight (gain) corr. for gravid uterus weight
Gravid Uterus weight (g)
Early resorptions (%)
NoNot statistically significant and only slightly < historical controls
Late resorptions (%)
Pre-Implantation loss (mean %)
within historical controls
Post-Implantation loss (mean %)
Viable foetuses (%/mean)
Dead foetuses (%)
NTRE= no treatment related effects
Fetal weight (mean g)
Sex ratio (%)
External findings(% litters affected)
- Omphalocele (no. foetuses)
Visceral malformations(no foetuses/no litters)
Malformations (no of foetuses):
Variations (no of foetuses):-Small supernumerary liver lobes/ appendix of the liver
Skeletal malformations(no foetuses/no litters)
Malformations (no foetuses)
- bent limb bones
- malpositioned metatarsals
- small mandibles
- vertebral centra anomaly
Variations (% litters)
*PELVIC GIRDLE- CAUDAL SHIFT,14TH FULL RIB(S), REDUCED OSSIFICATION OF THE SKULL, BENT RIB(S), STERNEBRA(E) MALALIGNED (SLIGHT OR MODERATE), METACARPAL(S) AND/OR METATARSAL(S) UNOSSIFIED, 7TH CERVICAL OSSIFICATION SITE(S), 7TH CERVICAL FULL RIB(S), STERNEBRA(E)- BRANCHED, VERTEBRAL CENTRA- REDUCED OSSIFICATION, SKULL- SUPERNUMERARY SITE ,VERTEBRAL ARCHES- REDUCED OSSIFICATION AND STERNEBRA(E) #5 AND/OR #6 UNOSSIFIED
Accuracy of preparation
The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 85% and 115%). The mean accuracy was 98% for Group 2, 96% for Group 3 and 103% for Group 4.
No test item was detected in the Group 1 formulation.
The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation = 10%). The coefficient of variation was 2.7% for Group 2 and 2.8% for Group 4.
For further detail on summary data,see attached document with tables.
No mortality occurred in this study.
No toxicologically relevant clinical signs were noted during the observation period. Alopecia was noted for single females of the control, 300 and 1000 mg/kg groups. This finding occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were considered signs of no toxicological relevance.
Mean body weights, body weight gain and weight gain corrected for gravid uterus of treated animals remained in the same range as controls over the treatment period.
Food consumption before or after correction for body weight was similar between treated and control animals over the treatment period.
Macroscopic examination at necropsy revealed no toxicologically relevant findings.
The only alteration observed was alopecia, noted for three females, confirming the clinical sign observed during the in-life phase.
2.6.Maternal Pregnancy Data
One female at 1000 mg/kg (no. 82) was not pregnant. All other females were pregnant and had litters with viable fetuses.
As all females were mated before start of treatment, the test item cannot have had an effect on the initial
There were no toxicologically relevant effects on the numbers of pregnant females, corpora lutea and implantation sites, or in pre- or post-implantation loss by treatment up to 1000 mg/kg.
The statistically significantly lower pre-implantation loss at 100 and 300 mg/kg were considered to be caused by a relatively high concurrent control value (11.2% compared to historical control mean value of 6.2%)
There were no treatment-related effects on litter size of any group.
Mean litter sizes were 10.0, 10.5, 10.2 and 9.3 fetuses/litter for the control, 100, 300 and 1000 mg/kg groups, respectively.
The percentage of viable fetuses was slightly lower in the 1000 mg/kg group (88.3%), when compared to the control group (94.6%). This was related to the slightly higher percentage of early resorptions at 1000 mg/kg (11.2%), compared to controls (4.5%). As these changes were not statistically significant and only slightly outside the range of the available historical control data, they were not considered to be toxicologically relevant.
Range of historical control data of viable fetuses/litter and early resorptions/litter: 88.9% - 98.4% and 1.6% -
The male:female ratio was unaffected by treatment up to 1000 mg/kg.
Mean sex ratios (males:females) were 44:56, 53:47, 51:49 and 47:53 for the control, 100, 300 and 1000 mg/kg groups, respectively.
3.3.Fetal Body Weight
There were no effects on fetal body weights (both sexes) noted by treatment up to 1000 mg/kg.
Mean combined (male and female) fetal body weights were 5.0, 5.2, 5.1 and 5.2 gram for the control, 100, 300 and 1000 mg/kg groups, respectively.
4.Fetal Morphological Examinations
The numbers of fetuses (litters) available for morphological examination were 221 (22), 232 (22), 225 (22) and 196 (21) in Groups 1, 2, 3, and 4, respectively. External examination was done for all fetuses, visceral examination was done for approximately half of the fetuses of all groups, and skeletal examination was done for the other half of fetuses.
4.1.Exteral Malformations and Variations
There were no treatment related effects on external morphology following treatment up to 1000 mg/kg.
The only external malformation (an omphalocele) observed in this study was noted in control fetus A020-10 and as such was considered a chance finding.
External variations were not seen in any group.
4.2.Visceral Malformations and Variations
There were no treatment related effects on visceral morphology following treatment up to 1000 mg/kg.
One visceral malformation was observed, which occurred in fetus A025-12 at 100 mg/kg. This fetus missed one of the two kidneys. As this rare malformation occurred singly, it was considered a chance finding.
The two visceral variations that were noted in this study both involved the liver (small supernumerary liver lobes and appendix of the liver) and as these occurred at low incidences and in the absence of a dose-related incidence, they were not considered to be treatment related.
4.3.Skeletal Malformations and Variations
There were no treatment related effects on skeletal morphology following treatment up to 1000 mg/kg.
Skeletal malformations were observed in 1 (1), 4 (4), 4 (3) and 2 (2) fetuses (litters) in Groups 1, 2, 3 and 4, respectively. The most common malformation was bent limb bones (scapulas and/or humeri) that occurred in one control (A008-02), one Group 2 (A031-11), four Group 3 (A047-11, A056-08, A065-07 and -09) and one Group 4 fetus (A084-09). The group distribution of this malformation did not indicate a relation to dose concentration and as it is also the most common observed malformation in historical controls, it was not considered tobe toxicologically relevant.
Other malformations that were revealed included malpositioned metatarsals noted in Group 4 fetus (A088-03) and small mandibles, vertebral centra anomaly and sternoschisis noted in Group 2(fetus A044-09, A033-03 and A032-05, respectively). Because these occurred singly, they were considered chance findings.
Skeletal variations occurred at an incidence of 84.8%, 78.0%, 84.2% and 79.7% per litter in Groups 1, 2, 3 and 4, respectively. All the ones noted, were not considered to be treatment related as they occurred in the absence of a dose-dependent relationship, infrequently and/or at frequencies that were within the range of available historical control data.
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 20 post-coitum at doses of 100, 300 and 1000 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 and body weight were determined at periodic intervals. Formulations prepared on one day during treatment were analyzed for accuracy and homogeneity. All animals surviving to Day 21 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. Gross lesions were collected and fixed from all animals at necropsy. 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; these fetuses were dissected and examined for visceral anomalies. The other one-half of the fetuses were processed and stained with Alizarin Red S for skeletal examinations.
Accuracy and homogeneity of formulations were demonstrated by analyses.
No maternal toxicity (i.e. mortality, clinical signs of toxicity, toxicologically relevant changes in body weight or food consumption or macroscopic alterations) was observed in the 100, 300 and 1000 mg/kg groups.
No developmental toxicity (i.e. toxicologically relevant changes in the number of implantation sites, pre- or post-implantation loss, litter size, sex ratio, fetal body weights or fetal morphological alterations) was observed in the 100, 300 and 1000 mg/kg groups.
Based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Levels (NOAEL) for reaction products of tall oil fatty acids with diethylenetriamine and maleic anhydride were established as being 1000 mg/kg.
Twenty-two female rats/group were exposed to the analogue substance during day 6 to 20 post-coitum at 0, 100, 300 and 1000 mg/kg bw by gavage. No effects on maternal mortality, bodyweight (gain), clinical signs, food consumption and macroscopy were found. No effects were reported on maternal developmental parameters like abortions, implantation loss, resorptions and fetal deaths. The litter size as well as the sex ratio, number and weight of the fetuses did not differ between dose groups. No treatment related external, visceral and/or skeletal malformations were observed. The NOAEL for maternal toxicity is 1000 mg/kg bw. The NOAEL for developmental toxicity is 1000 mg/kg bw.
Based on the developmental toxicity study as performed with the analogue substance and the outcome of the repeated dose/reproduction screening study with the other analogue, no classification is warranted.
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