Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

For the substance 14-day range finding studies in rat and rabbit are available in which the effects on the male reproductive organs are investigated. Since these studies do not lead to classification and labelling, only the study summaries are provided below.


Oral (gavage) 14 -day toxicity study in rat

Introduction and Method: In an oral (gavage) study in male Crl:CD(SD) rats, the animals were dosed once daily at 25, 75 and 250 mg/kg bw for 14 consecutive days according to GLP principles. 10 animals were included in each dose group and a vehicle control group (corn oil) was included. 

Rats were observed for viability at least twice each day throughout the study and were examined daily (and the first 4 hours after dosing) for clinical observations during the dosing period. Body weights were recorded daily during the dosage period and prior to sacrifice. Rats were fasted following the final dosage on day 14 to facilitate urine sample collection overnight, beginning on the evening of day 14. Fecal samples were collected following dosage administration on day 14. Surviving rats were sacrificed by carbon dioxide asphyxiation following the last administration (day 15).

All rats were subjected to a complete necropsy examination. For the surviving animals, weights of the epididymides, epididymis left cauda, kidneys, liver, prostate, seminal vesicles and testes were recorded. In addition, microscopic evaluation of the adrenal glands, gross lesions, kidney, liver, prostate, seminal vesicles and testes was performed. In addition, sperm concentration, motility and morphology were assessed in each male.

Results, Systemic effects: All rats survived until scheduled sacrifice and no treatment related clinical observations were recorded. At 250 mg/kg bw significant decreased body weight was observed in the first week of treatment, which was corresponding to the reduced food intake in this period. There were no biologically important differences between the vehicle and treated groups in the urinalysis and there were no substance-related necropsy observations. In the 250 mg/kg bw terminal body weights were significantly reduced in the high dose group. In the 250 and 75 mg/kg bw statistically significant increase in absolute and relative weights of the liver were seen, without related microscopic changes.

Results, Reproductive Organ effects: At 250 mg/kg bw the weights of the epididymides, caudal epididymis, testes and paired kidneys and the ratios of these organ weights to terminal body weight were unaffected. The weights of the seminal vesicle and prostate were reduced in this group. At this dose microscopic examination showed microscopic lesions in testes, epididymides and seminal vesicles including atrophy in the latter. At 250 mg/kg/day, values for the number and percent motile sperm, the number of non-motile sperm and the total sperm count from the vas deferens were unable to be determined.

Results, Reproductive-Sperm effects: At 250 and 75 mg/kg bw/day, the average sperm count and sperm density from the cauda epididymis was reduced or significantly reduced. In addition, the percentage of abnormal sperm, specifically sperm with detached heads or no heads, was significantly increased in the 75 and 250 mg/kg/day dosage groups. In these groups, also a slight increase in the number of sperm that had a broken flagellum.

In summary: In the male rat systemic organ effects are seen at >=75 mg/kg bw: relative liver weights are increased without microscopic findings. At 250 mg/kg bw reproductive organs are affected but not at 75 mg/kg bw. Sperm effects are seen at >=75 mg/kg bw: The overall number of sperm that appeared normal was significantly reduced. There was however no apparent effect on sperm motility at 75 mg/kg/day. At 25 mg/kg bw sperm parameters (motility, concentration and morphology) evaluated were unaffected in the 25 mg/kg/day dose group. Based on the observed effects, a NOAEL of 25 mg/kg bw/day was derived for both systemic effects and effects on reproductive organs.

Oral (gavage) 14 -day toxicity study in rabbit

Introduction and Method: In a non-GLP range finder study the substance was administered once daily via a stomach tube for 14 consecutive days to male New Zealand White (Hra:(NZW)SPF) rabbits. Initially the study was performed at dose levels of 10, 30 and 100 mg/kg bw/day, however since no toxicity was observed, a dose of 300 mg/kg bw/day was assessed in a study extension as well. 5 animals were included in each dose group and concurrent vehicle control groups (corn oil) were included. The rabbits were assessed for viability at least twice daily during the study. The animals were observed for clinical signs before each dose was administered and on the day of scheduled euthanasia. For the first 4 days of dosing in the initial study and the first 2 days in the extension study, post dose observations were conducted at hourly intervals. Body weight and food consumption were checked daily during the dose period, and on the day of scheduled euthanasia (body weight) or prior to placement in the metabolism cages (food consumption). Urine samples (as much as possible) were collected overnight from all rabbits. On day 14 semen samples were collected from each rabbit prior to initiation of dose administration and prior to euthanasia. Sperm motility, count and morphology were evaluated. On day 15, the animals were euthanized by an intravenous injection of a phenobarbital and phenytoin solution. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Microscopic evaluation of the Epididymis and Testis were performed and organ weights of the Epididymis, prostate gland, seminal vesicle gland, kidney, liver and testis were recorded.

Results, Systemic effects: No signs of toxicity were observed in the initial study (up to 100 mg/kg bw/day) in any of the assessments. In the extended study (300 mg/kg bw/day) all animals survived until scheduled euthanasia on Day 15 of study. No treatment related clinical observations were recorded and no gross lesions were revealed. Body weights and body weight gains were unaffected by the 300 mg/kg/day dosage. Absolute and relative food consumption values were unaffected and terminal body weights and organ weights were comparable to the control group. Relative liver and kidney weights were slightly increased at 300 mg/kg bw, 13 and 9%, respectively without reaching statistical significance.

Results, Reproductive effects: Test article-related microscopic findings were noted in the testes and epididymis of rabbits given 300 mg/kg/day. All five rabbits in this group had minimal or mild increases in residual bodies in the testes. Three of these rabbits also had mild or minimal depletion of spermatozoa in the epididymides and of these three rabbits, two also had detachment of the seminiferous tubules of the testes. The detachment in the seminiferous tubules was noted when large clear areas were present within the seminiferous epithelium separating the germ cells. The minimal to mild nature of these changes wouldn’t likely have biologic significance. Values for number and percent motile sperm, number of non-motile sperm and total sperm count were comparable to the control group. The values for sperm count and concentration from ejaculated semen samples were highly variable across the dose groups. The percentage of abnormal sperm on DS 15 was highest in the 300 mg/kg/day dose group (38.0%), as compared to the concurrent control value as well as the values in the initial study (ranged from 15.4% to 29.2%). The abnormal sperm consisted primarily of sperm with detached heads. The increase for the group average could be attributed to two rabbits, which had 49.5% and 60.0% abnormal sperm, respectively. The significance of this effect is somewhat inconclusive because the percentage of abnormal sperm before dose administration was also highest in the 300 mg/kg/day dose group (23.7%), as compared to the concurrent control (17.8%), and as compared to the pre-dose values for the rabbits in the other groups (ranged from 12.9% to 17.7%).

In conclusion administration of 300 mg/kg/day resulted in slight increase in relative liver and kidney weights. In this 300 mg/kg bw dose microscopic changes in the testis (increased residual bodies, detachment of seminiferous tubules) and epididymis (spermatozoal depletion) was seen. There was also a slight increase in the percentage of abnormal sperm (primarily detached heads). In absence of effects at 100 mg/kg bw, the NOAEL is set at this dose. 

Justification for classification or non-classification

Additional information