4-tert-butylbenzaldehyde

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

Several short-term testicular toxicity screening studies are available in different species, providing evidence testicular toxicity of p-tert-butylbenzaldehyde.

In SFP albino rats, a 5-day oral exposure to p-tert-butylbenzaldehyde caused marked testicular damage: 8 male rats per dose group received 0, 6.5, 12.5, 25 or 50 mg/kg bw/d of the test material via gavage once daily for 5 consecutive days; 4 additional control animals received the respective vehicle in the same manner (Giv B-77426). Body weights, clinical signs were assessed and gross necropsy was performed. Liver, kidneys and testes were weighed. The testes of all rats were microscopically examined. No mortality was observed. Three rats treated with 12.5 mg/kg bw/d showed slight aggressiveness on test days 3 and 4. From days 3 to 6, a slight loss of hair was seen in one animal of the 50 mg/kg bw/d group. The test material did not affect body weights of animals treated with 6.5 and 12.5 mg/kg bw/d. Rats treated with 25 mg/kg bw/d initially showed a slight weight loss and returned to normal at the end of the treatment. The animals of the highest dose group showed a severe weight loss throughout the study. During the dissection, a marbled liver was recorded in 2 rats treated with 50 mg/kg bw/d. In one rat treated with 25 mg/kg bw/d a small dell was seen in the right kidney. Testes weights of rats treated with 50 mg/kg bw/d were significantly lower than those recorded for the controls.

Histopathological changes of the testes were circumscribed in the seminiferous epithelium. Interstitial cells and Sertoli cells were unaffected. Disorganization of the epithelial structure, degeneration of cells and reduction of the spermatozoa were observed. One testis of a control rat showed about 80 % convoluted tubules with a normal epithelium, and about 20 % convoluted tubules with a normal epithelium, but with degenerated cells or detritus in the lumen. The same ratio occured in the animals of the 6.5 and in the 12.5 mg/kg bw/d dose group. An alteration of this ratio was seen from the 25 mg/kg bw/d group on. In addition, severe injuries were observed in the seminiferous epithelia of the testes of one animal treated with 25 mg/kg bw/d. Moderate to severe injuries were discovered in the seminiferous epithelia of all rats treated with 50 mg/kg bw/d. The NOAEL derived for testicular toxicity in rat was 12.5 mg/kg bw/d, based on the histological changes and a slight decrease of the testicular weights. Systemic toxicity in terms of body weight changes were found at doses also exerting testicular toxicity.

 

In further testicular toxicity screening studies with male SFP albino rats and mice, Himalayan guinea pigs and Beagle dogs, one dose (100 mg/kg bw/d) p-tert-butylbenzaldehyde was administered orally (gavage) once daily for five consecutive days (Giv 104`736; Giv 104`738; Giv 104`744; TSCATS-OTS0505405). In these experiments, body weights and clinical signs were monitored. Rats, mice, guinea pigs were inspected by gross necropsy. Testes were weighed in rats, mice, guinea pigs and histopathological examination of the testes was performed in all species examined.

 

In rats, no mortality occurred throughout the study and all animals appeared normal. During the first two days an initial body weight loss was observed, but these rats showed subsequent weight gain at the end of the treatment period. However, final mean body weights in treated animals were still below controls. One of the 7 tested animals had an agenesia of the left kidney and testis. Testes weights of the treated animals were decreased compared to controls whereas weight of liver and kidney showed no relevant difference. Histological examination revealed signs for acute hepatitis and acute interstitial nephritis occurred in animals of treated and control groups. Since these histological findings are commonly seen according to the authors, a parasitic infestation is considered to be the cause rather than compound related effects.

In the testes the treated animals showed injuries in the seminiferous epithelium. Five treated animals showed minimal to moderate degeneration of spermatids and spermatocytes. One treated animal showed a minimal reduction of spermatozoa and all treated animals showed minimal to moderate appearance of multinucleate giant cells. Sertoli cells and Leydig cells were unaffected. In contrast, these findings were not observed in control animals.

 

In mice, no treatment-related findings on body weights and clinical signs of toxicity were observed. At necropsy, a turbid pericardiopleural region with deposits was seen in 2 treated mice, but has been considered to be unrelated to treatment with the test substance. Testes weights of the treated animals showed no effect when compared to control animals. Histological examination revealed a slight damage of germinal epithelium in testes of 1 control and 4 treated animals. A marginally higher incidence of seminiferous tubules showing, many degenerated cells in the epithelium and disorganisation of the epithelial structure (0% versus 0.2%) or severe destruction of the epithelium (0.2% versus 1.2%) were observed for control and test substance treated animals respectively.

 

In guinea pigs, no treatment-related clincal findings, changes on body weights or necropsy findings were observed. The mean testes weights of the control group and of the treated group were not significantly altered. In histology, a slight damage of germinal epithelium was seen in 2 control animals and in 1 treated animal. Furthermore, marginal incidences of seminiferous tubules showing severe destruction of the epithelium (0.2% and 0.1%) were observed for control and test substance treated animals respectively.

 

In dogs, application of p-tert-butylbenzaldehyde resulted in a slight body weight loss up to day 6 (Dog 1, treated: 12.2 kg on day 1, 11.6 kg on day 6; dog 2, treated: 11.1 kg on day 1, 10.0 kg on day 6). There were about 60 cross sectioned seminiferous tubules with nearly total depopulation of germinal epithelium in both testes of one dog. In these seminiferous tubules, early stages of spermatogenesis and Sertoli cells were preserved only. With the exception of the occurrence of multinucleated giant cells - a background finding seen also in the control animal- , no abnormalities were discovered in the testes of the other treated dog. No changes were seen in epididymides of both dogs. The slight damage of germinal epithelium of one dog was considered to be related to treatment.

 

Overall, species specific testicular has been observed. Clear evidences, i.e. degeneration of the germinal epithelium without effects on Sertoli and Leydig cells, has been found in rats and a NOAEL was set at 12.5 mg/kg bw/d. Testicular toxicity was accompained by general toxicity in terms of body weight changes. Furthermore, evidences for comparable testicular effects were found in 1 / 2 beagle dogs, however, due to the low animal number, a final conclusion on suceptibility of dogs for p-tert-butylbenzaldehyde induced testicular toxicity cannot be drawn. Marginal incidences of degenerated tubuli seminiferi were found in mice and guinea pigs, which do not clearly differ from control animals, indicating an absence or lower suceptibility for p-tert-butylbenzaldehyde induced testicular toxicity in these species.

Short description of key information:
5 d, rat, gavage: NOAEL = 12.5 mg/kg bw/day (Giv B-77426)

Effects on developmental toxicity

Additional information

no data available

Justification for classification or non-classification

Overall in a weight of evidence, the present data on reproductive toxicity fulfill the criteria laid down in 67/548/EEC and 1272/2008/EEC and a classification as Repr. Cat3; R62 (67/548/EEC) and reproductive toxicant; Cat2 (1272/2008/EEC) is warranted.