3,7-bis(diethylamino)phenoxazin-5-ium acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 3,7-bis(diethylamino)phenoxazin-5-ium acetate. The NOAEL was estimated to be 512.5 mg/kg bw when rats were orally exposed with 3,7-bis(diethylamino)phenoxazin-5-ium acetate.  

Thus comparing this value with the criteria of CLP regulation, 1,3,3-trimethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)prop-1-en-1-yl]-3H-indolium acetate can be Not classified for reproductive toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

512.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimiach 2 and from OECD QSAR toolbox

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity:

In a study, 3,7-bis(diethylamino)phenoxazin-5-ium acetate has been investigated for reproductive toxicity to a greater or lesser extent. Studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 3,7-bis(diethylamino)phenoxazin-5-ium acetatealong with the study available on structurally similar read across substance Hexasodium 2,2'-[vinylenebis[(3-sulphonato-4,1-phenylene)imino[6-(diethylamino)-1,3,5-triazine-4,2-diyl]imino]]bis(benzene-1,4-disulphonate (Tinopal CH 3669) (CAS no 41098-56-0) and Benzenesulfonic acid, 2,2'-(1,2-ethenediyl)bis[5-[[4-(4-morpholinyl)-6-(phenylamino)-1,3,5-triazin-2-yl]amino]-, disodium salt (CAS no 16090-02-1). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 3,7-bis(diethylamino)phenoxazin-5-ium acetate. The NOAEL was estimated to be 512.5 mg/kg bw when rats were orally exposed with 3,7-bis(diethylamino)phenoxazin-5-ium acetate.  

 In another experimental study conducted by Central Inst Nutrit & Food Res (National Technical Reports Library, OTS0571834, 1992) on structurally similar read across Hexasodium 2,2'-[vinylenebis[(3-sulphonato-4,1-phenylene)imino[6-(diethylamino)-1,3,5-triazine-4,2-diyl]imino]]bis(benzene-1,4-disulphonate (Tinopal CH 3669) (CAS no 41098-56-0), Newly weaned albino male and female rats treated with Hexasodium 2,2'-[vinylenebis[(3-sulphonato-4,1-phenylene)imino[6-(diethylamino)-1,3,5-triazine-4,2-diyl]imino]]bis(benzene-1,4-disulphonate (Tinopal CH 3669) in the concentration of 0, 200, 1000 and 2000 mg/kg/day orally in feed for 90 days. All animals were died at 5^th week of study at 5000 mg/kg bw. Except for one female which succumbed in the 9^th week. No mortality was observed in 200 and 1000 mg/kg bw treated rats. All animals looked very sick in the second week of the experiment at 5000 mg/kg bw. No abnormalities in appearance were observed in 200 and 1000 mg/kg bw treated rats. Decrease in body weight were observed in treated rats at 1000 and 5000 mg/kg bw as compared to control. Slight decrease in body weight but not significant as compared to control from week 6 onwards at 200 mg/kg bw. Decrease in food consumption were observed in treated rats at 5000 mg/kg bw and slight decrease in food consumption were observed in treated rats at 200 and 1000 mg/kg bw as compared to control. Decrease in food efficiency were observed in treated rats at 5000 mg/kg bw and slight decrease in food efficiency were observed in treated rats at 1000 mg/kg bw as compared to control. Decrease in food efficiency were observed in treated rats at 200 mg/kg bw as compared to control. Similarly, significant increase in percentage of neutrophils and White blood cell counts were observed in treated male and female rats at 1000 mg/kg bw and significant increase in Packed cell volume were observed in male rats at 200 mg/kg bw but no dose-relationship was observed. Increase in SGOT activity of females and decreased in SAP activity of males were observed at 1000 mg/kg bw, decreased SGOT activity in males at 200 mg/kg bw but not observed at 1000 mg/kg bw and is therefore considered incidental. Slight decrease in G6Pase activity with increasing levels of Tinopal was observed in females only. When the enzyme activity is expressed per unit body weight the figures show a slight tendency to increase with increasing levels of Tinopal in males, while in females there are no distinct differences between the groups. Very slight decrease in G6PD enzyme activity with increasing levels of Tinopal in females. Here, too, this decrease disappeared when the enzyme activity was expressed per unit body weight. In addition, increase in relative weights of the kidney, liver and the brain and decrease in testis and ovary weight were observed at 1000 mg/kg bw as compared to control. No effect on reproductive organ weight of 200 mg/kg bw treated male and female rats were observed as compared to control. Large, pale kidneys in all male and female rats at 1000 mg/kg bw. Most of the male rats in this group had strikingly small testicles, other les ions noted at autopsy, such as unilateral hydronephrocis, eurly signs of murine pneuronia, and proteinaceous plugs in urinary bladder, are frequently encountered in the strain of used rats. They may therefore, not be related to the ingestion of the test compound. Necrosis, swelling, irregular vacuolization (Sudan III negative) and granular deterioration (eosinophylic, PAS-negative granules) of tubular epithelial cells in the renal cortex of all male and felllll1e rats at 1000 mg/kg bw. Sloughed necrotic tubular material was often found in tubular lumens. The nuclei of viable tubulur cells varied considerably in size and chromatin content. Dilated tubules lined by flattened epithelium and filled with proteinaceous casts were seen in most animals. Moderate degree of bilateral testicular atrophy were observed in male rats at 1000 mg/kg bw. A number of seminiferous tubules only contained Sertoli cells and occasional spermatogonia containing an irregularly vacuolated cytoplasm, Partial inhibition of spermatogenosis occurred in other tubules in which many polynucleated giant cells were seen. Varying numbers of seminiferous tubules still showed a normal development of sperm cells. In the epididymic tubules cellular debris, scattered spermatozoa and a few giant cells were found. Therefore, NOAEL was considered to be 200 mg/kg/day for P generation when Newly weaned albino male and female rats treated with Hexasodium 2,2'-[vinylenebis[(3-sulphonato-4,1-phenylene)imino[6-(diethylamino)-1,3,5-triazine-4,2-diyl]imino]]bis(benzene-1,4-disulphonate (Tinopal CH 3669) orally by feed for 90 days.

Further supported experimental study conducted by EPA (United States Environmental Protection Agency, data provided under the HPV Challenge Program, 2017) on structurally similar read across Benzenesulfonic acid, 2,2'-(1,2-ethenediyl)bis[5-[[4-(4-morpholinyl)-6-(phenylamino)-1,3,5-triazin-2-yl]amino]-, disodium salt (CAS no 16090-02-1),CD [Crl:CD(SD)IGS BR] male and female rats treated withBenzenesulfonic acid, 2,2'-(1,2-ethenediyl)bis[5-[[4-(4-morpholinyl)-6-(phenylamino)-1,3,5-triazin-2-yl]amino]-, disodium salt in the concentration of 0,100, 300, and 1000 mg/kg bw/day orally by gavage in CMC for 9 months. 3 females from the P generation died at 1000 mg/kg bw and 8 animals from the F1 generation died or were euthanized in extremis during the in-life phase of the study. No mortality was observed in 100 and 300 mg/kg bw treated rats. None of these deaths, however, was considered to be treatment related. No clinical signs were observed in F1 and F2 generation pups. No effects on body weight and food consumption were observed in treated P and body weight of F1 and F2 generation pups. Similarly, No effect was observed on estrous cycle of P and F1 generation and sperm analysis of F1 male rats as compared to control. No effect on pre-mating, gestation, or lactation of treated P rats and mating, fertility, and fecundity indices, copulatory interval, gestation length, and promordial follicle count of F1 male rats were observed as compared to control. In addition, A slight but statistically significant increase in absolute and relative kidney weights was evident in P females and F1 males and females at 1000 mg/kg bw/day. No macroscopic changes were observed in treated P generation and Mild dilatation of the pelvis in two F1 males and one F1 female and mild hemorrhage observed in the kidney of one F1 male rat at 1000 mg/kg bw, these effects were not regarded toxicologically relevant. No microscopic changs were observed in treated P generation rats as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg/day for P, F1 and F2 generation when CD [Crl:CD(SD)IGS BR] male and female rats treated withBenzenesulfonic acid, 2,2'-(1,2-ethenediyl)bis[5-[[4-(4-morpholinyl)-6-(phenylamino)-1,3,5-triazin-2-yl]amino]-, disodium saltorally by gavage for 9 months.

Thus, based on the above studies on1, 3, 3-trimethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)prop-1-en-1-yl]-3H-indolium acetate,it can be concluded that 512.5 mg/kg bw. Thus comparing this value with the criteria of CLP regulation, 1,3,3-trimethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)prop-1-en-1-yl]-3H-indolium acetate can be Not classified for reproductive toxicity.

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

Based on the above studies on1, 3, 3-trimethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)prop-1-en-1-yl]-3H-indolium acetate,it can be concluded that 512.5 mg/kg bw. Thus comparing this value with the criteria of CLP regulation, 1,3,3-trimethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)prop-1-en-1-yl]-3H-indolium acetate can be Not classified for reproductive toxicity.