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Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
16 mg/kg bw/day
Additional information

According to the HPV dossier (US EPA 2009, 1H-1,2,4 -triazole) :

In an OECD Guideline 416 "Two-generation Reproduction Toxicity Study", TA was administered continuously via the feed to Wistar Hannover rats (30/sex/dietary level) at nominal dietary concentrations of 0, 250, 500, and 3000 ppm (Bayer, 2005; RCC, 2003; TDMG, 2006). To maintain a more constant dosage (on basis of mg/kg bw/day) throughout the entirety of the study the dietary levels were reduced for females during lactation. In addition to fulfilling standard guideline requirements, this two-generation reproduction study contained the following additional investigations: (1) in-depth examinations of brain tissue from the P- and F1-generation adults, as well as the F1- and F2-generation 21-day-old pups, which included qualitative microscopic evaluations and gross and microscopic morphometric analyses; (2) the inclusion of additional microscopic investigative work on the ovarian tissue from the P-generation rats as it related to the identification of infertility in the 3000 ppm group during the conduct of this study; (3) a more in-depth study of the corpora lutea, based on findings from the P-generation ovarian data; and (4) determination of the onset of preputial separation and vaginal patency for F2 pups. There were no effects on food consumption or clinical signs in either generation at any dietary level. Compound-related declines in body weight and body weight gain were evident in the P-generation adult males and females of the 3000-ppm dose group. A slight decrease in body weight and weight gain that was attributed to treatment was also evident in F1-generation adult males in both the 250 and 500ppm dose groups. A marked reduction in fertility was evident at the 3000 ppm dietary level of the P-generation, with only two females delivering viable offspring (one each) and only three implantation sites (compared to 265 for controls). All high-dose (3000 ppm) P-generation females and pups were sacrificed before weaning, since there were too few pups to provide a second generation. There were no test substance-related effects on the mating, gestation, or fertility indices, number of days to insemination, or gestation length at any dietary level in either F1- or F2- generation except for decreased fertility in 3000 ppm P-generation females. No effects were observed on the oestrous cycle length or the number of cycles at any dose in either generation, including the 3000 ppm group of the P-generation. Other than the reduced fertility evident in the 3000 ppm dose group, no other effects were observed on any litter parameter in any dose group in either generation. There was also no effect on any sperm parameter that was attributed to the test substance. At termination, treatment-related findings were evident only in the P-generation at the 3000 ppm dietary level and included: 1) decreased absolute brain weights in males and females; 2)increased incidence of cerebellar degeneration/necrosis in both genders; 3) statistically increased number of total Corpora lutea measured by quantitative ovarian analysis and increased ovary weights; and 4) increased incidence of uterine horn dilatation. No similar findings were evident in P-generation animals at lower dietary levels or in the offspring from either generation. Based on these results, the reproductive (fertility) NOAEL is 34.4 mg/kg bw/day (500 ppm) and the LOAEL is 231.7 mg/kg bw/day (3000 ppm), based on findings in P-generation animals. No definitive parental NOAEL was established, based on a slight decrease in body weight in the F1-generation males at 16.0 mg/kg bw/day (250 ppm). However, for females, the parental NOAEL was demonstrated to be 36.2 mg/kg bw/day (500 ppm).


Short description of key information:
As 1,2,4 -Triazole, sodium salt dissociates to form 1,2,4 -Triazole, the toxicokinetics for 1,2,4 -Triazole, sodium salt can be read-across from the supporting 1,2,4 -Triazole.
In a two-generation study, TA produced evidence of toxicity in P-generation animals at a dietary level of 3,000 ppm (188.6 and 217.9 mg/kg/day for males and females, respectively), including reduced fertility and neuropathology. By comparison, the only evidence of toxicity at lower dietary levels of 250 and 500 ppm was slightly reduced body weight in F1-generation males. Based on these results, the reproductive (fertility) NOAEL is 34.4 mg/kg bw/day (500 ppm) and the LOAEL is 231.7 mg/kg bw/day (3000 ppm), based on findings in P-generation animals. No definitive parental NOAEL was established, based on a slight decrease in body weight in the F1-generation males at 16.0 mg/kg bw/day (250 ppm). However, for females, the parental NOAEL was demonstrated to be 36.2 mg/kg bw/day (500 ppm).

Effects on developmental toxicity

Description of key information
As 1,2,4 -Triazole, sodium salt dissociates to form 1,2,4 -Triazole, the toxicokinetics for 1,2,4 -Triazole, sodium salt can be read-across from the supporting 1,2,4 -Triazole.
In an OECD Guide-line 414 "Teratogenicity" study with pregnant Bor: WISW (SPF Cpb) rats the maternal NOAEL was = 30 mg/kg bw/day based on retarded weight gain at 100 mg/kg bw and the developmental NOAEL was = 30 mg/kg bw/day based on an increased incidence of runts and lower fetal weights at 100 mg/kg bw/day.
In an OECD Guide-line 414 "Teratogenicity" study with pregnant New Zealand White rabbits [Hra: NZW:SPF], the maternal NOAEL was = 30 mg/kg bw bw/day based on mortality, reduction in body weight gain, and clinical symptoms at 45 mg/kg bw/day and the developmental NOAEL was = 30 mg/kg bw/day based on lower fetal weights and a slight increase in urogenital alterations for several fetuses at 45 mg/kg bw/day.
In an OECD Guide-line 414 "Teratogenicity" study with pregnant Bor: WISW (SPF Cpb) rats, the maternal NOAEL was < 100 mg/kg bw/day based on retarded weight gain at 100 mg/kg bw and the developmental NOAEL was < 100 mg/kg bw/day based on an increased incidence of runts, lower fetal and placental weights, and a higher incidence of minor skeletal deviations at 100 mg/kg bw.
In an OECD 416 “Two Generation Reproductive Toxicity” study with Wistar Hannover rats, the developmental NOAEL was > 500 ppm (equivalent to > 35.8 mg/kg bw/day) based on lack of treatment-related effects in F1 and F2 pups at 250 and 500 ppm.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
30 mg/kg bw/day
Additional information

According to the HPV dossier (US EPA 2009, 1H-1,2,4 -triazole) :

In an OECD Guide-line 414 "Teratogenicity" study, TA was administered by oral gavage to groups of 25 successfully mated and presumably pregnant Bor: WISW (SPF Cpb) rats from day 6 to 15 of pregnancy at daily dose levels of 0, 10, 30, or 100 mg/kg bw/day (Bayer, 1989a; RCC, 2003). There were no mortalities. No treatment-related clinical signs were observed. Mean body weight gain was significantly reduced at 100 mg/kg bw. Fetal weight was reduced at 100 mg/kg bw/day. The incidence of runts was higher at 100 mg/kg bw/day. There were no treatment related malformations. The maternal NOAEL was =30 mg/kg bw/day based on retarded weight gain at 100 mg/kg bw and the developmental NOAEL was= 30 mg/kg bw/day based on an increased incidence of runts and lower fetal weights at 100 mg/kg bw/day. OECD Guide-line 414 "Teratogenicity" study, TA was administered by gavage to groups of twenty-five time-mated New Zealand White rabbits [Hra: NZW:SPF] in 0.5% aqueous CMC at dose levels of 0, 5, 15, 30 and 45 mg/kg bw/day on days 6 though 28 (Argus, 2004). Five does in the 45 mg/kg bw/day dosage group were sacrificed due to their moribund condition. All other does survived to day 29 of gestation (GD 29). Clinical observations were noted in the 45 mg/kg bw/day group and included decreased motor activity, clear perinasal substance, ptosis, excess salivation and hyperpnoea. Most of these observations occurred in the does that were sacrificed moribund. Additional observations included scant feces, ungroomed coat, head tilt, lacrimation, flared nostrils and cold to touch. Body weight gains were reduced and gravid uterine weights were significantly reduced in the 45 mg/kg bw/day group. Fetal weights were significantly reduced in the 45 mg/kg bw/day group. There were a few alterations of the urogenital system (low set, small, absent kidneys and/or an absent ureter) which occurred in several fetuses of the maternally toxic 45 mg/kg/day dosage group. There were no other dosage-dependent and/or significant differences in the litter or fetal incidences of any gross external, soft tissues or skeletal alterations. Skeletal ossification averages per foetus per litter did not differ among the groups. The maternal NOAEL was = 30 mg/kg bw bw/day based on mortality, reduction in body weight gain, and clinical symptoms at 45 mg/kg bw/day and the developmental NOAEL was = 30 mg/kg bw/day based on lower fetal weights and a slight increase in urogenital alterations for several fetuses at 45 mg/kg bw/day. In an OECD Guide-line 414 "Teratogenicity" study, TA administered by oral gavage to groups of 25 successfully mated and presumably pregnant Bor: WISW (SPF Cpb) rats from day 6 to 15 of pregnancy at daily dose levels of 0, 100 or 200 mg/kg bw/day in the vehicle (0.5% aqueous Cremophor-EL) (Bayer, 1989b; RCC, 2003). There were no mortalities. No treatment-related clinical signs were observed. Food consumption was not affected. Mean body weight gain was slightly reduced at 100 mg/kg bw/day and markedly lower at 200 mg/kg bw/day. Fetal weight and placental weight were reduced at 100 and 200 mg/kg bw/day. The incidence of runts was higher at 100 and 200 mg/kg bw/day. The incidence of fetuses with minor skeletal deviations was higher at 100 mg/kg bw/day. The number of surviving fetuses per dam was reduced at 200 mg/kg bw/day. The incidence of fetuses with malformations was higher at 200 mg/kg bw/day. The maternal NOAEL was fetal and placental weights, and a higher incidence of minor skeletal deviations at 100 mg/kg bw.

In an OECD 416 “Two Generation Reproductive Toxicity” study, TA was administered continuously via the feed to Wistar Hannover rats (30/sex/dietary level) at nominal dietary concentrations of 0, 250, 500, and 3000 ppm (Bayer, 2005; RCC, 2003; TDMG, 2006). The exposure period was from 10 weeks premating P-generation through 61 days old for F2-pups. The histopathological lesions in the cerebellum were identical to that observed in the sub-chronic and neurotoxicity study in rats and are characterized by variable loss of Purkinje cells, white matter degeneration and gliosis. The white matter tract degeneration presented as nerve fiber (axonal) swelling or fragmentation often with digestion chambers containing debris and macrophage. No similar changes were noted in the 500 ppm animals. The statistical differences associated with certain parameters of F2-pups (pup weights, preputial separation, brain-and spleen weights) are considered to be attributed to an incidental difference in the time of delivery for both the 250- and 500-ppm dietary groups, relative to concurrent controls, rather than exposure to the test substance. The control pups were heavier than the treated group pups and above the range of historic controls because more control dams delivered on gestation day 23 and fewer on day 21 in comparison to the treatment groups. These results, including an extensive investigation of brain morphology, provided no evidence of developmental neurotoxicity at a dietary level of 500-ppm. The developmental NOAEL was > 500 ppm (equivalent to > 35.8 mg/kg bw/day) based on lack of treatment-related effects in F1 and F2 pups at 250 and 500 ppm.

Justification for classification or non-classification

As 1,2,4 -Triazole, sodium salt dissociates to form 1,2,4 -Triazole, the toxicokinetics for 1,2,4 -Triazole, sodium salt can be read-across from the supporting 1,2,4 -Triazole.

1,2,4 -triazole sodium salt (and 1,2,4 -triazole) is classified in category 2, H361 "Suspected of damaging fertility or the unborn child" according to the Regulation EC no. 1272/2008 (CLP) and classified R63 according to the EU Directive 67/548/EEC.

Additional information

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