Nitrapyrin

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

75 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available study investigated the toxicity of the test material to reproduction over two generations. The study was conducted under GLP conditions and in accordance with a standardised guideline. The study was assigned a reliability score of 1 in line with the criteria of Klimisch et al. (1997). The overall quality of the database is high.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The toxicity of the test material to reproductive capability and neonatal survival and growth in rats was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guideline EPA OPP 83-4.

During the study groups of 30 male and 30 female Fischer 344 rats (F0 generation) were exposed to test material at dose levels of 0, 5, 20 or 75 mg/kg bw/day in the diet. Following 10 weeks of exposure the F0 rats were mated to produce F1 litters. After weaning, 30 F1 pups/sex/dose level were randomly selected to become the F1 adults. Following 12 weeks of exposure to test material these animals were mated to produce the F2 litters. Body weights, feed consumption, liver and kidney weights and gross pathologic and histopathologic examinations were evaluated for evidence of toxicity. Reproductive performance and neonatal survival and development were evaluated to assess the reproductive effects of treatment.

Test material administration produced parental toxicity in both the F0 and F1 adult male and female rats at 20 and 75 mg/kg bw/day. Body weights of both the F0 and F1 adult females and the F1 males receiving test material at 75 mg/kg bw/day were significantly lower when compared to their respective control groups. Liver and kidney weights (absolute and relative) were significantly increased in the F0 and F1 males and F1 females receiving the test material at 20 and 75 mg/kg bw/day relative to their respective control groups. The liver and kidney weights (absolute and relative) of the 75 mg/kg bw/day F0 females were significantly increased relative to their controls. The increased liver weights were associated with histopathologic alterations that were dose-related. The hepatic changes were characterised by hypertrophy of centrilobular hepatocytes and lipid vacuolation. In both the F0 and F1 animals the male rats showed a greater degree of hepatocellular hypertrophy and a more pronounced accumulation of lipid vacuoles than the female rats. The kidney weight changes were unassociated with histopathologic changes except for the F0 male 75 mg/kg bw/day dose group. These histopathologic changes were characterised by slight necrosis of the intratubular epithelium in the F0 high dose males.

The average pup body weights (F1 and F2) of the 75 mg/kg bw/day dose level were significantly lower than their respective controls on Day 4 Postpartum for the F1 pups and on Day 1 Postpartum for the F2 pups. Their body weights remained lower through the end of the study. Treatment-related histopathologic changes were observed in the livers of the F1 and F2 male and female weanling rats at the 75 mg/kg bw/day dose level. These changes were similar to those observed in the adult animals and were characterised by centrilobular vacuolation. Even though the F1 pups had lower body weights that persisted through their adult life and histopathologic hepatic alterations that were evident at weaning as well as at the terminal necropsy, no adverse effects were observed in their development to sexually mature rats and their subsequent reproductive performance.

Although test material administration resulted in parental toxicity in the 20 and 75 mg/kg bw/day dose levels, no adverse treatment-related effects were observed on the reproductive parameters; specifically the mating, conception and gestation indices, neonatal survival, litter size or gestation duration.

Test material, when fed via the diet, produced parental toxicity in both male and female Fischer 344 rats at dose levels of 20 and 75 mg/kg bw/day. The No Observable Effect Level (NOEL) for toxicity in adult rats was 5 mg/kg bw/day. Neonatal rats (males and females) of the 75 mg/kg bw/day dose group had histopathologic liver alterations and decreased body weights. The NOEL for neonatal toxicity was 20 mg/kg bw/day. No adverse effects on reproduction or neonatal survival were demonstrated.

The NOEL for reproduction and neonatal survival was 75 mg/kg bw/day, the highest dose level tested.

Short description of key information:

NOEL (parental toxicity) = 5 mg/kg bw/day, NOEL (neonatal toxicity) = 20 mg/kg bw/day, NOEL (reproductive toxicity and neonatal survival) = 75 mg/kg bw/day, rat (male/female); EPA OPP 83-4; Zempel et al. (1988)

Justification for selection of Effect on fertility via oral route:

Only one study is available.

Effects on developmental toxicity

Description of key information

NOEL (maternal toxicity) = 15 mg/kg/day; NOEL (developmental toxicity) = 50 mg/kg/day (rat); EPA OPP 83-3, OECD 414; Schroeder (1994)

NOEL (maternal toxicity) = 50 mg/kg/day; NOEL (developmental toxicity) = 100 mg/kg/day (rat); Screening study (no guideline); Schroeder (1994)

NOEL (maternal toxicity) = 15 mg/kg/day; NOEL (foetotoxicity and teratogenicity) = 50 mg/kg/day (rat); Teratogenicity study (no guideline); Berdasco et al. (1986)

NOEL (maternal toxicity) = 10 mg/kg/day; NOEL (teratogenicity and embryotoxicity) = 30 mg/kg/day; Teratogenicity study (no guideline); Berdasco et al. (1985)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study was conducted under GLP conditions and to a standardised guideline. Supporting information is available in the form of a GLP screening study, a non-GLP teratogenicity study (with rats), and a GLP teratogenicity study (with rabbits). The overall quality of the database is therefore high.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In the key study, reported by Schroeder (1994), the maternal toxicity, embryonal/foetal toxicity and teratogenicity potential of the test material were investigated in a study which was conducted under GLP conditions and in accordance with the standardised guidelines EPA OPP 83-3 and OECD 414. The study was assigned a reliability score of 1 in accordance with the criteria of Klimisch et al. (1997).

During the study, groups of 28 bred female adult Sprague-Dawley rats were administered test material via gavage at targeted dose levels of 0 (corn oil vehicle), 15, 50, or 120 mg/kg/day on days 6 through 15 of gestation. In-life parameters evaluated included clinical signs of toxicity, feed consumption, body weights and body weight gains. On gestation day 20, all females were euthanised and examined for gross pathologic changes and alterations in liver, kidney and gravid uterus weights. The ovaries were examined to determine the number of corpora lutea and the uterine contents were evaluated for number of implantations and resorptions. The foetuses were removed, weighed, sexed and examined for external, visceral and skeletal alterations.

All animals survived to the scheduled necropsy. There was no evidence of maternal toxicity in dams given 15 mg/kg/day. Statistically significant decreases in body weight gain were noted on days 12 - 16 and 6 - 16 in rats given 50 mg/kg/day. At 120 mg/kg/day, statistically significant decreases in body weight gain occurred for the day 6 - 9 and 6 - 16 intervals. Decreased feed consumption also was observed on days 6 - 9, 12 - 16 and 16 - 20 in this group. Increased incidences of ossification variations, such as unossified fifth and sixth sternebrae and rudimentary first lumbar rib were the only treatment-related developmental effects noted in foetuses from the high dose group and the increased incidence of rudimentary rib structures in this group was considered related to maternal toxicity. No treatment-related effects were observed on reproductive or embryonal/foetal parameters at 50 or 15 mg/kg/day.

Thus, the no-observed-effect-level (NOEL) for maternal toxicity in this study was 15 mg/kg/day. The NOEL for developmental toxicity was 50 mg/kg/day.

 

Several studies are available in support of the key study, as follows:

In the screening study, reported by Schroeder (1994), the maternal toxicity and embryolethality potential of the test material were investigated in a range-finding study which was conducted under GLP conditions. The study was assigned a reliability score of 2 in accordance with the criteria of Klimisch et al. (1997).

During the study groups of 10 bred female adult Sprague-Dawley rats were administered test material via gavage at targeted dose levels of 0 (corn oil vehicle), 50, 100, or 200 mg/kg/day on days 6 through 15 of gestation. In-life parameters evaluated included clinical signs of toxicity, feed consumption, body weights and body weight gains. On gestation day 16, all surviving females were euthanised and examined for gross pathologic changes and alterations in liver, kidney and gravid uterus weights. The ovaries were examined to determine the number of corpora lutea and the uterine contents were evaluated for number of implantations and resorptions.

At the 50 mg/kg/day dose level, the only statistically significant differences from controls were increased relative liver and kidney weights; these changes were considered to be of little toxicological significance. At the 100 mg/kg/day dose level, slight, but non-significant decreases in body weight gain during days 6 - 9 and 6 - 16 corresponded with reduced feed consumption during days 6 - 9. Statistically significant increases in relative liver and kidney weights were also noted at this dose level. Due to excessive toxicity, manifested primarily as body weight loss during gestation days 6 - 12, the 200 mg/kg/day group was terminated on gestation day 12, 13 or 14 with no further data being collected.

There were no treatment-related effects observed on reproductive or embryonal/foetal parameters at 50 or 100 mg/kg/day.

Thus, the no-observed-effect-level (NOEL) for maternal toxicity in this study was considered to be 50 mg/kg/day while the NOEL for developmental toxicity was 100 mg/kg/day.

 

In the study reported by Berdasco et al. (1986), assigned a reliability score of 2 in accordance with the criteria of Klimisch et al. (1997), the teratogenic potential of the test material was investigated in a study in which groups of 29 - 30 bred Fischer 344 rats were administered test material in corn oil by gavage on days 6 through 15 of gestation at dose levels of 0, 5, 15, or 50 mg/kg/day and the foetuses examined for evidence of toxicity.

Maternal toxicity was evidenced as minimal histopathologic changes in hepatic tissue among animals given 50 mg/kg/day. However, no evidence of embryotoxicity, foetotoxicity, or teratogenicity was indicated at any of the dose levels tested. Based on these results, the no-observed-effect level for foetotoxicity and teratogenicity of test material administered to pregnant rats was 50 mg/kg/day.

 

In the study, reported by Berdasco (1985), assigned a reliability score of 2 in accordance with the criteria of Klimisch et al. (1997),

the teratogenic potential of the test material was investigated in a study which was conducted under GLP conditions.

During the study, groups of 25 - 28 inseminated New Zealand White rabbits were administered test material in corn oil by gavage on days 6 through 18 of gestation at dose levels of 0, 3, 10, or 30 mg/kg/day and the foetuses examined for evidence of toxicity.

Slight maternal toxicity was evident in the 30 mg/kg/day dose group in the form of decreased weight gain during dosing, and increased absolute and relative liver weights at caesarean section. There were no treatment-related increases in the incidence of malformations in any of the groups when compared to controls. An increased incidence of crooked hyoid bones at 30 mg/kg/day, indicative of only slight foetotoxicity, was the only evidence of any treatment-related effect observed among foetal rabbits.

Thus, oral administration of test material to rabbits during the period of organogenesis produced evidence of slight foetotoxicity only at a dose level which produced maternal toxicity, with no indication of a teratogenic response. 

Justification for selection of Effect on developmental toxicity: via oral route:

The study was conducted under GLP conditions and to a standardised guideline. Furthermore, effect levels were identified.

Justification for classification or non-classification

There are no data to suggest that classification of the substance for either reproductive or developmental toxicity is required.

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the substance does not require classification with respect to either reproductive or developmental toxicity.

In accordance with the criteria for classification as defined in Annex VI, Directive 67/548/EEC (DSD), the substance does not require classification with respect to either reproductive or developmental toxicity.