Nitrapyrin

Endpoint summary

Description of key information

ORAL

LD50 = 1072 mg/kg (rat, male); LD50 = 1231 mg/kg (rat, female); method similar to OECD 401; Norris (1971)

LD50 >5000 mg test material formulation/kg; >895 mg registered substance/kg (rat, female); substance present in test material formulation at 17.9 % w/w; OECD 425, EPA OPPTS 870.1100; Lowe (2007)  

INHALATION

LC50 >3.51 mg test material/L air; >0.63 mg registered substance/L air (rat, male/female); substance present in test material formulation at 17.9 % w/w; EPA OPPTS 870.1300, OECD 403, EU Method B.4 and the JMAFF guideline for acute inhalation toxicity; Krieger & Radtke (2007)

DERMAL

LD50 > 2000 mg/kg (rabbit, male/female), method analogous to OECD 402, Carreon et al. (1986)

LD50 = 2830 mg/kg (rabbit, male/female), method similar to OECD 402, Norris (1971)

LD50 > 5000 mg test material/kg; > 895 mg registered substance/kg (rat, male/female), substance present in test material formulation at 17.9% w/w, EPA OPTS 870.1200, OECD 402, EU Method B.3 and JMAFF 12 -Nouan-8147, Lowe (2007)

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 066 mg/kg bw

Quality of whole database:

Findings from three studies were considered together in a weight of evidence approach. All studies were assigned a reliability score of 2 in line with the criteria of Klimisch et al. (1997). The overall quality of the database is considered to be good.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The study was conducted under GLP conditions and in accordance with standardised guidelines; however, since the study was conducted with a formulation, containing only 17.9 % w/w registered substance, it has been assigned a reliability score of 2 in line with the criteria of Klimisch et al. (1997). The overall quality of the database is fair.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 830 mg/kg bw

Quality of whole database:

The three available studies have been assigned a reliability score of 2 in line with the criteria of Klimisch et al. (1997). The overall quality of the database is considered to be high.

Additional information

Oral

Six studies were conducted to assess the acute oral toxicity of the substance.

Norris (1971) investigated the acute oral toxicity of the test material (registered substance: 90 % minimum), in 5 different species using a methodology that was largely related to that which is outlined in the standardised guideline OECD 401.

The species were Sprague Dawley rats (male), Wistar rats (female), Swiss Webster mice (female), New Zealand White rabbits (male and female) and Hartley guinea pigs (male). The studies which were conducted with rats were assigned a reliability score of 2 in line with the criteria of Klimisch et al. (1997) and were considered in a weight of evidence approach. The studies which were conducted with non-standard species (mice, rabbits, guinea pigs) were assigned a reliability score of 4 and are included as supporting data.

During each study, groups of animals received a single dose of test material, by gavage, in either corn oil or as a 9:1 corn oil and acetone solution. Animals were weighed before dosing, the following day and weekly thereafter. They were also observed periodically, over the two weeks post-test material administration, for signs of toxicity.

Deaths occurred in most instances within 5 days post-administration of the test solutions. The signs of toxicity observed in the high dose level rats were diuresis (male and female) and incoordination of the hind quarters (females) and bloody nares (males). Prior to death the rabbits were hyperexcitable and sometimes vocal. Terminal body weights of surviving animals were equal to or greater than pre-exposure body weights. Signs of toxicity were not noted in the other species.

Under the conditions of the studies, the acute oral LD50 values for animals administered solutions of test material were determined to be: 1072 mg/kg in male rats, 1231 mg/kg in female rats, 713 mg/kg in female mice, 713 mg/kg in rabbits, and < 252 mg/kg in male guinea pigs.

 

The study reported by Lowe (2007) was conducted under GLP conditions and in accordance with the standardised guidelines OECD 425 and EPA OPPTS870.1100.

Since the study was conducted with a formulation, containing only 17.9% w/w registered substance, it has been assigned a reliability score of 2 in line with the criteria of Klimisch et al. (1997) and has been included in the weight of evidence approach.

Based on an estimate of the LD50 (1400 mg/kg), a Main Test was conducted in Female Fischer 344 rats using a default starting dose level of 880 mg/kg which was administered to one healthy female rat by oral gavage. Following the Up and Down procedure, seven additional animals were dosed at levels of 1400 (1 animal), 2220 (2 animals), 3500 (1 animal) and 5000 (3 animals) mg/kg.

All animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for up to 14 days after dosing. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing. Necropsies were performed on all animals at terminal sacrifice.

All animals from each dose level survived and gained body weight during the study. Apart from one rat in the 5000 mg/kg dose group that appeared hypoactive and exhibited a hunched posture 1 to 5 hours post-dosing, all animals from all dose levels appeared active and healthy over the entire 14 day observation period. No gross abnormalities were noted.

Under the conditions of the study, the acute oral LD50 of the test material was determined to be greater than 5000 mg/kg bw when dosed to female Fischer 344 rats.

Inhalation

The acute inhalation toxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guidelines EPA OPPTS 870.1300, OECD 403, EU Method B.4 and the JMAFF guideline for acute inhalation toxicity. Since the study was conducted with a formulation, containing only 17.9 % w/w registered substance, it has been assigned a reliability score of 2 in line with the criteria of Klimisch et al. (1997).

During the study groups of five F344/DuCrl rats per sex were exposed for four hours, using a nose-only inhalation exposure system, to a time-weighted average chamber concentration of 3.51 mg test material per litre of air. The mass median aerodynamic diameter (MMAD) of particulate test material present in the exposure chamber test atmosphere averaged 2.84 µm with an average geometric standard deviation of 2.65. Approximately 23 % of the particle mass was contained in a size fraction with an aerodynamic diameter less than 1.3 µm. Approximately 76 % of the particulate mass was present in size fractions with an aerodynamic diameter less than 6.1 µm.

All animals survived the four-hour exposure to the test material as well as the two-week post-exposure period. There were no clinical effects noted during the four-hour exposure period or during the two-week observation period post-exposure. Mean body weight losses of 0.6 and 1.8 % were noted for male and female rats, respectively, on test day 2. Pre-exposure mean body weight values were exceeded on test day 4. There were no visible treatment-related lesions noted in any of the rats exposed to test material at the test day 15-scheduled necropsy.

Under the conditions of the study the acute inhalation LC50 of the test material was determined to be in excess of 3.51 mg/L for male and female rats.

Dermal

Three studies, investigating the acute dermal toxicity of the substance are available.

In the study reported by Carreon et al. (1986), the acute dermal toxicity of the test material was investigated in a study which was conducted following a method which was similar to that of the standardised guideline OECD 402.

During the study, a group of 5 male and 5 female New Zealand White rabbits were dermally treated with 2000 mg/kg test material moistened with water. Animals were exposed to test material in an occlusive fashion for a period of 24 hours.

All rabbits survived the two-week observation period. Following treatment, lethargy and an apparent decrease in appetite were observed in all rabbits, rapid shallow respiration was also observed in approximately half of the animals. Twenty-four hours post-treatment, slight to moderate erythema was observed on the skin at the site of application. A slight decrease in weight was observed in most rabbits following treatment. At the end of the two week study however, the majority of rabbits had gained weight. Gross necropsy revealed all rabbits within normal limits with the exception of one male and one female which had observations that were considered nonspecific and not related to treatment.

Under the conditions of the study the acute dermal LD50 of the test material was determined to be in excess of 2000 mg/kg bw when administered to New Zealand White rabbits.

In the study reported by Norris (1971), the acute dermal toxicity of the test material was investigated in a study which was conducted using a method which is similar to that outlined in the standardised guideline OECD 402.

During the study groups of New Zealand White rabbits received a single dermal application of test material either neat (as a solid), or as a solution (in glycol ether product). The dose levels were 2000 and 3980 mg/kg bw for the neat product; 252, 500 and 1000 mg/kg bw as a 25 % solution in glycol ether product; and 500, 1000 and 2000 mg/kg bw as a 50 % solution in glycol ether product.

In each case, test material was applied to the skin of the rabbits under a heavy gauge plastic cuff which was held in place with rubber bands and a cloth bandage taped securely to the marginal hair. At the end of the 24 hour exposure period, the cuffs were removed and the skin was washed.

The high dose rabbits treated with neat test material died either during the 24 hour exposure (2 rabbits) or within 24 hours after the exposure (2 rabbits). No signs of toxicity were observed in the surviving rabbits. Terminal body weights of these rabbits were greater than the pre-exposure body weights.

Death of rabbits treated with the solvent solutions of test material, in glycol ether, at doses of 1000 and 2000 mg/kg body weight occurred 24 to 48 hours after termination of the 24 hour exposure. Prior to death some of the rabbits were hyperexcitable and vocal.

Therefore, under the conditions of the study the acute dermal LD50 of the test material was determined to be 2830 mg/kg bw. When the test material was applied as a solution in glycol ether product the LD50 was determined to be 848 mg/kg bw (95 % CL 604 - 1191 mg/kg bw).

In the study reported by Lowe (2007), the acute dermal toxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guidelines EPA OPPTS 870.1200, OECD 402, EU Method B.3 and JMAFF 12 -Nouan-8147. Since the study was conducted with a formulation containing only 17.9 % w/w registered substance, it has been assigned a reliability score of 2.

During the study 5000 mg/kg bw test material was applied to the skin of ten healthy Fischer 344 (male and female) rats for 24 hours. The animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for 14 days. Body weights were recorded prior to application and again on Days 7 and 14 (termination). Necropsies were performed on all animals at terminal sacrifice.

All animals survived, appeared active and healthy and gained body weight during the study. There were no signs of gross toxicity, dermal irritation, adverse clinical signs, or abnormal behaviour. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Under the conditions of the study, the acute dermal LD50 of the test material was determined to be greater than 5000 mg/kg bw when dosed to male and female Fischer 344 rats.

Carreon et al (1986) was selected as the key study since it was conducted with the registered substance itself and its methods were more similar to standardised guidelines than Norris (1971). Furthermore, the test material was moistened with water to enhance contact with the skin in Carreon et al., whereas Norris applied the test material to the skin dry.

Justification for selection of acute toxicity – oral endpoint

A key study has not been selected as findings from three separate studies were considered together as part of a weight of evidence approach.

Justification for selection of acute toxicity – inhalation endpoint

Only one study is available.

Justification for selection of acute toxicity – dermal endpoint

The study was conducted with the registered substance itself following a method analogous to that which is outlined in the standardised guideline OECD 402. Furthermore, the test material was moistened with water to ensure enhanced contact with the skin.

Justification for classification or non-classification

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 acute inhalation toxicity or acute dermal 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 acute inhalation toxicity or acute dermal toxicity.

For acute toxicity via the oral route:

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the substance should be classified as Category 4 H302 (Harmful if swallowed) with the signal word "Warning".

In accordance with the criteria for classification as defined in Annex VI, Directive 67/548/EEC, the substance should be classified as R22 (Harmful if swallowed), with the symbol Xn.