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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic information given
Justification for type of information:
Since in the stomach the gastic juice is acidic, made up of acids and enzymes, it is suggested that in this evironment it is highly unlikely that the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites substance (s) will remain ionically bound to each other and thus are prone to dissociation in which case the released cation(s) will associate with other anions and the released anion will associate with cations. Thererfore, it is suggested that read-across data from sodium nitrite is considered appropriate in order to arrive at a conclusion in terms of any health effects that may be incurred from exposure to "nitrite" whichever cation it may be associated with.

In addition, in 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded and that the counter anion could be regarded as "any anionic species" then it would seem that to consider available toxicological data on sodium nitrite, in order to evaluate any health effects that may be incurred from exposure to the nitrite anion (NO2-), is justifiable.

Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2001
Reference Type:
secondary source
Title:
Sodium Nitrite
Author:
OECD SIDS
Year:
2005
Bibliographic source:
UNEP publications

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: FDA (21 CFR, Part 58)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Didecyldimethylammonium chloride
EC Number:
230-525-2
EC Name:
Didecyldimethylammonium chloride
Cas Number:
7173-51-5
Molecular formula:
C22H48N.Cl
IUPAC Name:
Didecyldimethylammonium chloride
Test material form:
liquid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animal Source: Taconic Farms (Gemantown, NY)
Time Held Before Studies:14 days (males) or 15 days (females)
Average Age When Studies Began:7 weeks
Duration of Exposure:14 weeks
Average Age at Necropsy: 20 weeks
Animals were distributed randomly into groups of approximately equal initial mean body weights
Animals per Cage: 5
Method of Animal Identification: Tail tattoo
Diet: NIH-07 open formula powdered diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly
Water: Charcoal-filtered deionized water via amber glass bottles with stainless steel sipper tubes, available ad libitum and changed twice weekly
Cages: Solid-bottom polycarbonate
Bedding: Sani-ChipsCage
Filters: DuPont 2024 spun-bonded polyester filter (Snow Filtration Co., Cincinnati, OH)
Racks: Stainless steelAnimal Room Environment:
Temperature: 72 degree +/-3 degree F;
Relative humidity: 50% +/-15%;
Room fluorescent light: 12 hours/day;
Room air changes: Minimum 10/hour

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
Continuously
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
Doses / Concentrations:0, 375, 750, 1,500, 3,000, or 5,000 ppm sodium nitrite (equivalent to average daily doses of ca. 30, 55, 115, 200, or 310 mg sodium nitrite/kg body weight to males and 40, 80, 130, 225, or 345 mg/kg to females)
Basis:nominal in water
Dose / conc.:
375 ppm
Remarks:
Equivalent to 30 mg sodium nitrite/kg bw for males and 40 mg/kg bw for females;
Basis: nominal in water
Dose / conc.:
750 ppm
Remarks:
Equivalent to 55 mg sodium nitrite/kg bw for males and 80 mg/kg bw for females;
Basis: nominal in water
Dose / conc.:
1 500 ppm
Remarks:
Equivalent to 115 mg sodium nitrite/kg bw for males and 130 mg/kg bw for females;
Basis: nominal in water
Dose / conc.:
3 000 ppm
Remarks:
Equivalent to 200 mg sodium nitrite/kg bw for males and 225 mg/kg bw for females;
Basis: nominal in water
Dose / conc.:
5 000 ppm
Remarks:
Equivalent to 310 mg sodium nitrite/kg bw for males and 345 mg/kg bw for females;
Basis: nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
Type and Frequency of Observation: twice daily. Core study animals were weighed and clinical findings were recorded initially, weekly, and at the end of the studies. Drinking water consumption was measured daily.
Sacrifice and pathology:
Method of Sacrifice: CO2 asphyxiation
Necropsy: Necropsy was performed on all core study. Organs weighed were heart, right kidney, liver, lung, spleen, right testis, and thymus.
Clinical Pathology: Blood for hematology and clinical chemistry was collected from the retroorbital sinus of anesthetized clinical pathology study rats on days 5 and 19 and from core study rats at the end of the study. Two blood samples each were collected from the abdominal aorta of 15 male and 15 female clinical pathology study rats on day 70 (20.00 or 22.00 hours) or 71 (09.00 hours) for hemoglobin, methemoglobin and nitrosamine concentrations; stomach contents were also collected for nitrosamine concentrations. Blood and stomach contents were collected from five males and five females at each time point.
Hematology: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; leukocyte count and differentials; erythrocyte and platelet morphologic assessments; methemoglobin concentration; reduced glutathione concentration in erythrocytes; and Heinz body count.
Clinical chemistry: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids.
Nitrosamine concentrations: serum and gastric nitrosamine
Histopathology: Complete histopathology was performed on 0 and 5,000 ppm core study animals. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone and marrow, brain, clitoral gland, esophagus, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, muscle, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, spleen, skin, stomach (forestomach and glandular), testis (and epididymis and seminal vesicle), thymus, thyroid gland, trachea, urinary bladder, and uterus. The forestomach of 750 (males), 1,500, and 3,000 ppm animals were also examined.
Other examinations:
Sperm Motility and Vaginal Cytology: At the end of the studies, samples were collected for sperm motility or vaginal cytology evaluations from male rats in the 0, 375, 1,500, and 5,000 ppm groups and female rats in the 0, 375, 750, and 3,000 ppm groups. The left cauda, epididymis, and testis were weighed. The following parameters were evaluated: spermatid heads per gram testis, spermatid heads per testis, spermatid count, motility, and concentration. Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies for vaginal cytology evaluations. The length of the estrous cycle and the length of time spent in each stage of the cycle were evaluated.
Statistics:
Statistical analyses were conducted about survival rate, neoplasm and non-neoplastic lesion incidences.

Results and discussion

Results of examinations

Details on results:
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
Clinical signs: Brown discoloration in the eyes and cyanosis of the mouth, tongue, ears, and feet of 200 and 310 mg/kg bw/day males and of 130 mg/kg bw/day and higher females.
Bodyweight and food consumption: Body weights of 200 and 310 mg/kg bw/day males and 345 mg/kg bw/day females were significantly less than those of the controls. Water consumption by 310 mg/kg bw/day males and 225 and 345 mg/kg bw/day females was less than that by the controls at weeks 2 and 14.
Mortality and time to death: One 225 mg/kg bw/day female died before the end of the study.
Clinical Pathology: Methaemoglobin levels were significantly elevated in all treated groups compared to the controls by the end of the treatment period. For males, mean methaemoglobin levels after 14 weeks were 0.03±0.01, 0.08±0.01, 0.12±0.02, 0.25±0.07, 0.71±0.20 and 3.38±0.80 g/dL at doses of 0, 30, 55, 115, 200, and 310 mg/kg bw/day. For females, mean methaemoglobin levels after 14 weeks were 0.06±0.02, 0.14±0.02, 0.16±0.02, 0.48±0.05, 0.99±0.20 and 2.27±0.54 g/dL at doses of 0, 40, 80, 130, 225 and 345 mg/kg bw/day.
Haematology: Reticulocyte counts were increased in 200 and 310 mg/kg bw/day males and 225 and 345 mg/kg bw/day females. The erythron was decreased on day 19 but increased by week 14 in 310 mg/kg bw/day males and 345 mg/kg bw/day females.
Gross pathology incidence and severity: The incidences of squamous cell hyperplasia of the forestomach in 310 mg/kg bw/day males and 345 mg/kg bw/day females were significantly increased.Organ weight changes: The relative kidney and spleen weights of 200 and 310 mg/kg bw/day males and 225 and 345 mg/kg bw/day females were significantly greater than those of the controls.
Histopathology: Increased erythropoietic activity in the bone marrow of exposed males and females was observed.
Sperm Motility and Vaginal Cytology: Sperm motility in 115 and 310 mg/kg bw/day males was significantly decreased.

Effect levels

open allclose all
Key result
Dose descriptor:
LOAEL
Effect level:
115 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: decreased sperm motility
Key result
Dose descriptor:
LOAEL
Effect level:
225 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: increased relative weight of the kidney and spleen

Target system / organ toxicity

open allclose all
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
6 000 ppm
System:
other: histiocytosis, mastocytosis and sinusal hemorrhage in the mesenteric lymph node
Organ:
lymph node
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
3 000 ppm
System:
other: histiocytosis and mastocytosis in the mesenteric lymph node
Organ:
lymph node
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 500 ppm
System:
other: changes in hematological and blood biochemical parameters were recorded
Organ:
lymph node
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
In a NTP study (2001), as a primary source, groups of male and female F344/N rats (10 animals/sex/group) were exposed to 0, 375, 750, 1,500, 3,000, or 5,000 ppm sodium nitrite (equivalent to average daily doses of approximately 0, 30, 55, 115, 200, or 310 mg sodium nitrite/kg bw/day in males and 0, 40, 80, 130, 225, or 345 mg/kg bw/day in females) in drinking water for 14 weeks.

The LOAEL were determined to be :
Males = 115 mg/kg bw/day
Females = 225 mg/kg bw/day
Executive summary:

In a NTP study (2001), as a primary source, groups of male and female F344/N rats (10 animals/sex/group) were exposed to 0, 375, 750, 1,500, 3,000, or 5,000 ppm sodium nitrite (equivalent to average daily doses of approximately 0, 30, 55, 115, 200, or 310 mg sodium nitrite/kg bw/day in males and 0, 40, 80, 130, 225, or 345 mg/kg bw/day in females) in drinking water for 14 weeks.

This study is also referenced in the The Screenimg Information DataSet (SIDS) for sodium nitrite as a secondary source and in the disseminated REACH regiatration dossier for sodium nitrite.

The study was assigned a reliability score of 2 in accordance with the criteria for assessing data quality set forth by Klimisch et al. (1997).

Under the conditions of the study the NOAELs were not determined although all animals showed methaemoglobin formation.

However, the LOAEL were determined to be :

Males = 115 mg/kg bw/day

Females = 225 mg/kg bw/day

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