Phosphorus tribromide

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

Subacute

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from secondary source

Data source

Reference

Reference Type:

other: NTRL

Title:

Acute and Subchronic Toxicity Evaluations of the Halon Replacement Candidate Phosphorus Tribromide.

Author:

Robin E. Wolfe,Marcia L. Feldmann,David H. Ellis,Harry F. Leahy,arlyle D. Flemming,Darol E. Dodd

Year:

1997

Bibliographic source:

Armstrong Laboratory, Occupational and Environmental Health Directorate Toxicology Division, Human Systems Center Air Force Materiel Command,Wright-Patterson, 1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: No data

Principles of method if other than guideline:

Subacute repeated dsoe inhalation toxicity study of phosphorus (3+) tribromide in male rat

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phosphorus tribromide

EC Number:

232-178-2

EC Name:

Phosphorus tribromide

Cas Number:

7789-60-8

Molecular formula:

Br3P

IUPAC Name:

phosphorus tribromide

Test material form:

liquid

Details on test material:

- Name of test material : Phosphorus tribromide
- Molecular formula: Br3P
- Molecular weight : 270.686 g/mol
- Smiles notation :P(Br)(Br)Br
- InChl :1S/Br3P/c14(2)3
- Substance type: Inorganic
- Physical state: Solid

Specific details on test material used for the study:

- Name of test material (as cited in study report): Phosphorus tribromide (phosphorus (3+) tribromide)
- Molecular formula (if other than submission substance): Br3P
- Molecular weight (if other than submission substance): 270.686 g/mol
- Substance type: Inorganic
- Physical state: Liquid

Test animals

Species:

rat

Strain:

Fischer 344

Remarks:

CDF®[F-344]/CrIBR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: No data available
- Weight at study initiation: Males: 100-125g and Females- 75-100 g
- Fasting period before study: No fasting before study
- Housing: the animals (two per cage) were housed in laminar air flow rooms in clear plastic cages with hardwoodchip bedding
- Diet (e.g. ad libitum): Purina Certified Rodent Diet #5002 ad libitum except during the inhalation exposure period
- Water (e.g. ad libitum): Water ad libitum except during the inhalation exposure period and for 12 h prior to sacrifice for the 5-day study
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 25°C
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): light/dark cycle was set at 12-h intervals

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

nose only

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Cannon chambers
- Method of holding animals in test chamber: Plexiglas restraining tubes with nose only chambers were used to hold the test animals
- Source and rate of air: Four Cannon nose-only inhalation chambers were supplied with dried laboratory air with a minimal air flow delivery rate of 500 mL/animal
- Method of conditioning air: No data
- System of generating particulates/aerosols: The required concentration of phosphorous tribromide was generated using Sage syringe pumps delivering the required mass of test material into the air supply for the Cannon-52 chambers.
- Temperature, humidity, pressure in air chamber: The temperature of the carrier air was monitored
- Air flow rate: 500 mL/min of dry (<3% RH) filtered house air with a minimum of 10 L/min used for each of the test groups
- Air change rate: No data available
- Method of particle size determination: No data available
- Treatment of exhaust air: A bypass and containment dump system was employed to allow for smooth initiation of exposures and for use as a safety measure in case of abnormal syringe pump operation. The containment areas were further isolated vfrom the general laboratory area through use of a separate exhaust line which vented the enclosures.

TEST ATMOSPHERE
- Brief description of analytical method used: A Bromide specific ion electrode permitted quantification of the test material concentration through analysis of the bromide ion absorbed in an ionic strength buffer (pH 4.0). In order to monitor the lower concentrations, the ratio of vapor sample to buffer had to be increased from 10:1 air/absorber to 20:1 and 40:1. This allowed operation in the linear portion of the response curve. Sixty-mL plastic syringes containing 5.0 mL buffer were used to quantify the 50 mL vapor samples and acted as the reaction vessel for the absorption of PBr3. Multiple absorption samples were required to analyze the lower chamber concentrations.
- Samples taken from breathing zone: No data available

VEHICLE (if applicable)
- Justification for use and choice of vehicle: Air
- Composition of vehicle: No data available
- Type and concentration of dispersant aid (if powder): No data available
- Concentration of test material in vehicle: 0, 0.05, 0.1, and 0.5 mg/L (Mean ± SD exposuer concentrations are 0.06 ± 0.01,0.16 ± 0.03, and 0.51 ± 0.08 mg/L)
- Lot/batch no. of vehicle (if required): No data available
- Purity of vehicle: No data available

Details on mating procedure:

Reproductive organ were examined.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

A Bromide specific ion electrode permitted quantification of the test material concentration through analysis of the bromide ion absorbed in an ionic strength buffer (pH 4.0). In order to monitor the lower concentrations, the ratio of vapor sample to buffer had to be increased from 10:1 air/absorber to 20:1 and 40:1. This allowed operation in the linear portion of the response curve. Sixty-mL plastic syringes containing 5.0 mL buffer were used to quantify the 50 mL vapor samples and acted as the reaction vessel for the absorption of PBr3. Multiple absorption samples were required to analyze the lower chamber concentrations.

Duration of treatment / exposure:

5 days

Frequency of treatment:

4 hrs /day

Doses / concentrations

Remarks:

0, 0.06, 0.16, 0.51 mg/L

No. of animals per sex per dose:

Total: 20
0 mg/L: 5 males
0.06 mg/L: 5 males
0.16 mg/L: 5 males
0.51 mg/L: 5 males

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The highest concentration of PBr3 was determined considering the results of the acute inhalation toxicity test
- Rationale for animal assignment (if not random): No data
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data

Positive control:

No data available

Examinations

Parental animals: Observations and examinations:

Mortality, Clinical signs, Body weight, Haematology and Clinical chemistry were examined.

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

Organ weights, Gross pathology and Histopathology were examined.

Postmortem examinations (offspring):

No data available

Statistics:

Body weights were analyzed using the repeated mUltivariate analysis of variance with Scheffe pairwise comparisons. Hematology, clinical chemistry, and organ weights were analyzed using a two-factorial analysis of variance with multivariate comparisons. Histopathology data were analyzed through use of the Fischer Exact Test, or, if not valid, Yates' Corrected Chi-square was used.

Reproductive indices:

No data available

Offspring viability indices:

No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, non-treatment-related

Clinical biochemistry findings:

effects observed, non-treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Details on results (P0)

Mortality: No mortality was observed in treated male rats at 0.06, 0.16, 0.51 mg/L as compaed to control.

Clinical signs: No signs of toxic stress were observed in treated male rats at 0.06, 0.16, 0.51 mg/L as compaed to control.

Body weight: When treated with 0.51 mg/L, significantly significant decrease in body weight was observed as compared to control.

Haematology: Statistically significant decrease in Basophils level were observed in 0.05 mg/L treated rats as compared to control.

Clinical chemistry:
Statistically significant increased in calcium, potassium, Chloride and Potassium values and Decrease in alkaline phosphatase, creatine and ALT kinase were observed as compared to control when treated with 0.51 mg/L.
Decrease in ALT and increase in Chloride values were observed as compared to control when treated with 0.16 mg/L.

Organ weights: No statistically significant effect on Absolute and relietive Liver, Kidneys, Testes, Brain, Spleen, Adrenals, Lungs, Thymus and Heart weight were observed in treated rats compared to control.

Gross pathology: When treated with 0.51 mg/L, irregular shaped and reddened nares in 3 male rats were observed.
When treated with 0.06 and 0.16 mg/L, no gross pathological changees were observed in treated male rats as compared to control.

Histopathology: When treated with 0.51 mg/L, lesions were observed in the anterior-most
segment of the nasal passages, statistically higher incidence of suppurative (acute) inflammation of the mucosa of the nasal passages, Chronic ulceration of the epithelium of the external nares was observed in 3 male and Minimal squamous metaplasia of the respiratory epithelium in the trachea of one male rat wereobserved as compared to control.
When treated with 0.16 mg/L, in one rat slight inflammation of the nasal mucosa (most anterior regions) were observed as compared to control.
When treated with 0.06 mg/L, no microscopic lesions were observed in treated male rats as compared to control.

Effect levels (P0)

Dose descriptor:

NOAEC

Effect level:

0.51 mg/L air

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

other: No effect on reproductive organ

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Effect levels (P1)

Dose descriptor:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Target system / organ toxicity (P1)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Results: F2 generation

General toxicity (F2)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F2)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:

not specified

Effect levels (F2)

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Target system / organ toxicity (F2)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Any other information on results incl. tables

Organ Weights and Organ-To-Bodyweight Ratios Of Male F-344 Rats After Five-Day, Nose-Only Inhalation Exposure To Phosphorus Tribromide

Organ	Control	0.05 mg/L	0.1 mg/L	0.5 mg/L
Body Wt	226 ± 8.6	225 ± 8.6	221 ± 10.6	214 ± 7.9
Liver	7.12 ± 0.72	6.88 ± 0.57	6.65 ± 0.37	6.47 ± 0.56
Kidneys	1.77 ± 0.08	1.76 ± 0.08	1.52 ± 0.41	1.68 ± 0.08
Testes	2.84 ± 0.13	2.78 ± 0.09	2.53 ± 0.46	2.65 ± 0.12
Brain	1.79 ± <0.01	1.79 ± 0.04	1.78 ± 0.01	1.74 ± 0.06
Adrenals	0.04 ± 0.02	0.05 ± 0.01	0.05 ± 0.01	0.05 ± 0.01
Lungs	1.45 ± 0.14	1.34 ± 0.10	1.46 ± 0.07	1.09 ± 0.61
Thymus	0.25 ± 0.04	0.22 ± 0.03	0.20 ± 0.03	0.19 ± 0.02
Heart	0.79 ± 0.04	0.81 ± 0.05	0.81 ± 0.02	0.82 ± 0.06

 a Mean ± SO, N=5.

b Organ weight/body weight x 100.

Applicant's summary and conclusion

Conclusions:

NOAEC was considered to be 0.51 mg/l when Fischer 344 (F-344) CDF®[F-344]/CrIBR male rats were treated with phosphorus (3+) tribromide by Nose only vapor inhalation for 4 hrs /day for 5 days.

Executive summary:

In a Subacute inhalation toxicity study, Fischer 344 (F-344) CDF®[F-344]/CrIBR male rats were treated with phosphorus (3+) tribromide in the concentration of 0, 0.06,0.16, 0.51 mg/L by Nose only vapor inhalation for4 hrs /day for 5 days. No mortality and signs of toxic stress were observed in treated male rats at 0.06, 0.16, 0.51 mg/L as compared to control. Significantly significant decrease in body weight was observed in0.51 mg/L treated male rats as compared to control. Similarly, Statistically significant decrease in Basophils level were observed in 0.05 mg/L and Statistically significant increased in calcium, potassium, Chloride and Potassium values and Decrease in alkaline phosphatase, creatine and ALT kinase were observed at 0.51 mg/L and Decrease in ALT and increase in Chloride values were observed as compared to control when treated with 0.16 mg/L. Additional statistically significant differences in mean values of serum chemistry or hematologic parameters were sporadic and were not considered biologically important. In addition, No statistically significant effect on Absolute and relietive Liver, Kidneys, Testes, Brain, Spleen, Adrenals, Lungs, Thymus and Heart weight were observed in treated rats compared to control. Irregular shaped and reddened nares in 3 male rats were observed at 0.51 mg/L and no gross pathological changes were observed in treated male rats at 0.06 and 0.16 mg/L as compared to control. Lesions were observed in the anterior-most segment of the nasal passages, statistically higher incidence of suppurative (acute) inflammation of the mucosa of the nasal passages, Chronic ulceration of the epithelium of the external nares was observed in 3 male and Minimal squamous metaplasia of the respiratory epithelium in the trachea of one male rat were observed at 0.51 mg/L as compared to control. In one rat slight inflammation of the nasal mucosa (most anterior regions) were observed at 0.16 mg/L as compared to control andno microscopic lesions were observed in treated male rats at0.06 mg/L as compared to control. Therefore, NOAEC was considered to be 0.51 mg/l when Fischer 344 (F-344) CDF®[F-344]/CrIBR male rats were treated with phosphorus (3+) tribromide by Nose only vapor inhalation for4 hrs /day for 5 days..