Phosphoryl trichloride

Endpoint summary

Description of key information

For phosphoryl trichlorid no valid repeated dose studies are reported for the oral, dermal and inhalation route.

"In water, phosphoryl trichloride hydrolyzes to phosphoric acid and hydrochloric acid with t1/2 < 10 seconds (Riess, 2002): POCl3+ 3 H2O→H3PO4+ 3 HCl"(OECD SIDS for phosphoryl trichloride, 2004).  The pH value of phosphoryl trichloride at 25 °C is approximately 1 (at 5 g/L). Further testing is not required and cannot be justified on scientific grounds or for reasons of animal welfare. The available data of the OECD SIDS (HCl) and the MAK commission (H3PO4) are reported.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Principles of method if other than guideline:

In a 90-day inhalation study using B6C3F1 mice, Sprague-Dawley, and Fisher 344 rats groups of 31 males and 31 females of each species and strain were exposed (whole body) to HCl at 0, 10, 20 or 50 ppm (0, 15, 30, or 75 mg/m3), 6 h/day, 5 days/week for 90 days.

GLP compliance:

not specified

Species:

other: rat and mouse

Strain:

other: Sprague Dawley, fisher 344 rats, and B6C3F1 mice

Sex:

male/female

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: not applicable

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 h/day, 5 days/week for 90 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 10, 20, or 50 ppm (0, 15, 30 or 75 mg/m³)
Basis:
nominal conc.

No. of animals per sex per dose:

31 males and 31 females of each species and strain/dose

Control animals:

yes, concurrent vehicle

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Severe irritation/corrosion effect at the site of entry.

Critical effects observed:

not specified

Several animals died during the study; however, the deaths did not appear to be exposure related. There was a slight, but significant

decrease in body weight gain in male and female mice and male Fisher 344 rats in the high dose groups. There was no effect on hematology, clinical chemistry, and urinalysis. Histologic examination showed minimum to mild rhinitis in both strains of rats. Lesions occurred in the anterior portion of the nasal cavity and were concentration and time related. In mice exposed to 50 ppm, there was cheilitis and accumulation of macrophages in the peripheral tissues after 90 days. Mice in all exposure groups developed eosinophilic globules in the epithelial lining of the nasal tissues

Conclusions:

All findings were confined to the site of first contact and can be explained by the irritating/corrosive properties of the acid. No signs of systemic effects were reported. Therefore systemic availability is unlikely. The local NOAEC is below 10 ppm (15 mg/m³). No statement is possible about a systemic NOAEC because of the severe irritation/corrosion effect occurring at the site of entry. Potential systemic effects are considered as consequences of these local effects.

Executive summary:

In a 90-day inhalation study using B6C3F1 mice, Sprague-Dawley, and Fisher 344 rats groups of 31 males and 31 females of each species and strain were exposed (whole body) to HCl at 0, 10, 20 or 50 ppm (0, 15, 30, or 75 mg/m³), 6 h/day, 5 days/week for 90 days. Several animals died during the study; however, the deaths did not appear to be exposure related. There was a slight, but significant decrease in body weight gain in male and female mice and male Fisher 344 rats in the high dose groups. There was no effect on hematology, clinical chemistry, and urinalysis. Histologic examination showed minimum to mild rhinitis in both strains of rats. Lesions occurred in the anterior portion of the nasal cavity and were concentration and time related. In mice exposed to 50 ppm, there was cheilitis and accumulation of macrophages in the peripheral tissues after 90 days. Mice in all exposure groups developed eosinophilic globules in the epithelial lining of the nasal tissues.

 

All findings were confined to the site of first contact and can be explained by the irritating/corrosive properties of the acid. No signs of systemic effects were reported. Therefore systemic availability is unlikely. The local NOAEC is below 10 ppm (15 mg/m³). No statement is possible about a systemic NOAEC because of the severe irritation/corrosion effect occurring at the site of entry. Potential systemic effects are considered as consequences of these local effects.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Principles of method if other than guideline:

"In two parallel inhalation studies male Sprague-Dawley rats were exposed either to filtered air or to an aerosol consisting of combustion products of red phosphorus/butyl rubber (95:5). Exposure took place 2.25 hours per day, 4 days per week, for 13 weeks to 0, 300, 750 or 1200 mg aerosol/m³ and in a second experiment to 0, 50, 180 or 300 mg/m³."

GLP compliance:

not specified

Remarks:

Review article or handbook.

Specific details on test material used for the study:

Combustion products of red phosphorus/butyl rubber (95:5).

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

air

Duration of treatment / exposure:

2.25 hours per day, 4 days per week, for 13 weeks

Frequency of treatment:

4 days per week

Remarks:

Doses / Concentrations:
In a first test 0, 300, 750 or 1200 mg aerosol/m³ and in a second test 0, 50, 180 or 300 mg aerosol/m³
Basis:
nominal conc.

No. of animals per sex per dose:

In the first study, each 176 animals were used in the control, the middle and the high exposure group in the lowest group 84, in the second study each 40 animals per group.

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

37.5 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no effects observed

Critical effects observed:

not specified

"In both studies, the target organ is the respiratory tract, with the terminal bronchioles being particularly affected. The only concentration-dependent effect in the surviving animals was a moderate to severe terminal bronchiolar fibrosis with or without a weak involvement of the lung tissue with a NOAEC of 50 mg/m3, corresponding to approximately 37.5 mg phosphoric acid/m3 (phosphoric acid concentration about 75% of the aerosol concentration[...]).

Conclusions:

The target organ is the respiratory tract, with the terminal bronchioles being particularly affected. The only concentration-dependent effect in the surviving animals was a moderate to severe terminal bronchiolar fibrosis with or without a weak involvement of the lung tissue with a NOAEC of 50 mg/m3, corresponding to approximately 37.5 mg phosphoric acid/m3.

Executive summary:

“In two parallel inhalation studies male Sprague-Dawley rats were exposed either to filtered air or to an aerosol consisting of combustion products of red phosphorus/butyl rubber (95:5). Exposure took place 2.25 hours per day, 4 days per week, for 13 weeks to 0, 300, 750 or 1200 mg aerosol/m3 and in a second experiment to 0, 50, 180 or 300 mg/m3. The average phosphoric acid concentrations were analyzed weekly after oxidation of the dissolved collected samples and were between 71% and 80% of the aerosol concentration. In the second study, in which the animals were treated with lower concentrations and in which the focus was on the lung examination, tissue sections of the five lung lobes of 20 rats per exposure group and control group and additionally tissue sections of nasal concha and trachea of 10 animals per group were investigated. An accurate description of the method and results can be found in the [MAK] justification for "diphosphorus pentoxide" (2006).

In both studies, the target organ is the respiratory tract, with the terminal bronchioles being particularly affected. The only concentration-dependent effect in the surviving animals was a moderate to severe terminal bronchiolar fibrosis with or without a weak involvement of the lung tissue with a NOAEC of 50 mg/m3, corresponding to approximately 37.5 mg phosphoric acid/m3 (phosphoric acid concentration about 75% of the aerosol concentration, see above) (Aranyi et al. 1988; US Army Medical Research and Development Command 1986, [MAK] justification for "diphosphorus pentoxide" 2006). The composition of the aerosol is unclear. It can be assumed to contain elemental phosphorus, diphosphorus pentoxide, and phosphoric acid” (Phosphorsäure (ortho-Phosphorsäure) [MAK Value Documentation in German language, 2006]). 

Reference 3

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Insufficient details on experimental design; study duration and the species investigated are unclear.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Chronic exposure study: duration and frequency of exposure unknown, duration of study unknown, species unclear

GLP compliance:

no

Remarks:

: study pre-dates GLP

Limit test:

no

Species:

other: not reported (rats, mice, guinea pigs and/or rabbits)

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

646 white rats, 57 guinea pigs, 102 white mice and 12 rabbits.

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: Not reported

Details on inhalation exposure:

No information available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 months

Frequency of treatment:

Not reported

Remarks:

Doses / Concentrations:
0.00048 and 0.00134 mg/L in air
Basis:
no data

No. of animals per sex per dose:

Not reported

Control animals:

yes

Details on study design:

The acute and chronic effects of phosphoryl trichloride were investigated. Information on the methods and study design is limited, but animals were exposed to several concentrations. Some chronic exposure groups were permitted a 4 month recovery period to determine the reversibility of the effects of the test substance. A control group is referred to, but no further details are provided. In the acute test, a single exposure period of 4 hours is referred to.

Positive control:

Not reported

Observations and examinations performed and frequency:

Body weight gain and determination of the respiration rate were determined.

Sacrifice and pathology:

Gross pathology was carried out. Vital staining of the lung tissue, and weight coefficients of the lungs were determined. Blood and urine pH were measured in single-exposure animals.

Other examinations:

Cytogenicity (chromosome aberrations). Rat bone marrow was subject to ana-telophasis analysis. Sperm morphology was investigated.

Statistics:

None reported.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

Single administration of a high concentration resulted in clinical and pathomorphological changes in the internal organs, which showed pronounced irritation. Dystrophic changes occurred particularly in the kidneys, liver and nervous system, and were reportedly connected to the absorption of the decomposition products from the extensive necrotic surface of the respiratory passages. A single exposure to a concentration of 10 mg/m3 over the course of 4 hours caused a statistically significant drop in pH of the blood and urine; blood pH was 5.98±0.02 in treated animals compared to 6.84 in controls (p=0.01), and urine pH was 5.25±0.12 in treated animals compared to 6.73±0.17 in controls (p=0.01).

Chronic exposure induced pronounced chronic intoxication of the animals. Body weight gain was affected, as was respiration rate and oxygen consumption. A decrease in the excretion of hippuric acid in the urine was observed in rats.
After 4 months exposure at a concentration of 0.00134 mg/L, pronounced morphological changes were observed; catarrhal desquamative rhinitis, tracheitis, bronchitis, and degenerative changes in brain nerve cells. Mild protein dystrophy in the liver and kidneys and moderate small-droplet lipodystrophy in the liver were also observed. Signs of enterocolitis were seen in the gastrointestinal tract. The greatest morphological changes were observed in the respiratory tract, in the kidneys and intestine (region of elimination of the substance) and in the liver (region of detoxication). The animals also showed considerable changes in the bone tissue in the form of osteoporosis.
Four months after termination of the chronic experiment in rats and guinea pigs the pathological signs had subsided, but not returned to normal. Considerable changes remained in the respiratory tract.
A concentration of 0.00048 mg/L caused only irritation of the mucous membrane of the respiratory passages and bronchi in the form of rhinits and catarrhal bronchitis. In rats an increase in the weight coefficients of the kidneys was observed. After the period of recovery the morphological picture of the internal organs of the exposed animals did not differ from the control group.
Exposure to a concentration of 0.00134 mg/L caused a cytogenic effect; there was an increased number of chromosomal anomalies and cytostatic activity was affected. At a concentration of 0.00048mg/L the number of chromosomal anomalies was increased but was not statistically significant from controls.
Bone marrow ana-telophase analysis demonstrated that phosphoryl trichloride induced all types of nuclear disturbances and was one of the factors of the non-arresting activity. Phosphoryl trichloride was also reported to have a cytostatic effect, the severity of which was concentration dependent.
Phosphoryl trichloride affected the motility of spermatozoids, though it did not affect spermatogenesis.

Dose descriptor:

LOAEC

Effect level:

0 mg/L air

Sex:

not specified

Basis for effect level:

other: Irritation of the mucous membrane of the respiratory passages and bronchi in the form of rhinits and catarrhal bronchitis.

Critical effects observed:

not specified

The decrease in excretion of hippuric acid in the urine of rats indicated a disturbance of the detoxicating function of the liver. The effects on the kidneys may be indicative of the elimination of the substance in the urine. The authors report that generalisation of the results of the chronic experiment leads to the conclude that a concentration of 0.00048 mg/L approaches the threshold of the chronic effect. The mutagenic and gondaotropic activities of phosphoryl trichloride and its effect of the skeletal system suggest that the coefficient of cumulation is higher than 10, and consequently the highest admissible concentration (HAC) amounts to 0.00005 mg/L. Long term exposure causes a disturbance of mineral metabolism (disturbance of the elimination of calcium, phosphorous and chlorine) and changes in the bone tissue. The authors report that damage to the bone substance caused by phosphoryl trichloride is different to damage caused by elemental phosphorous, indicating that the pathological bone changes seen in the experiment were not solely due to the presence of phosphorous in phosphoryl trichloride.

Conclusions:

The highest admissable concentration in air of the working place was set as 0.05 mg/m³.

Executive summary:

The study investigate the effects of phosphoryl trichloride on various species, the methods are poorly reported therefore it is difficult to draw conclusions from the results. Repeated inhalation exposure to phosphoryl trichloride (0.00048 and 0.00134 mg/L in air) in rats (also mice, guinea pigs and rabbits) for 4 months affected body weight gain, respiration rate and oxygen consumption. A decrease in the excretion of hippuric acid in the urine was observed in rats. The greatest morphological changes were observed in the respiratory tract, the kidneys, intestine and the liver. Bone changes were observed in the form of osteoporosis. A 4 month recovery period saw the pathological signs subside, but not return to normal. At the higher dose a cytogenic effect was observed in the form of chromosomal anomalies and cytostatic activity. Exposuure induced all types of nuclear disturbance in rat bone marrow. Exposure to phosphoryl trichloride also affected the motility of spermatazoids.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

30 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data are reviewed and published in the OECD SIDS for hydrogen chloride and phosphoric acid.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Principles of method if other than guideline:

In a 90-day inhalation study using B6C3F1 mice, Sprague-Dawley, and Fisher 344 rats groups of 31 males and 31 females of each species and strain were exposed (whole body) to HCl at 0, 10, 20 or 50 ppm (0, 15, 30, or 75 mg/m3), 6 h/day, 5 days/week for 90 days.

GLP compliance:

not specified

Species:

other: rat and mouse

Strain:

other: Sprague Dawley, fisher 344 rats, and B6C3F1 mice

Sex:

male/female

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: not applicable

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 h/day, 5 days/week for 90 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 10, 20, or 50 ppm (0, 15, 30 or 75 mg/m³)
Basis:
nominal conc.

No. of animals per sex per dose:

31 males and 31 females of each species and strain/dose

Control animals:

yes, concurrent vehicle

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Severe irritation/corrosion effect at the site of entry.

Critical effects observed:

not specified

Several animals died during the study; however, the deaths did not appear to be exposure related. There was a slight, but significant

decrease in body weight gain in male and female mice and male Fisher 344 rats in the high dose groups. There was no effect on hematology, clinical chemistry, and urinalysis. Histologic examination showed minimum to mild rhinitis in both strains of rats. Lesions occurred in the anterior portion of the nasal cavity and were concentration and time related. In mice exposed to 50 ppm, there was cheilitis and accumulation of macrophages in the peripheral tissues after 90 days. Mice in all exposure groups developed eosinophilic globules in the epithelial lining of the nasal tissues

Conclusions:

All findings were confined to the site of first contact and can be explained by the irritating/corrosive properties of the acid. No signs of systemic effects were reported. Therefore systemic availability is unlikely. The local NOAEC is below 10 ppm (15 mg/m³). No statement is possible about a systemic NOAEC because of the severe irritation/corrosion effect occurring at the site of entry. Potential systemic effects are considered as consequences of these local effects.

Executive summary:

In a 90-day inhalation study using B6C3F1 mice, Sprague-Dawley, and Fisher 344 rats groups of 31 males and 31 females of each species and strain were exposed (whole body) to HCl at 0, 10, 20 or 50 ppm (0, 15, 30, or 75 mg/m³), 6 h/day, 5 days/week for 90 days. Several animals died during the study; however, the deaths did not appear to be exposure related. There was a slight, but significant decrease in body weight gain in male and female mice and male Fisher 344 rats in the high dose groups. There was no effect on hematology, clinical chemistry, and urinalysis. Histologic examination showed minimum to mild rhinitis in both strains of rats. Lesions occurred in the anterior portion of the nasal cavity and were concentration and time related. In mice exposed to 50 ppm, there was cheilitis and accumulation of macrophages in the peripheral tissues after 90 days. Mice in all exposure groups developed eosinophilic globules in the epithelial lining of the nasal tissues.

 

All findings were confined to the site of first contact and can be explained by the irritating/corrosive properties of the acid. No signs of systemic effects were reported. Therefore systemic availability is unlikely. The local NOAEC is below 10 ppm (15 mg/m³). No statement is possible about a systemic NOAEC because of the severe irritation/corrosion effect occurring at the site of entry. Potential systemic effects are considered as consequences of these local effects.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Principles of method if other than guideline:

"In two parallel inhalation studies male Sprague-Dawley rats were exposed either to filtered air or to an aerosol consisting of combustion products of red phosphorus/butyl rubber (95:5). Exposure took place 2.25 hours per day, 4 days per week, for 13 weeks to 0, 300, 750 or 1200 mg aerosol/m³ and in a second experiment to 0, 50, 180 or 300 mg/m³."

GLP compliance:

not specified

Remarks:

Review article or handbook.

Specific details on test material used for the study:

Combustion products of red phosphorus/butyl rubber (95:5).

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

air

Duration of treatment / exposure:

2.25 hours per day, 4 days per week, for 13 weeks

Frequency of treatment:

4 days per week

Remarks:

Doses / Concentrations:
In a first test 0, 300, 750 or 1200 mg aerosol/m³ and in a second test 0, 50, 180 or 300 mg aerosol/m³
Basis:
nominal conc.

No. of animals per sex per dose:

In the first study, each 176 animals were used in the control, the middle and the high exposure group in the lowest group 84, in the second study each 40 animals per group.

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

37.5 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no effects observed

Critical effects observed:

not specified

"In both studies, the target organ is the respiratory tract, with the terminal bronchioles being particularly affected. The only concentration-dependent effect in the surviving animals was a moderate to severe terminal bronchiolar fibrosis with or without a weak involvement of the lung tissue with a NOAEC of 50 mg/m3, corresponding to approximately 37.5 mg phosphoric acid/m3 (phosphoric acid concentration about 75% of the aerosol concentration[...]).

Conclusions:

The target organ is the respiratory tract, with the terminal bronchioles being particularly affected. The only concentration-dependent effect in the surviving animals was a moderate to severe terminal bronchiolar fibrosis with or without a weak involvement of the lung tissue with a NOAEC of 50 mg/m3, corresponding to approximately 37.5 mg phosphoric acid/m3.

Executive summary:

“In two parallel inhalation studies male Sprague-Dawley rats were exposed either to filtered air or to an aerosol consisting of combustion products of red phosphorus/butyl rubber (95:5). Exposure took place 2.25 hours per day, 4 days per week, for 13 weeks to 0, 300, 750 or 1200 mg aerosol/m3 and in a second experiment to 0, 50, 180 or 300 mg/m3. The average phosphoric acid concentrations were analyzed weekly after oxidation of the dissolved collected samples and were between 71% and 80% of the aerosol concentration. In the second study, in which the animals were treated with lower concentrations and in which the focus was on the lung examination, tissue sections of the five lung lobes of 20 rats per exposure group and control group and additionally tissue sections of nasal concha and trachea of 10 animals per group were investigated. An accurate description of the method and results can be found in the [MAK] justification for "diphosphorus pentoxide" (2006).

In both studies, the target organ is the respiratory tract, with the terminal bronchioles being particularly affected. The only concentration-dependent effect in the surviving animals was a moderate to severe terminal bronchiolar fibrosis with or without a weak involvement of the lung tissue with a NOAEC of 50 mg/m3, corresponding to approximately 37.5 mg phosphoric acid/m3 (phosphoric acid concentration about 75% of the aerosol concentration, see above) (Aranyi et al. 1988; US Army Medical Research and Development Command 1986, [MAK] justification for "diphosphorus pentoxide" 2006). The composition of the aerosol is unclear. It can be assumed to contain elemental phosphorus, diphosphorus pentoxide, and phosphoric acid” (Phosphorsäure (ortho-Phosphorsäure) [MAK Value Documentation in German language, 2006]). 

Reference 3

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Insufficient details on experimental design; study duration and the species investigated are unclear.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Chronic exposure study: duration and frequency of exposure unknown, duration of study unknown, species unclear

GLP compliance:

no

Remarks:

: study pre-dates GLP

Limit test:

no

Species:

other: not reported (rats, mice, guinea pigs and/or rabbits)

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

646 white rats, 57 guinea pigs, 102 white mice and 12 rabbits.

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: Not reported

Details on inhalation exposure:

No information available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 months

Frequency of treatment:

Not reported

Remarks:

Doses / Concentrations:
0.00048 and 0.00134 mg/L in air
Basis:
no data

No. of animals per sex per dose:

Not reported

Control animals:

yes

Details on study design:

The acute and chronic effects of phosphoryl trichloride were investigated. Information on the methods and study design is limited, but animals were exposed to several concentrations. Some chronic exposure groups were permitted a 4 month recovery period to determine the reversibility of the effects of the test substance. A control group is referred to, but no further details are provided. In the acute test, a single exposure period of 4 hours is referred to.

Positive control:

Not reported

Observations and examinations performed and frequency:

Body weight gain and determination of the respiration rate were determined.

Sacrifice and pathology:

Gross pathology was carried out. Vital staining of the lung tissue, and weight coefficients of the lungs were determined. Blood and urine pH were measured in single-exposure animals.

Other examinations:

Cytogenicity (chromosome aberrations). Rat bone marrow was subject to ana-telophasis analysis. Sperm morphology was investigated.

Statistics:

None reported.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

Single administration of a high concentration resulted in clinical and pathomorphological changes in the internal organs, which showed pronounced irritation. Dystrophic changes occurred particularly in the kidneys, liver and nervous system, and were reportedly connected to the absorption of the decomposition products from the extensive necrotic surface of the respiratory passages. A single exposure to a concentration of 10 mg/m3 over the course of 4 hours caused a statistically significant drop in pH of the blood and urine; blood pH was 5.98±0.02 in treated animals compared to 6.84 in controls (p=0.01), and urine pH was 5.25±0.12 in treated animals compared to 6.73±0.17 in controls (p=0.01).

Chronic exposure induced pronounced chronic intoxication of the animals. Body weight gain was affected, as was respiration rate and oxygen consumption. A decrease in the excretion of hippuric acid in the urine was observed in rats.
After 4 months exposure at a concentration of 0.00134 mg/L, pronounced morphological changes were observed; catarrhal desquamative rhinitis, tracheitis, bronchitis, and degenerative changes in brain nerve cells. Mild protein dystrophy in the liver and kidneys and moderate small-droplet lipodystrophy in the liver were also observed. Signs of enterocolitis were seen in the gastrointestinal tract. The greatest morphological changes were observed in the respiratory tract, in the kidneys and intestine (region of elimination of the substance) and in the liver (region of detoxication). The animals also showed considerable changes in the bone tissue in the form of osteoporosis.
Four months after termination of the chronic experiment in rats and guinea pigs the pathological signs had subsided, but not returned to normal. Considerable changes remained in the respiratory tract.
A concentration of 0.00048 mg/L caused only irritation of the mucous membrane of the respiratory passages and bronchi in the form of rhinits and catarrhal bronchitis. In rats an increase in the weight coefficients of the kidneys was observed. After the period of recovery the morphological picture of the internal organs of the exposed animals did not differ from the control group.
Exposure to a concentration of 0.00134 mg/L caused a cytogenic effect; there was an increased number of chromosomal anomalies and cytostatic activity was affected. At a concentration of 0.00048mg/L the number of chromosomal anomalies was increased but was not statistically significant from controls.
Bone marrow ana-telophase analysis demonstrated that phosphoryl trichloride induced all types of nuclear disturbances and was one of the factors of the non-arresting activity. Phosphoryl trichloride was also reported to have a cytostatic effect, the severity of which was concentration dependent.
Phosphoryl trichloride affected the motility of spermatozoids, though it did not affect spermatogenesis.

Dose descriptor:

LOAEC

Effect level:

0 mg/L air

Sex:

not specified

Basis for effect level:

other: Irritation of the mucous membrane of the respiratory passages and bronchi in the form of rhinits and catarrhal bronchitis.

Critical effects observed:

not specified

The decrease in excretion of hippuric acid in the urine of rats indicated a disturbance of the detoxicating function of the liver. The effects on the kidneys may be indicative of the elimination of the substance in the urine. The authors report that generalisation of the results of the chronic experiment leads to the conclude that a concentration of 0.00048 mg/L approaches the threshold of the chronic effect. The mutagenic and gondaotropic activities of phosphoryl trichloride and its effect of the skeletal system suggest that the coefficient of cumulation is higher than 10, and consequently the highest admissible concentration (HAC) amounts to 0.00005 mg/L. Long term exposure causes a disturbance of mineral metabolism (disturbance of the elimination of calcium, phosphorous and chlorine) and changes in the bone tissue. The authors report that damage to the bone substance caused by phosphoryl trichloride is different to damage caused by elemental phosphorous, indicating that the pathological bone changes seen in the experiment were not solely due to the presence of phosphorous in phosphoryl trichloride.

Conclusions:

The highest admissable concentration in air of the working place was set as 0.05 mg/m³.

Executive summary:

The study investigate the effects of phosphoryl trichloride on various species, the methods are poorly reported therefore it is difficult to draw conclusions from the results. Repeated inhalation exposure to phosphoryl trichloride (0.00048 and 0.00134 mg/L in air) in rats (also mice, guinea pigs and rabbits) for 4 months affected body weight gain, respiration rate and oxygen consumption. A decrease in the excretion of hippuric acid in the urine was observed in rats. The greatest morphological changes were observed in the respiratory tract, the kidneys, intestine and the liver. Bone changes were observed in the form of osteoporosis. A 4 month recovery period saw the pathological signs subside, but not return to normal. At the higher dose a cytogenic effect was observed in the form of chromosomal anomalies and cytostatic activity. Exposuure induced all types of nuclear disturbance in rat bone marrow. Exposure to phosphoryl trichloride also affected the motility of spermatazoids.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

15 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data are reviewed and published in the OECD SIDS for hydrogen chloride and phosphoric acid.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In parallel studies in rats and guinea pigs animals were exposed for 4 months with a 1 month recovery period to concentrations of 0 (control), 0.48 or 1.34 mg phosphoryl trichloride/m³ (0.075 or 0.21 ppm). A severe irritation of the mucous membranes of the respiratory tract and a chronic rhinitis, tracheitis, desquamating bronchial catarrh, hyperplasia of mucus cells and round cell infiltration of the submucosa was found. Even after 4 weeks after the end of exposure recovery was still incomplete.

It is not possible to allocate the descriptions to one specific species. The LOAEL was 0.48 mg/m³. Due to methodical and documentation deficiencies the studies are judged as non valid.

As phosphoryl trichloride hydrolyzes quickly to form hydrochloric and phosphoric acids, chronic effects are expected mostly from exposure to these degradation products.

In a 90-day inhalation study using B6C3F1 mice, Sprague-Dawley, and Fisher 344 rats groups of 31 males and 31 females of each species and strain were exposed (whole body) to HCl at 0, 10, 20 or 50 ppm (0, 15, 30, or 75 mg/m3), 6 h/day, 5 days/week for 90 days. Systemic availability is unlikely. Histologic examination showed minimum to mild rhinitis in both strains of rats. Lesions occurred in the anterior portion of the nasal cavity and were concentration and time related

The local NOAEC is below 10 ppm (15 mg/m³). In a reevaluation of the same study by the German MAK commission a NOAEC (systemic) of ca. 30 mg/m³ and a LOAEC (local) of 15 mg/m³ was stated.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Phosphoryl trichloride is hydrolyzed in seconds or minutes in water or moist air. Phosphoryl trichloride reacts with water, forming hydrochloric acid and phosphoric acid. Data are available regarding hydrochloric acid/hydrogen chloride (OECD SIDS for phosphoryl trichloride). According to the MAK collection for phosphoryl trichloride, 41. Supplement, 2006, a NOAEC of 37.5 mg/m³ for phosphoric acid (2.25 h per day/ 4 days per weak for 13 weeks) can be assumed.

Altogether the NOAEC of phosphoric acid (ca. 37.5 mg/m³) is higher than the NOAEC (systemic) of hydrogen chloride (30 mg/m³). Therefore, hydrogen chloride is regarded as the more toxic hydrolysis product of phosphoryl trichloride and a read-across with hydrochloric acid/hydrogen chloride is performed.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

Phosphoryl trichloride is hydrolyzed in seconds or minutes in water or moist air. Phosphoryl trichloride reacts with water, forming hydrochloric acid and phosphoric acid. Data are available regarding hydrochloric acid/hydrogen chloride (OECD SIDS for phosphoryl trichloride). According to the MAK collection for phosphoryl trichloride, 41. Supplement, 2006, a NOAEC of 37.5 mg/m³ for phosphoric acid (2.25 h per day/ 4 days per weak for 13 weeks) can be assumed.

Altogether the NOAEC of phosphoric acid (ca. 37.5 mg/m³) is higher than the LOAEC (local) of hydrogen chloride (15 mg/m³). Therefore, hydrogen chloride is regarded as the more toxic hydrolysis product of phosphoryl trichloride and a read-across with hydrochloric acid/hydrogen chloride is performed.

Justification for classification or non-classification

In invalid studies (insufficient details on experimental design; study duration and the species investigated are unclear (see Roshchin & Molodinka, 1977) effects on the lung were observed. For phosphoryl trichloride a harmonized classification is available which is adopted.