Diphenyl methylphosphonate

Endpoint summary

Description of key information

DPP was found to be toxic via oral and dermal routes of exposure (oral LD50 of 233 mg/kg bw in male Wistar rats; dermal LD50 of 786 mg/kg bw and 569 mg/kg bw for male and female Wistar rats)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05 SEP 1979 - 01 JUN 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented old study, which meets basic scientific principles

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen
- Age at study initiation: approximately 9 weeks
- Weight at study initiation: ca. 190 gr
- Fasting period before study:
- Housing: groups of five, conventionally in Makrolon cages on dust-free wood granules
- Diet (e.g. ad libitum): Altromin R1324 (Altromin GmbH, Lage), ad libitum
- Water (e.g. ad libitum): drinking water ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1.5 °C
- Humidity (%): 60 +/- 5 %
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 h light/ 12 hours dark

OTHER: identification of the animals was secured by marking of the fur with picrinic acid and cage-labels

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 0.4 mL / kg bw

Doses:

0.05, 0.1, 0.2, 0.3, 0.35 and 0.4 mL/kg bw

No. of animals per sex per dose:

10

Control animals:

not specified

Details on study design:

The test item was administered with the aid of a rigid oesophagus-tube to 10 animals.
The animals were inspected repeatedly on the day of administration, thereafter the animals were inspected twice daily (once daily on weekend days and on holidays) for 14 days and the character, onset, duration and intensity of the clinical symptoms was recorded. Whenever dead animals were found they were removed.
Bodyweights were determined individually shortly before adminsitration and after the end of the observation period.

Statistics:

The LD50 value was calculated (p < 0.05) according to the programmed Probit-analysis (Fink and HUnd (Arzneimittelforschung 15, 1965, p. 624).

Sex:

male

Dose descriptor:

LD50

Effect level:

0.19 mL/kg bw

Based on:

test mat.

95% CL:

>= 0.14 - <= 0.25

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

233 mg/kg bw

Based on:

test mat.

Remarks on result:

other: conversion of the above mentioned value, based on density available for the test item

Mortality:

no animal died in the dose group, which received 0.05 mL/kg bw. 3 animals died in the dose group of 0.1 mL/kg bw. 4 and 6 animals died in the dose groups 0.2 and 0.3, respectively. 8 animals died, dosed with 0.35 mL/kg bw and all animals died in the highest dose group (0.4 mL/kg bw).

Clinical signs:

other: The signs of intoxication were ruffled fur, sedation, bloody eyes and nose, these clinical signs were to be noted in all dose groups beside 0.05 mL/kg bw.

The single doses of 0.1 - 0.4ml/ kg bw had the following symptoms of poisoning in all animals: shaggy fur,sedation, bloody eyesand nose.
At starting doses of 0.3 to 0.35mL/ kg bw weight loss was also observed.
The symptoms occurred within 30 minutes after application and were slightly pronounced and lasted until the last day of the observation period. The deaths were reported from day 1to 7.
The calculated LD50 value was 0.19 ml/ kgbw (confidence interval for p<0.05 =0:14 to 0:25mL kgbw).

When increasing the probit regression line(probit-slope-factor) resulted in a value of b=3.36.
The dose of 0.05 mL/ kgbw was tolerated without symptoms.

Interpretation of results:

Category 3 based on GHS criteria

Remarks:

based on EU GHS

Conclusions:

The study was performed equivalent of similar to the OECD TG401 and therefore considered to be of high quality (reliability Klimisch 2). The test material did induce mortality and treatment-related clinical signs in the dose groups of 0.1 - 0.4 mL/kg bw (100, 80 %, 60 & 40 % and 30 % mortality). The test material was considered to be toxic if swallowed after oral application under the conditions of the test and as the LD50 of the test item is 50 - 300 is has to classified as GHS Category 3.

Executive summary:

The acute oral toxicity of diphenyl methylphosphonate (MPS) was investigated in rats (Löser, 1980). The study was performed equivalent or similar to the OECD Guideline 401 and considered to be of high quality (reliability Klimisch 2). 10 male rats per group received doses of 0.05 mL/kg bw, 0.1 mL/kg bw, 0.2 mL/kg bw, 0.3 mL/kg bw, 0.35 mL/kg bw or 0.4 mL/kg bw via a rigid tube orally. The symptoms of intoxications were ruffled hair coat, sedation, bloody eyes and nose and in addition body weight loss (0.3 and 0.35 mL/kg bw). All animals in the highest dose group died within the observation period. In the 0.35 and the 0.3mL/kg bw dose group 8 and 6 animals died, respectively. In the 0.2 and 0.1 mL/kg bw dose group 4 and 2 animals died, respectively. No animals died in the lowest dose group. No clinical symptoms were noted in the lowest dose group. Therefore the oral toxicity can be characterised by a LD50 value of 233 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

233 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991-01-17 to 1991-03-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Richtlinie 84/449/EWG (Amtsblatt der Europäischen Gemeinschaften Nr. L 251 vom 19.09.1984, S.103)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen (Germany)
- Age at study initiation: 10wk (males), 15 wk (females, nulliparous and non-pregnant)
- Weight at study initiation: 244g (males), 214g (females)
- Fasting period before study: no
- Housing: Makrolon cages Typ II with low-dust wood-pellet
- Diet (e.g. ad libitum): ad libitum ( "fixed-formula" Altromin® 1324 Pellets)
- Water (e.g. ad libitum):ad libitum (tape water)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C,
- Humidity (%):ca. 50 ± 10 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Type of coverage:

semiocclusive

Vehicle:

peanut oil

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: 10
- Type of wrap if used: aluminum foil

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with lukewarm water
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5 mL (for dose groups 200 and 447 mg / kg/ bw).
- Concentration (if solution): not reported
- Constant volume or concentration used: yes (only for 200 and 447 mg/kg bw)
- For solids, paste formed: yes. The test substance for the dose groups 2000 and 1000 mg/kg was weighed individually for each animal according to the dose and body weight in aluminum foil, with a few drops of peanut oil DAB 9 into a paste, applied to the prepared skin area and fixed with non-irritating skin patch.

VEHICLE
- Amount(s) applied (volume or weight with unit): 5 mL
- Concentration (if solution): undilited peanut oil
- Lot/batch no.: (Fa. Lamotte, Bremen; Art.-G: 166; Charge: 5917)
- Purity: not reported

Duration of exposure:

24h

Doses:

200, 447, 1000 and 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days and 28 days
- Frequency of observations and weighing: twice daily (once on weekends and holidays). Immediately before application (day 1), after a week and at the end of the 14 to 28-day observation period the surviving animals were weighed individually.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology.

Statistics:

LD50 was calculated according to Spearman - Kärber (adopted from SACHS, L. (Angewandte Statistik, 6. Aufl. (1984) 178).

Preliminary study:

no

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

569 mg/kg bw

Based on:

test mat.

Sex:

male

Dose descriptor:

LD50

Effect level:

786 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities occured in both sexes in the dose group of 200 mg/kg bw. No mortalities occured in males in the dose group of 447 mg/kg bw. One female animal in the 447 mg/kg bw dose group was found dead at the 5th day of postapplication period. The mortalities in the 1000 and in the 2000 mg/kg bw occured in the first week of observation period.

Clinical signs:

other: Single administration of 1000 and 2000 mg/kg bw of test material produced systemic poisoning symptoms: poor general condition, ruffled fur, chromodakryorrhoe, tremors, snap or labored breathing, apathy and loss of weight. In females of the dose group 447

Gross pathology:

No gross pathologic findings were noted in treated animals. In some animals the eye rims and nose were bloody, which is in accordance with the clinically observed Chromodakryorrhoe.

Other findings:

no

Table 1. Mortalities

Dose (mg/kg bw)	No. of animals	Time of death	Mortality (%)
Males
200	0/5	-	0
447	0/5	-	0
1000	4/5	2d-7d	80
2000	3/5	2d-3d	60
Females
200	0/5	-	0
447	1/5	5d	20
1000	5/5	1d-3d	100
2000	4/5	2h-4d	80

  Table 2. Body weights

Dose (mg/kg bw)

Males (g)^

Females (g)^

Day 1

Day 8

Day 15

Day 1

Day 8

Day 15

200

264

284

304

221

226

240

447

227

245

276

215

216°

222°

1000

252

227*

248*

217*

--

--

Day 1

Day 8

Day 15

Day 21

Day 28

Day 1

Day 8

Day 15

Day 21

Day 28

2000

234

168**

194**

223**

248**

202

156*

182*

199*

207*

^Mean of bodyweights
°based on 4 animals
*based on 1 animal
**based on 2 animals
-- Dead animals

Table 3. Clinical signs

Dose (mg/kg bw)	200	447	1000	2000
Males
Number of dead animals	0	0	4	3
Number of animals with symptoms	0	0	5	5
Number of treated animals	5	5	5	5
Symptoms from day	--	--	2	4
Symptom-free from day	--	--	13	--0
	Number of animals with symptoms/number of animals with symptoms of the highest intensity
Ruffled fur	0	0	5/3	1/3
Poor general condition	0	0	2/3	5/3
Tremors	0	0	3/3	5/1
Chromodakryorrhoe	0	0	5/*	5/*
Snap breathing	0	0	5/*	0
Apathy	0	0	5/3	0
Females
Number of dead animals	0	1	5	4
Number of animals with symptoms	0	3	4	5
Number of treated animals	5	5	5	5
Symptoms from day	--	2	2	2h
Symptom-free from day		6	3	14
	Number of animals with symptoms/number of animals with symptoms of the highest intensity
Ruffled fur	0	0	4/3	1/1
Poor general condition	0	3/3	1/3	4/3
Tremors	0	3/2	2/3	5/2
Chromodakryorrhoe	0	0	3/*	4/*
Snap breathing	0	1/*	3/*	1/1
Apathy	0	0	4/3	0
Eyes whitish discoloured	0	0	1/*	0

* Without finding any indication of intensity

Interpretation of results:

Category 3 based on GHS criteria

Remarks:

based on EU GHS

Conclusions:

Diphenyl methylphosphonate is considered to possess toxicity via dermal route of exposure and is classified as Cat 3 (H311 toxic in contac with skin) due to LD50 of 569 mg/kg bw for females and LD50 of 786 mg/kg bw for males.

Executive summary:

The objective of this study was to determine the acute dermal LD50 of diphenyl methylphosphonate applied to the skin of male and female Wistar rats. 5 animals of each sex were dosed with 200, 447, 1000 and 2000 mg/kg bw. The test material remained in contact with the skin for 24 hours. All surviving animals were observed closely for gross signs of systemic toxicity and mortality at frequent intervals during the day of dosing and at least twice daily thereafter for a total of 14 days (animals in the dose group of 2000 mg/kg bw were observed during 28 days). Immediately before application (day 1), after a week and at the end of 14- or 28 -day observation period the surviving animals were weighed individually. A necropsy was conducted on all surviving animals at the end of observation period.

Males tolerated 200 and 447 mg/kg bw without symptoms, while females tolerated only 200 mg/kg bw. Clinical signs of sytemic toxicity were poor general condition, ruffled fur, chromodakryorrhoe, tremors and difficulties in breathing (or snaping). general condition of the surviving animals in the highest dose group was normalized till the 28 -day of observation. No local skin reactions were noted in animals at the test site of application. Body weights of animals in the 1000 and 2000 mg/kg bw decrased significantly. The growth of males treated with 200 and 447 mg/kg bw was not affected. The body weight of three females in the dose group of 447 mg/kg bw decreased marginally in the first week of observation period. Body weights increased clearly in all surviving animals at the end of the observation period. No gross pathological findings were noted in treated animals. In some animals the eye rims and nose were bloody, which is in accordance with the clinically observed chromodakryorrhoe.

The calculated LD50 values were 786 mg/kg bw and 569 mg/kg bw for males and females, respectively. Based on these LD50 values, the classification is warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008:

Acute dermal toxicity: Cat3 (H311 - toxic in contact with skin)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

569 mg/kg bw

Additional information

Acute oral toxicity:

The acute oral toxicity of Diphenyl methylphosphonate was investigated in rats (Loeser, 1980). The study was performed equivalent or similar to the OECD Guideline 401 and considered to be of high quality (reliability Klimisch 2). 10 male rats per group received doses of 0.05 mL/kg bw, 0.1 mL/kg bw, 0.2 mL/kg bw, 0.3 mL/kg bw, 0.35 mL/kg bw or 0.4 mL/kg bw via a rigid tube orally. The symptoms of intoxications were ruffled hair coat, sedation, bloody eyes and nose and in addition body weight loss (0.3 and 0.35 mL/kg bw). All animals in the highest dose group died within the observation period. In the 0.35 and the 0.3 mL/kg bw dose group 8 and 6 animals died, respectively. In the 0.2 and 0.1 mL/kg bw dose group 4 and 2 animals died, respectively. No animals died in the lowest dose group. No clinical symptoms were noted in the lowest dose group. Therefore the oral toxicity can be characterised by a LD50 value of 233 mg/kg bw.

 

Acute dermal toxicity:

The objective of the acute dermal toxicity study (GLP, procedure similar with the OECD 402) was to determine the acute dermal LD50 of diphenyl methylphosphonate applied to the skin of male and female Wistar rats (Bomhard, 1991). 5 animals of each sex were dosed with 200, 447, 1000 and 2000 mg/kg bw. The test material remained in contact with the skin for 24 hours. All surviving animals were observed closely for gross signs of systemic toxicity and mortality at frequent intervals during the day of dosing and at least twice daily thereafter for a total of 14 days (animals in the dose group of 2000 mg/kg bw were observed during 28 days). Immediately before application (day 1), after a week and at the end of 14- or 28-day observation period the surviving animals were weighed individually. A necropsy was conducted on all surviving animals at the end of observation period.

Males tolerated 200 and 447 mg/kg bw without symptoms, while females tolerated only 200 mg/kg bw. Clinical signs of sytemic toxicity were poor general condition, ruffled fur, chromodakryorrhoe, tremors and difficulties in breathing (or snaping). The general condition of the surviving animals in the highest dose group was normalized till the 28 -day of observation. No local skin reactions were noted in animals at the test site of application. Body weights of animals in the 1000 and 2000 mg/kg bw decreased significantly. The growth of males treated with 200 and 447 mg/kg bw was not affected. The body weight of three females in the dose group of 447 mg/kg bw decreased marginally in the first week of observation period. The surviving animals gained the body weight at the end of the observation period. No gross pathological findings were noted in treated animals. In some animals the eye rims and nose were bloody, which is in accordance with the clinically observed chromodakryorrhoe.

The calculated LD50 values were 786 mg/kg bw and 569 mg/kg bw for males and females, respectively.

Justification for classification or non-classification

The classification is warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008:

Acute oral toxicity: Cat3 ( H301 - toxic if swallowed)

Acute dermal toxicity: Cat3 (H311 - toxic in contact with skin).