Diphenyl methylphosphonate

Acute Toxicity: dermal

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

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

Test material

Test material information

Constituent 1

Reference substance name:

Diphenyl methylphosphonate

EC Number:

231-388-1

EC Name:

Diphenyl methylphosphonate

Cas Number:

7526-26-3

Molecular formula:

C13H13O3P

IUPAC Name:

diphenyl methylphosphonate

Details on test material:

- Name of test material (as cited in study report): VP AC 4028
- Substance type: organic
- Physical state: solid, colourless to white
- Stability under test conditions: The performed analytical studies on the stability of the application formulations showed that VP AC 4028 was in a concentration range of about 10 to 200 mg/mL stable over the period of use.
- Storage condition of test material: dry at room temperature

Test animals

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:

Administration / exposure

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).

Results and discussion

Preliminary study:

no

Effect levels

Effect levels 1

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

569 mg/kg bw

Based on:

test mat.

Effect levels 2

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

Any other information on results incl. tables

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

Applicant's summary and conclusion

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)