Reaction products of bis([tetrakis(hydroxyalkyl)phosphonium] sulfate and alkanamine with Urea

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2016-05-30 to 2016-08-31

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes (incl. QA statement)

Remarks:

2015-09-22

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Test material form:

liquid

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: 8 - 12 weeks old
- Weight at study initiation: 150-300 g. The maximum difference of individual animal weights from the mean of the treatment group will not exceed 20%.
- Fasting period before study: Yes
- Housing: Group caging (3 animals / cage) Cage type: Type II. polypropylene / polycarbonate Bedding: Certified laboratory wood bedding
- Diet Animals will receive ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany, ad libitum,
- Water: tap water from the municipal supply, as for human consumption from a 500 ml bottle, ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From: 31st May 2016 To: 17 June 2016.

Administration / exposure

Route of administration:

oral: gavage

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration:14 dzys
- Frequency of observations and weighing:
Animals will be observed individually after dosing at least once during the first 30 minutes, then 1, 2, 3, 4 and 6 hours after the treatment and once each day for 14 consecutive days thereafter.
The body weights will be recorded on Days -1 (prior to removal of food), 0 (prior to administration), 7 and 14 with a precision of 1 g. Terminal body weight of animals found dead or sacrificed in extremis will also be recorded.
- Necropsy of survivors performed: yes
- Other examinations performed: All gross macroscopic changes will be recorded for each animal.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mg/kg bw

Based on:

act. ingr.

Mortality:

Two of three animals were found dead at a dose level of 300 mg a.i./kg bw on Day 1.
No mortality occurred at 50 mg a.i./kg bw.

Clinical signs:

Decreased activity (slight to severe), prone position, hunched back and piloerection was noted at the dose level of 300 mg a.i./kg body weight during the period of Day 0-1. The single surviving rat at this dose level was symptom-free from Day 2.
All animals were symptom-free during the entire observation period when treated at 50 mg a.i./kg bw.

Body weight:

There were no effects on body weights or body weight gains that could be attributed to treatment with of Tetrakis[hydroxymethyl]phosphonium sulphate urea-amine copolymer in the surviving animals.

Gross pathology:

Found dead animals at 300 mg a.i./kg bw:
Reddish or yellowish liquid material was seen on the fur of the perinasal area as external findings in the found dead animals at necropsy.

Thickening and/or dark red, diffuse discoloration in the glandular mucosa of the stomach, yellowish mucoid material in the stomach or duodenum/jejunum, dark red diffuse discoloration in the non-collapsed lungs and/or reddish, foamy material in the trachea were noted, as internal macroscopic changes at necropsy.

Surviving animals at 300 or 50 mg a.i./kg bw:
No external or internal macroscopic changes were observed in the surviving animals at the scheduled necropsy on Day 14.

Any other information on results incl. tables

Dose: 300 mg/kg Sex: Female

Cage Number	Animal Number	Body Weight (g) Days				Day / Body Weight (g) at death	Body weight gain (g)
		-1	0	7	14		-1 – 0	0 – 7	7 - 14	-1 - 14
1	381#	239	219	-	-	1/227	-20	-	-	-
	382#	236	221	-	-	1/216	-15	-	-	-
	383	234	208	252	268	-	-26	44	16	34
Mean		236.3	216.0	252.0	268.0	-	-20.3	44.0	16.0	34.0
SD		2.5	7.0	-	-	-	5.5	-	-	-

 

Dose: 50 mg/kg Sex: Female

Cage Number	Animal Number	Body Weight (g) Days				Day / Body Weight (g) at death	Body weight gain (g)
		-1	0	7	14		-1 – 0	0 – 7	7 - 14	-1 - 14
2	384	228	213	241	248	-	-12	28	7	23
	385	220	207	238	250	-	-13	31	12	30
	386	224	206	245	250	-	-18	39	5	26
3	387	240	223	250	252	-	-17	27	2	12
	388	222	212	229	243	-	-10	17	14	21
	389	229	218	245	238	-	-11	27	-7	9
Mean		226.7	213.2	241.3	246.8	-	-13.5	28.2	5.5	20.2
SD		7.2	6.5	7.3	5.3	-	3.3	7.1	7.6	8.1

- = No data

# = Found dead

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item, Tetrakis[hydroxymethyl]phosphonium sulphate urea-amine copolymer was found to be between 300 and 50 mg/kg bw in female Crl:WI rats.

According to the GHS criteria, Tetrakis[hydroxymethyl]phosphonium sulphate urea-amine copolymer can be ranked as "Category 3".

The study result triggers the following classification/labelling:
- Regulation (EC) No 1272/2008 (CLP): Category 3, H301 (Toxic if swallowed)
- GHS (rev. 6) 2015: Category 3, H301 (Toxic if swallowed)

Executive summary:

Assessment of acute oral toxicity Tetrakis[hydroxymethyl]phosphonium sulphate urea-amine copolymer in the rat (Acute Toxic Class Method) was realised according to the OECD 423 guideline and under GLP conditions.

Initially, Tetrakis[hydroxymethyl]phosphonium sulphate urea-amine copolymer was administered by oral gavage to three female Wistar rats at 300 mg/kg a.i. body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice.

At 300 mg/kg, two animals were found dead on Day 1.

The dose of 50 mg/kg a.i. was therefore tested.

At 50 mg/kg, no mortality occurred.

Decreased activity (slight to severe), prone position, hunched back and piloerection was noted at the dose level of 300 mg a.i./kg body weight during the period of Day 0-1. The single surviving rat at this dose level was symptom-free from Day 2.

All animals were symptom-free during the entire observation period when treated at 50 mg a.i./kg bw.

Macroscopic examination of the found dead animals at 300 mg/kg showed Reddish or yellowish liquid material was seen on the fur of the perinasal area as external findings in the found dead animals at necropsy.

Thickening and/or dark red, diffuse discoloration in the glandular mucosa of the stomach, yellowish mucoid material in the stomach or duodenum/jejunum, dark red diffuse discoloration in the non-collapsed lungs and/or reddish, foamy material in the trachea were noted, as internal macroscopic changes at necropsy.

No external or internal macroscopic changes were observed in the surviving animals at the scheduled necropsy on Day 14.

 

The oral LD50 value Tetrakis[hydroxymethyl]phosphonium sulphate urea-amine copolymer in Wistar rats was established to be within the range of 50-300 mg/kg a.i. body weight.