[No public or meaningful name is available]

Endpoint summary

Description of key information

Acute Toxicity:

Oral: LD50> 2000 mg/kg b.w. for rat (OECD 423)

Dermal: LD50> 2000 mg/kg b.w. for rat (OECD 402, 24h exposure)

Inhalation:  LC50= 3110 mg/m³ for rat (OECD 403, 4 h exposure)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
[Describe why the read-across can be performed (e.g. common functional group(s), common precursor(s)/breakdown product(s) or common mechanism(s) of action]

The two substances ADK STAB NA-11 (CAS no. 85209-91-2, EC no. 286-344-4) and ADK STAB NA-70 (CAS no. 85209-93-4, EC no. 458-880-0) have the same molecular structure, i.e. 2,4,8,10-tetra-tert-butyl-6-hydroxy-12H-dibenzo[d,g][1.3.2]-dioxaphosphocin-6-oxide. The substances only differ in the counter ion of the cyclic diarylphosphoric acid ester, i.e. sodium and lithium, respectively. Water solubility of NA-11 amounts to 1850 mg/l, that of NA-70 to 390 mg/l. Both substances dissociate at low concentration in aqueous environments.
With both substances, many toxicity studies were performed to determine their hazard potential. In short-term studies for determination of the hazard potential after single or short-term exposure, i.e. skin and eye irritation, skin sensitisation and systemic toxicity after single oral or dermal application, the two substances did not exhibit adverse effects. The LD50 after single oral or dermal exposure was > 2000 mg/kg body weight. In a study for acute inhalation toxicity performed with NA-70 (in powder form), at high concentrations acute toxicity was observed leading to classification for acute toxicity category 4.
In genetic toxicity tests, the two substances exhibited high cytotoxicity in mammalian cell cultures. Based on the results of in vitro and vivo tests, a genotoxic potential can be excluded. The results from these short-term tests confirm the expectation that the two different salts of the cyclic diarylphosphoric acid ester exhibit well comparable toxic properties.
In oral toxicity studies with repeated dosing, at high doses some toxic effects were observed with both substances. A detailed assessment of all toxicological data available on NA-11 and NA-70 and two other substances with the same chemical structure was performed. It was concluded that read-across from data obtained in studies performed with any of the substances is appropriate including the studies for reproduction and developmental toxicity performed with NA-11. See attached review.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
[Provide here, if relevant, additional information to that included in the Test material section of the source and target records]
See attached review.

3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]
See attached review.

4. DATA MATRIX
See attached review.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No deaths at 2000 mg/kg bw

Interpretation of results:

other: LD50 > 2000 mg/kg

Conclusions:

No labelling regarding acute oral toxicity according to Regulation (EC) No 1272/2008 is required.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

(1981) Method B2, Commission Directive 92/69/EEC

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS: Sprague-Dawley Crl:CD® (SD) IGS BR
- Source:Charles River (UK) Ltd, Margate, Kent
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 200g - 350g
- Fasting period before study: none
- Housing:in groups of five by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes and provided with environmental enrichment items: wooden chew blocks
- Diet (e.g. ad libitum): ad libidtum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: min. 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: SAG 410 Solid Aerosol Generator (TOPAS GmbH, Dresden, Germany)
- Exposure chamber volume: 30 l
- Method of holding animals in test chamber: tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber
- Source of air: Compressed air, passed through a water trap and respiratory quality filters
- Method of particle size determination: Marple Personal Cascade Impactor, (Westech IS Ltd, Beds., UK); six impactor stages (9.6, 6.6, 3.5, 1.8, 0.87
and 0.33 μm cut points
- Treatment of exhaust air: passed through a scrubber trap, connected with a filter

- Samples taken from breathing zone: yes

TEST ATMOSPHERE (see Any other information on materials and methods incl. tables, table 1)

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric method

Duration of exposure:

4 h

Concentrations:

see Any other information on materials and methods incl. tables, table 1

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: hourly during exposure, at the end of exposure and 1h later. Once daily up to 14 days.
and weighing: prior to exposure on the day of treatment, days 7 and 14.
- Necropsy performed: yes (all animal, surviving, died, killed)
- Other examinations performed: clinical signs, body weight, macroscopic examination, esp. of the respiratory tract, behavioural observations

Statistics:

LC50’s estimated by Linear Interpolation (US EPA, 1989)

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

3.11 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

see Any other information on results incl. tables, table 2

Clinical signs:

other: Common abnormalities:increased respiratory rate, hunched posture, pilo-erection and wet fur. Frequent instances of decreased respiratory rate, laboured respiration, noisy respiration, ataxia and red/brown staining around the head. Occasional instances of

Body weight:

Normal bodyweight development for all surviving animals during the study with the following exeptions:
Group 1: 1 male and 1 female showed reduced bodyweight gain or slight bodyweight loss during Week 1 but recovered to show normal development during Week 2. A further female from Group 1 showed slight bodyweight loss during Week 2.
Group 2: 5 females exhibited a reduced bodyweight gain or slight bodyweight loss during Week 1 but recovered to show normal development during Week 2.

Gross pathology:

Macroscopic abnormalities detected amongst
- animals that survived until Day 14 at necropsy:
Lungs – enlarged, fluid filled, abnormally dark, pale patches, dark patches (in all animals of the low and mid dose groups);
- animals that died or were humanely killed during the course of the study at necropsy:
Lungs – haemorrhagic, fluid filled, abnormally dark, pale patches;
Liver – dark;
Kidneys – dark or pale;
Stomach – gaseous distension; Small Intestine – gaseous distension; Large Intestine – gaseous distension.

Table 2: Mortality data

Group Number	Mean Achieved Atmosphere Concentration (mg/L)		Deaths
		Male	Female	Total
1	1.00	0/5	0/5	0/10
2	1.96	2/5	0/5	2/10
3	5.03	5/5	5/5	10/10

Interpretation of results:

other: Acute Toxicity Inhalation Category 4, H332: [Regulation (EC) No 1272/2008]

Conclusions:

Acute Toxicity Inhalation Category 4, H332: [Regulation (EC) No 1272/2008]

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

3.11 mg/L

Physical form:

inhalation: dust / mist

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

24 February 1987

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Sprague-Dawley origin (Crl:CD (SD) IGS BR)
- Source: Charles River (UK) Ltd., Margate, Kent, UK.
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: at least 200 g
- Housing: in solid-floor polypropylene cages furnished with woodflakes. Individual housing during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): standard laboratory rodent diet (Certified Rat and Mouse Diet (Code 5LF2))
- Water (e.g. ad libitum): drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12h/12h

Type of coverage:

semiocclusive

Vehicle:

arachis oil

Details on dermal exposure:

back and flanks
- approximately 10% of total body surface area
- Type of wrap if used: surgical gauze semioccluded with a piece of self-adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with cotton wool moistened with arachis oil BP
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution):200 mg/ml w/v
- Constant volume or concentration used: yes
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 10 ml/kg

Duration of exposure:

24 h

Doses:

2000 mg/kg

No. of animals per sex per dose:

10 rats (5 of each sex)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. After removal of dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored. Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: local dermal irritation (erythema, eschar formation, oedema formation), any other lesion or reaction (spots, scabbing)

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

none

Clinical signs:

none

Body weight:

All animals showed expected gains in bodyweight over the study period.

Gross pathology:

no abnormalities

Other findings:

no signs of dermal irritation

Interpretation of results:

other: LD50 > 2000 mg/kg

Conclusions:

No labelling regarding acute dermal toxicity according to Regulation (EC) No 1272/2008 is required.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Justification for classification or non-classification

In both, the acute oral and the acute dermal toxicity studies with NA-70, all animals survived the limit dose of 2000 mg/kg b.w. Therefore, classification for acute oral or dermal toxicity is not required [REGULATION (EC) 1272/2008].

According to the result of the acute inhalation toxicity study, NA - 70 has to be classified as acute toxic category 4 [REGULATION (EC) 1272/2008].