Pyrasulfotole

Endpoint summary

Description of key information

Oral (OECD 423), rat: LD50 > 2000 mg/kg bw (LD50 cut-off value = 5000 mg/kg bw according to OECD 423)

Inhalation (OECD 403), rat: LC50 > 5000 mg/m3 air

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw

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 Dec 2003 - 28 Jan 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

adopted 17 Dec 2001

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL: Analysis of the test compound formulations confirmed stability at room temperature for at least 4 hours and that the test compound is homogeneously distributed in the 0.5 and 200 mg/ml formulations. Suspensions had to be stirred for homogenization.

Species:

rat

Strain:

Wistar

Remarks:

(HsdCpb:Wu)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan/Winkelmann GmbH, Borchen, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 9 - 10 weeks
- Weight at study initiation: 162 - 170 g
- Fasting period before study: yes (16 - 24 h)
- Housing: group housing
- Diet: Provimi Kliba 3883.0.15 Maus/Ratte Haltung, Kaiseraugst, Switzerland (ad libitum)
- Water: tap water (ad libitum)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 05 Dec 2003 To: 28 Jan 2004

Route of administration:

oral: gavage

Vehicle:

other: 2% polyethoxylated castor oil (Cremophor(R)) in demineralized water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females each in the first and second step

Control animals:

other: not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Signs of poisoning and mortality rates were determined several times on the day of administration and subsequently at least once daily. Body weights were determined weekly.
- Necropsy of survivors performed: yes

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 cut-off 5000 mg/kg bw according to OECD 423

Mortality:

No mortality was noted in the course of the study.

Clinical signs:

other: No clinical signs were noted in the course of the study.

Gross pathology:

No gross pathological findings were noted at scheduled necropsy.

Interpretation of results:

other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

The study was performed in accordance to OECD TG 423 under GLP conditions and is considered reliable. The LD50 was determined to be > 2000 mg/kg bw (LD50 cut-off of 5000 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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

Study period:

04 Nov - 24 Nov 2003

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:

adopted 12 May 1981

Deviations:

yes

Remarks:

Mean maximum attainable diameter (MMAD) was slightly higher than recommended.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted 7 Sep 2009

Deviations:

yes

Remarks:

see field "Principles of method if other than guideline"

Principles of method if other than guideline:

MMAD was slightly higher than recommended, however, animals were exposed to the highest attainable concentration and efforts were made to maximize both the test concentration as well as the respirability of dust. Animals were not acclimatised to the test apparatus prior to testing. Animals were not group housed during the non-exposure periods.

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Specific details on test material used for the study:

FORM AS APPLIED IN THE TEST: aerosol (dust)

Species:

rat

Strain:

Wistar

Remarks:

(HsdCpb:Wu)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 2 months
- Weight at study initiation: males: 166 - 186 g; females: 156 - 183 g
- Housing: individually in Macrolon Type III H cages
- Diet: KLIBA 3883 = NAFAG 9441 pellets maintenance diet for rats and mice; PROVlMl KLIBA SA, Kaiseraugst, Switzerland (ad libitum)
- Water: tap water (ad libitum)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 40 - 60
- Air changes (per hr): approximately 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 04 Nov 2003 To: 24 Nov 2003

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

clean air

Remarks:

(compressed air, freed from water, dust and oil)

Mass median aerodynamic diameter (MMAD):

5.93 µm

Geometric standard deviation (GSD):

1.88

Remark on MMAD/GSD:

MMAD was slightly higher than recommended. However, extensive measures were taken to maximize both the test concentration as well as the respirability of dust.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: aluminum inhalation chamber with the following dimensions (inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm)
- Exposure chamber volume: internal volume about 3.8.L
- Method of holding animals in test chamber: tubes were chosen that accommodated the animals' size.
- Source and rate of air: compressed air supplied by Boge compressors, inlet air flow: 28 L/min
- Method of conditioning air: compressed air was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer; adequate control devices were employed to control supply pressure.
- System of generating particulates/aerosols: under dynamic conditions the test substance was fed into the intake of the cylindrical inhalation chamber; for the generation of test atmosphere an EXACTOMAT 4200 (TSE, Bad Homburg, Germany) was used. For powder dispersion, conditioned compressed air (28 L/min; continuous operation) was used.
- Method of particle size determination: the particle-size distribution was analyzed using an ANDERSEN cascade impactor; the individual impactor stages were subjected to gravimetric analysis; adhesive stage coating (silicone spray) was used to prevent particle bounce and reentrainment due to the adsorptive capacity of the filter; gravimetric analyses were made using a digital balance.
- Treatment of exhaust air: exhaust air was purified via cotton-wool/HEPA filters
- Temperature and humidity in air chamber: mean temperature: 22.8°C, relative humidity: 33.8 %

TEST ATMOSPHERE
- Brief description of analytical method used: the test-substance concentration was determined by gravimetric analysis (filter: glass-fiber filter, Sartorius, Göttingen, Germany; electronic balance)
- Samples taken from breathing zone: yes ("in the vicinity of the breathing zone")


TEST ATMOSPHERE
- Particle size distribution: The samples for the analysis of the particle-size distribution were taken in the vicinity of the breathing zone. During each exposure two samples were taken.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 5.93 µm / 1.88

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5030 mg/m3 (gravimetric concentration), maximum technically attainable concentration

No. of animals per sex per dose:

5 males and 5 females

Control animals:

yes

Remarks:

(no concurrent control but periodic in-house control group, utilized for several studies)

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical signs were recorded several times on the day of exposure and at least once daily thereafter; body weights were determined before exposure, on days 3 and 7 and weekly thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: rectal temperatures were measured shortly after cessation of exposure (approximately within 0.5 hour after the end of exposure) using a digital thermometer with a rectal probe for rats; a battery of reflex measurements was made on the first post-exposure day

Statistics:

Necropsy findings: Specific findings from the respiratory tract of surviving rats were evaluated using the pair-wise Fisher test after the R x C chisquared test. The Fisher test was only performed if differences occurred between groups in the R x C chi-squared test or if a frequency value of < 5 was calculated. This procedure was performed in accordance with Gad and Weil (1982). For calculation of the unilateral p value a symmetrical distribution was assumed (p unilateral = (p bilateral)/2).
Body weights: Means and single standard deviations of body weights are calculated. Since in acute studies individual group means may differ prior to commencement of the first exposure, the body weight gain was statistically evaluated for each group. For these evaluations a one-way ANOVA (vide infra) is used.
Physiological data: Data of rectal temperature are evaluated using the ANOVA procedure (vide infra).
Calculation of the LC50: not applicale as no mortalities occurred
Analysis of variance (ANOVA): This parametric method checks for normal distribution of data by comparing the median and mean. The groups are compared at a confidence level of (I-a) = 95% (p = 0.05). The test for the between-group homogeneity of the variance employed Box's test if more than 2 study groups were compared with each other. If the above F-test shows that the intra-group variability is greater than the inter-group variability, this is shown in the Appendix as ''no statistical difference between the groups". If a difference is found then a paitwise post-hoc comparison is conducted (1- and 2-sided) using the Games and Howell modification of the Tukey-Kramer significance test. This program was originally obtained from BCTIC.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 000 mg/m³ air (analytical)

Based on:

test mat.

Remarks:

(maximum attainable concentration)

Exp. duration:

4 h

Remarks on result:

other: No mortality occurred in the course of the study.

Mortality:

No mortality occurred during the study.

Clinical signs:

other: Clinical signs were noted in all five animals exposed to the test item. These signs consisted of ungroomed hair / coat and piloerection and were noted on Days 1 and 2 (males) or 1 to 3 (females), respectively.

Body weight:

Comparisons between the control and exposure group did not reveal any statistically significant and toxicologically relevant changes in body weights.

Gross pathology:

No macroscopic changes attributable to exposure of the test item were noted during scheduled necropsy.

Other findings:

- Other observations: Statistical comparisons between the control and test item-exposed group revealed that the body temperature was mildly, although statistically significantly decreased.
In comparison to the rats of the control group, none of the rats exposed to the test item experienced any changes in their reflex behavior.

Table 1: Summary of acute inhalation toxicity - 4 hour exposure to aerosolized test substance

Group	Target concentration [mg/m^3]	Toxicological results^$	Duration of clinical signs	Time of death	Mortality (%)	Rectal Temperature (°C)
Males
1	0	0/0/5	---	---	0	37.8
2	5000	0/5/5	Day 1-2	---	0	35.4*
Females
1	0	0/0/5	---	---	0	38.1
2	5000	0/5/5	Day 1-3	---	0	36.1**
	LC50 > 5000 mg/m^3

*= p < 0.05, ** = p < 0.01

^$number of dead animals / number of animals with clinical signs / number of animals used

Interpretation of results:

other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

The study was performed in accordance to OECD TG 403 under GLP conditions and is considered reliable. The LC50 was determined to be > 5000 mg/m3.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 5 000 mg/m³ air

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

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:

10 Sep - 24 Sep 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 12 May 1987

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)

Version / remarks:

adopted 9 Oct 2017

Deviations:

yes

Remarks:

The current guideline requires a Fixed Dose Procedure. However, the study was correctly conducted in accordance with an old version of the guideline as a standard acute method.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

(HsdCpb:Wu)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan/Winkelmann GmbH, Borchen, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 9 - 13 weeks
- Weight at study initiation: males: 236 - 252 g, females: 209 - 221 g
- Fasting period before study: no fasting period
- Housing: animals were individually housed
- Diet: Provimi Kliba 3883.0.15 Maus/Ratte Haltung, Kaiseraugst, Switzerland (ad libitum)
- Water: tap water (ad libitum)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 10 Sep 2003 To: 24 Sep 2003

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: shaven skin on the back, males: 22.5 cm2, females 20.25 cm2
- Type of wrap: the treated skin was covered with a wet gauze-layer of a "Cutiplast steril" coated with air-tight "Leukoflex" and secured in place with "Peha-Haft" cohesive stretch tape; additionally, the mobility of the rats was impaired by a "Lomir Biomedical Inc." rat jacket, which was connected with a safety pin to the stretch tape

REMOVAL OF TEST SUBSTANCE
- Washing: the treated area was cleaned with soap and water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (weight with unit): 2000 mg/kg bw
- Constant concentration used: yes
- For solids, paste formed: no

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The signs of poisoning and mortality rates were determined several times on the day of application and subsequently at least once daily for an observation period of 14 days. Body weights were determined weekly until the end of the study.
- Necropsy of survivors performed: yes

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality occured and no clinical signs were noted in the course of the study.

Mortality:

No mortality occurred in the course of the study.

Clinical signs:

other: No clinical signs were noted in the course of the study.

Gross pathology:

During scheduled necropsy no macroscopic findings were noted.

Interpretation of results:

other: CLP/GHS criteria not met; no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

The study was performed in accordance to OECD TG 402 under GLP conditions and is considered reliable. The LD50 was determined to be > 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Reliable studies regarding acute oral, inhalation and dermal toxicity are available for the test substance.

 Oral:

The acute oral toxicity of the test substance was assessed in a study performed according to OECD 423 and in compliance with GLP (M-001078-01-2, 2004). A group of three fasted female Wistar rats was treated with the test material at a dose level of 2000 mg/kg bw. This was followed by a further group of three fasted females treated with the same dose level. The test material was administered by gavage as a suspension in water with 2% Cremophor (polyethoxylated castor oil). The animals were observed for 14 days. There were no deaths and all the animals showed the expected gains in bodyweight over the study period. No abnormalities were detected at necropsy.

The acute oral LD50 value of the test material was therefore > 2000 mg/kg (LD50 cut-off according to OECD 423).

Inhalation:

The acute inhalation toxicity of the test substance was assessed in a study according to OECD 403 and performed in compliance with GLP (M-121743-01-2). A group of 10 Wistar rats (5/sex) was exposed to the test substance as a dust. The animals were exposed for 4 h using a nose-only exposure system, followed by a 14-day observation period. The mean achieved atmosphere concentration was 5030 mg/m³ which was the mean maximum attainable concentration. The mean mass median aerodynamic diameter was 5.93 µm with a geometric standard deviation of 1.88 and therefore small enough for particles to be inhalable. No animal died during this study. Clinical signs were ungroomed coat and piloerection, which were observed on the day of treatment and the following two days only. Approximately 30 minutes after the inhalation period body temperatures were slightly but statistically significantly decreased. However, this was considered to be an indirect evidence of a mild respiratory tract sensory irritation possibly through desiccating the mucous membranes of the upper respiratory tract due to the high dust loading and was therefore not indicative of a toxic effect. There were no effects on body weight or body weight gain.

No abnormalities were detected at necropsy.

The acute inhalation LC50 was considered to be greater than 5000 mg/m³ air (analytical).

Dermal:

The acute dermal toxicity of the test substance was assessed in a study performed according to OECD 402 and in compliance with GLP (M-001029-01-2). A group of ten Wistar rats (5/sex) was given a single, 24-hour, semi-occluded dermal application of the test material to intact, shaven skin at a dose level of 2000 mg/kg bw. The animals were observed for 14 days. There were no mortalities or clinical signs of toxicity. Body weight and body weight gain in males were unaffected. One female showed decreased body weight on Day 15.

No signs of dermal irritation were observed. No abnormalities were noted at necropsy.

The acute dermal LD50 of the test material was found to be greater than 2000 mg/kg bw.

Justification for classification or non-classification

The available data on acute oral, inhalation and dermal toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.