Propargite

Endpoint summary

Description of key information

ORAL

The NOAEL was determined to be 7.1 mg/kg bw/day (males) and 8.3 mg/kg/day (females) according to a 13 week rat study performed in line with EPA Guideline 82-1.

The NOAEL was determined to be 4 mg/kg bw/day according to a 1 year dog study performed in line with a method considered to be equivalent to OECD 452.

DERMAL

The NOEL was determined to be >100 mg/kg bw/day according to a 21 day rabbit study performed in line with EPA Guideline 82-2.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12th January 1988 to 28th February 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OTS 798.3260 (Chronic Toxicity)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Marshall Research Animals, Inc., North Rose, New York, USA
- Age at study initiation: 5-7 months old
- Weight at study initiation: 7.2-10.6 kg (males); 6.3-9.1 kg (females)
- Housing: individually in elevated metal grid cages
- Diet: 400 g Purina® Certified Canine Diet #5007 presented fresh daily for 4.5 hours
- Water: ad libitum
- Acclimation period: 39 days

ENVIRONMENTAL CONDITIONS
- Temperature: 60-85 ºF
- Humidity: 13-90 %
- Photoperiod: 12 hours light/12 hours dark

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of the diet containing the test material were homogenised and analysed by GC.

Duration of treatment / exposure:

One year

Frequency of treatment:

Daily for approximately 4.5 hours/day.

Dose / conc.:

160 mg/kg diet

Remarks:

5.0 mg/kg bw/day

Dose / conc.:

1 250 mg/kg diet

Remarks:

38.0 mg/kg bw/day

Dose / conc.:

1 875 mg/kg diet

Remarks:

Weeks 9 to 13; 44.0 mg/kg bw/day

Dose / conc.:

2 500 mg/kg diet

Remarks:

Weeks 1 to 8

No. of animals per sex per dose:

Six

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based upon results in previous dog chronic and subchronic studies

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: pretest and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: pretest, weekly to week 13 and monthly thereafter. High-dose animals were weighed weekly from week 38 to study termination.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: pretest, weekly to week 13 and monthly thereafter.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and study termination

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest, months 3 and 6 and study termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- Parameters checked: hemoglobin concentration, haematocrit, erythrocyte count, reticulocyte count, platelet count, mean corpuscular volume/hemoglobin/haemoglobin concentration, total and differential leukocyte counts, erythrocyte morphology.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pretest, months 3 and 6 and study termination
- Parameters checked: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, fasting glucose, cholesterol, total protein, albumin, A/G ratio, total bilirubin, sodium potassium, chloride, calcium, inorganic phosphorus.

URINALYSIS: Yes
- Time schedule for collection of urine: pretest, months 3 and 6 and study termination
- Animals fasted: No
- Parameters checked: appearance, specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, microscopic analysis

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Parameters checked: organ weights - adrenals, heart, kidneys, liver, ovaries, testes, thyroid/parathyroid

HISTOPATHOLOGY: Yes
- Parameters checked: adrenals, aorta (abdominal), bone (sternum), bone marrow (sternum), brain, epididymides, oesophagus, eyes with optic nerve, gall bladder, heart, intestine, kidneys, liver, lungs, lymph nodes (mesenteric, mediastinal), mammary gland, nerve (right sciatic), ovaries, pancreas, pituitary, prostate, salivary gland, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid/parathyroid, tongue, trachea, urinary bladder. uterus, gross lesions

Statistics:

Statistical evaluation applied to body weight, food consumption, haematology, clinical chemistry, terminal organ weight, and organ:body weight ratio data. Difference among means of data was determined by one-way analysis of variance if groups had equal variance (assessed by Bartlett's test), otherwise differences among means determined by Kruskal-Wallis test. Significance of difference from controls assessed by Dunnett's test where variance among means was equal and by Dunn's Rank Sum where variances where not equal. Trend in the dose levels were identified by either regression techniques (equal variance) or by Jonckheeres test (non-equal variance).

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

From week 8 until test termination, the high dose animals were observed to be thin. During the last 3 months, the high dose animals were observed to be dehydrated. In addition, the high dose animals developed scabs/sores and alopecia from week 29 at a higher incidence than in the control animals.

Mortality:

mortality observed, treatment-related

Description (incidence):

A high dose male and a high dose female were sacrificed on days 81 and 349, respectively due to a moribund and emaciated condition. The marked loss of body weight in these animals was considered to be treatment related.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weight and body weight gain was significantly reduced in the 1250 and 1875/2500 mg/kg groups compared to the controls. During the first 8 weeks of the study, mean weight loss in the 1250 and 2500 mg/kg animals was severe (0.4-0.5 and 1.9-2.6 kg, respectively). As a result of this marked weight loss, the high dose level was reduced to 1875 mg/kg to avoid early mortality due to rapid weight loss. Once the dose was reduced to 1875 mg/kg, weight loss was less rapid over the remainder of the study, with losses of 0.1 and 0.6 kg recorded in high dose males and females, respectively. There was a slight weight gain in the 1250 mg/kg animals over this period, although the gain was markedly lower than in the control groups. Overall, body weight at week 52 was reduced by 42.5 and 49.5 % in males and females administered 1850 mg/kg test material in the diet when compared to the controls (statistically significant at P<0.01 level), while corresponding male and female weight loss in the 1250 mg/kg group at week 52 was 17.7 and 19.8 % (statistically significant at P<0.05 level) (see Table 1).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Decreased food consumption in the high dose animals was noted from week 1 and was observed to continue throughout the study. On decreasing the high dose at week 8, food consumption increased, but was still lower than in the controls.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Ophthalmoscopic examination indicated no treatment related ocular effects at any dose level.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

There was a statistically significant decrease in erythrocyte count and associated haematocrit and haemoglobin levels in the 1875 mg/kg males and females at months 3, 6 and 12 and in the 1250 mg/kg males at months 6 and 12. Platelet count was greater than control values in the 1250 and 1875 mg/kg females at all intervals and at months 6 and 12 in the high dose males.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Slight, but statistically significant, differences were recorded for blood urea nitrogen, total protein, albumen, alkaline phosphatase and serum electrolytes, most notable in the high dose group, but also sporadically across all dietary dose levels. However, the absolute values are all considered to be within normal limits for these parameters and so the differences from the control were not considered to be toxicologically significant.

Urinalysis findings:

no effects observed

Description (incidence and severity):

There were no treatment related trends or differences from the control animals in the urinalysis data.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Organ to body weight ratios were increased from the controls, predominantly in the high dose group, but incidences were also noted in some of the 1250 mg/kg animals. The increased organ to body weight ratios were attributed to the reduced overall body weights in these groups. A decrease in the absolute organ weight of heart, kidneys and ovaries was measured in the high dose animals, but these effects were again attributed to the low overall body weight.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

With the exception of erythroid/myeloid depletion of the bone marrow in one of the two high dose animals sacrificed prior to study termination, there were no other remarkable findings in these animals. Necropsy of all the other animals at test termination revealed an increased incidence of red/tan/white foci in the lungs of high dose group. Microscopically, these changes were associated with congestion or serosal inflammation and were considered to be treatment related. Other treatment related changes included an increased incidence of erythroid/myeloid depletion/atrophy of the bone marrow in the high dose animals and a slightly increased incidence/severity of involution of the thymus in the 1250 mg/kg females and the high dose males and females. All other pathological observations were not considered to be treatment related.

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

160 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

histopathology: non-neoplastic

Remarks on result:

other: Equivalent to 4 mg/kg bw/day

Key result

Critical effects observed:

no

Table 1: Mean terminal body weights

Dose (mg/kg diet)	Body weight (kg) - males	Body weight (kg) - females
0	11.3	10.1
160	11.6	9.5
1250	9.3	8.1
2500/1875	6.5	5.1

Conclusions:

Under the conditions of the test, based on the reduced body weight, haematological effects and pathological findings, recorded in this study, the No Observed Adverse Effect Level was 160 mg/kg in the diet. This is equivalent to 5 mg/kg body weight/day.

Executive summary:

The test material was administered orally at dose levels of 160, 1250 and 2500 ppm for a period of 12 months to six dogs per sex per group. The high-dose level was reduced to 1875 ppm at week 9 as a result of excessive body weight loss. Physical observations, ophthalmoscopic examinations, body weight, food consumption measurements, hematology, clinical chemistry and urinanalysis were performed on all animals pretest and at selected intervals throughout the study. At the end of the study, all survivors were sacrificed, selected organs were weighed and organ/body weight ratios calculated. Complete gross post-mortem examinations and histopathological examinations of selected tissues were conducted on all animals.

Treatment with the test material at doses up to 1875 ppm for one year did not produce any ocular abnormalities or differences in clinical chemistry or urinanalysis parameters.

Two high-dose animals died during the study; the deaths were attributed to marked body weight loss and this was considered to be treatment-related. Physically the high-dose animals were thin over the majority of the study period and were frequently noted as dehydrated over the last three months of the study.

Marked decreases in group mean body weight and body weight gain were noted in the mid- and high-dose groups compared to the controls. Controls gained approximately 2 kg over the study period, the mid-dose group gained very little weight (<0.3 kg) while high-dose males and females lost 2.9 and 2.6 kg respectively. The decreased weight gain is most likely due to decreased food consumption.

Erythrocyte count and associate hematocrit and haemoglobin levels were significantly decreased compared to controls in high-dose males and females at months 3, 6 and 12 and in mid-dose males at months 6 and 12. Platelet counts were elevated from controls in the 1250 and 1875 ppm females at all intervals and in high-dose males at 6 and 12 months.

Organ to body weight ratios were increased from controls predominantly in the high-dose animals and occasionally in the mid-dose animals. The differences were attributed to low body weights.

Microscopic examination of tissues revealed treatment-related findings in the lungs, thymus and bone marrow. Red/tan/white foci were noted in the lung of high-dose males. Microscopic examination revealed these foci to be areas of congestion or aerosol subacute/chronic inflammation. Involution of the thymus occurred with slightly greater severity and incidence than controls in mid-dose females and high-dose males and females. Erythroid/myleoid depletion/atrophy of the bone marrow also occurred with a greater incidence and severity in high-dose animals compared to controls.

The NOAEL was determined to be 160 ppm (equivalent to 5 mg/kg/day). In females, treatment at this dietary concentration only induced 26 % lower weight gain which had limited impact on the mean body weight that was only 5.9 % lower than the control at week 52 and therefore not statistically or toxicologically significant.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

4 mg/kg bw/day

Study duration:

chronic

Species:

dog

Quality of whole database:

Five studies with Klimisch score of 1 or 2 are available; the key study was performed to GLP and has a Klimisch score of 1 and was selected on the basis that it is the longest duration. The quality of the database is therefore high.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

7th June 1989 to 29th June 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

no

Principles of method if other than guideline:

During the study, one animal was overdosed by 12.5 % and another underdosed by 11.1 % for one day of the study due to error in assigning animals to treatment cages.

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazelton Research Animals, Inc., Denver, Pennsylvania, USA
- Age at study initiation: approximately 3 months old
- Fasting period before study: yes
- Housing: individually in stainless steel cages
- Diet: Certified Rabbit Chow® #5322, Ralston Purina ad libitum
- Water: ad libitum
- Acclimation period: 38 days

ENVIRONMENTAL CONDITIONS
- Temperature: 69 ± 2.1 ºC
- Humidity: 60 ± 5.5 %
- Photoperiod: 12 hours light/12 hours dark

Type of coverage:

not specified

Vehicle:

not specified

Details on exposure:

TEST SITE
- Area of exposure: 2.1 mg/cm2 (0.1 mg/kg); 4.5 mg/cm2 (1.0 mg/kg); 12.5 mg/cm2 (10 mg/kg); 28 mg/cm2 (100 mg/kg)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 hours

Frequency of treatment:

Once daily; 5 days/week for 3 weeks

Dose / conc.:

0.1 other: mg/kg nominal per unit area

Dose / conc.:

1 other: mg/kg nominal per unit area

Dose / conc.:

10 other: mg/kg nominal per unit area

Dose / conc.:

100 other: mg/kg nominal per unit area

No. of animals per sex per dose:

Five

Control animals:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: pretest, weekly and at terminal necropsy

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest and on day 21
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked: erythrocyte count, haematocrit, haemoglobin, mean corpuscular volume/haemoglobin/haemoglobin concentration, total and differential leukocyte count, platelet count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pretest and on day 21
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked: aspartate aminotransferase, alanine aminotransferase, glucose, urea nitrogen, total bilirubin, total cholesterol, albumin, globulin, total protein, creatinine, sodium potassium, chloride, calcium, inorganic phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Parameters checked: absolute and relative weights of liver, kidneys and testes.

HISTOPATHOLOGY: Yes
- Parameters checked: treated skin (3 sections), untreated skin (3 sections), liver, kidneys, all gross lesions.

Statistics:

Body weight, food consumption, organ weight and clinical pathology parameters analysed using analysis of variance and Bartlett's test. Treatment and control groups compared by sex using appropriate t-statistic (equal or unequal variance) and Dunnett's multiple comparison tables. Nonparametric procedures by rank transformation.

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment related signs of toxicity.

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Dermal irritation was seen in all treated animals, with erythema, oedema, eschar, exfoliation, atonia, desquamation, fissuring, blanching and/or coriaceousness observed at all dose levels, the severity depending on the dose.

Mortality:

no mortality observed

Description (incidence):

There were no mortalities during the study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The mean body weight of all treated male groups and the high dose female group was slightly reduced compared to the control, while the mean body weight of the remaining females was slightly higher than the controls. However, none of these differences were statistically significant and weight gain was normal in all animals over the course of the study.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was slightly reduced at some doses/time points, with statistical significance in the 0.1, 1.0 and 10 mg/kg female groups at week 2, in the 100 mg/kg females at week 1 and at test termination in the 0.1 and 1.0 mg/kg males (see Table 1).

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Haematological data indicate that there was a statistically significant increase in segmented neutrophil values in males dosed with 100 mg/kg bw. There were no other treatment related haematological effects.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There were no treatment related biochemical effects.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No treatment related organ weight changes were observed at any dose level.

Gross pathological findings:

no effects observed

Description (incidence and severity):

On necropsy, aside from skin damage associated with dermal irritation, there were no treatment related systemic macroscopic or microscopic observations.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Test material related microscopic pathology changes were observed on the treated skin of animals for all treatment groups. These changes included acanthosis, hyperkeratosis, dermal inflammation, necrosis (epidermis and dermis) and abscess (epidermal/dermal). While hyperkeratosis and acanthosis showed a dose-related pattern, the incidence and severity of dermal inflammation was similar for all treated groups. No other test material related microscopic findings were observed.

Histopathological findings: neoplastic:

not specified

Key result

Dose descriptor:

NOEL

Effect level:

> 100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Other than dermal irritation, the only systemic treatment related effect was an increase in segmented neutrophils in the 100 mg/kg bw males. Since this is an isolated finding, it is considered to have no biological significance.

Key result

Critical effects observed:

no

Table 1: Summary of food consumption values (g/animal/day)

Week	0 mg/kg	0.1 mg/kg	1.0 mg/kg	10 mg/kg	100 mg/kg
Males
1	179.2 ± 23.59	147.1 ± 8.38	160.2 ± 22.04	151.1 ± 19.75	157.5 ± 24.79
2	173.4 ± 21.75	145.6 ± 13.07	155.8 ± 22.39	153.2 ± 22.53	155.2 ± 16.99
3	172.3 ± 19.80	143.6 ± 18.59	145.3 ± 18.49	150.2 ± 18.77	154.0 ± 22.83
Females
1	187.0 ± 18.88	177.1 ± 15.56	175.7 ± 9.58	165.9 ± 3.92	157.3* ± 17.97
2	188.8 ± 8.51	172.9* ± 3.94	167.6** ± 8.11	173.1* ± 5.33	178.8 ± 28.29
3	176.9 ± 24.18	187.6 ± 12.75	177.3 ± 9.56	182.3 ± 6.15	165.1 ± 31.06

*significantly different from control (p<0.05)

**significantly different from control (p<0.01)

Conclusions:

Under the conditions of the test, the test material was irritating to skin (as expected). However, the only systemic treatment related effect was an increase in segmented neutrophils in the 100 mg/kg bw males. Since this is an isolated finding, it is considered to have no biological significance. Therefore, the NOEL in this study is >100 mg/kg bw. Since the dose was applied daily, 5 days per week, for a 3 week period, this is equivalent to 100 mg/kg body weight/day.

Executive summary:

In a GLP compliant repeated dose toxicity (dermal) study conducted in accordance with standardised guideline EPA OPP 82-2, the repeat dose dermal toxicity of the test material was determined over 21 days. Under the conditions of the test, the NOEL of the substance was determined to be >100 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rabbit

Quality of whole database:

The key study was performed to GLP and has a Klimisch score of 1.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Exposure of rats and dogs to propargite in the diet for a period of 90 days at 1000 and 2000 mg/kg, respectively, led to reductions in body weight/body weight gain, increases in organ:body weight ratios and changes in haematology/blood chemistry. In addition, rats exposed for 90 days to a dietary concentration of 2000 mg/kg displayed significantly reduced absolute weights for kidney, liver and testes. Dogs exposed for 1 year to a dietary concentration of 1250 mg/kg exhibited reduced body weight/body weight gain, some incidences of increased organ:body weight ratios and changes in haematology/blood chemistry although the latter were not considered to be biologically significant. Based on these findings, NOELs of 100 mg/kg diet (5 mg/kg bw/d), <2000 mg/kg diet (<50 mg/kg bw/d) and 160 mg/kg diet (4 mg/kg bw/d) were established for rats and dogs receiving propargite in the diet for 90 days, 13 weeks and 1 year, respectively.

Following exposure of rabbits to dermally applied technical propargite for a period of 21 days, a daily dose of 100 mg/kg bw did not have any treatment related systemic effects. This dose was associated with a significant increase in segmented neutrophils in blood although this finding was not considered to have biological relevance. The NOEL for systemic effects was determined to be >100 mg/kg bw (equivalent to 100 mg/kg bw/d), the highest dose tested.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to repeated dose toxicity.