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Administrative data

Description of key information

Two acute oral toxicity studies are available with a K2 score. Several K4 studies are available as well, but these were not taken into account for the risk assessent.

Based on these studies an LD50 of 271 mg/kg bw was selected for further evaluation.

With regard to the inhalation route of exposure, only limited (K4) information is available. However, as the information was consistent it was found suitable for use.

Based on these studies an LD50 of 600 mg/m3 was selected for further evaluation.

With regard to the dermal route of exposure there are again 2 K2 studies and several K4 studies. The evaluation is done based on the K2 studies leading to an LD50 of 756 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:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study. No internationally accepted protocol followed, but study well documented and acceptable protocol. However, no confidence limits could be calculated for male rats. Apparently the study did not include any control animals.
Justification for type of information:
Key study, GLP, Klimisch score 2.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Santoflex 44 was administered to fasted albino rats of both sexes as a 392 mg/mL solution in corn oil by oral intubation. The volume administered was adjusted according to body weight and dosage to be given. Following dosing, each rat was individually housed and clinical observations were made twice daily until sacrifice at day 15. Body weights were recorded weekly and necropsies were performed on all animals.
GLP compliance:
yes
Test type:
other: not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sasco Inc., O'Fallon, MO
- Age at study initiation: approx. 8 weeks (young adults)
- Weight at study initiation: 225-247 g (males); 166-182 g (females)
- Fasting period before study: overnight
- Housing: individually, stainless steel cages or polycarbonate cages with stainless steel mesh bottom
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: quarantine, at least 5 days

ENVIRONMENTAL CONDITIONS: no data
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 392 mg/mL
- Amount of vehicle (if gavage): depends on body weight and dosing

ADMINISTRATION
- Rats are dose by gavage using a hypodermic syringe and ball tipped, stainless steel needle.
Doses:
200, 313, 490, 767, 1200 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females per dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 3 time/d during first 8 hours, twice daily after that
- Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
271 mg/kg bw
Based on:
test mat.
95% CL:
146 - 366
Sex:
male
Dose descriptor:
LD50
Effect level:
281 mg/kg bw
Based on:
test mat.
95% CL:
0
Sex:
female
Dose descriptor:
LD50
Effect level:
265 mg/kg bw
Based on:
test mat.
95% CL:
108 - 383
Mortality:
In many cases, mortality followed after the observation of other clinical abnormalities.
Clinical signs:
Lethargy was observed in 32 rats. The following observations were also made in animals that suffered from lethargy: ptosis (21 of 32 animals), ataxa (15 of 32 animals), prostration and lacrimation (5 of 32 animals). These effects were observed only in animals that were or had previously been lethargic. Most of the rats that had at least one of these clinical signs subsequently died.
Other commonly observed clinical abnormalities include abnormal urinary coloration, lack of fecal material beneath the cage, salivation.
In most cases, clinical abnormalities were observed on the day of dosing and the two following days.
Gross pathology:
Necropsy findings indicated that toxicity to the gastrointestinal tissue may have contributed to lethality in all but one of the 36 decedents. Signs of gastrointestinal inflammation were observed in 30 animals, in 15 rats irritation was sufficiently severe to result in hemorrhage. Each of five other animals had gelatinous red material, a red fluid filled mass, or a red/green fluid filled mass in the stomach. Gastrointestinal tracts of 14 animals were distended. Eleven rats had green fluid in the urinary bladder or green urinary staining of fur. Eight animals had red/brown fluid in the urinary bladder or fur stained with urine of a similar coloration.
Conclusions:
The LD50 of the test material is 271 mg/kg bw with 95% confidence limts 146-366 mg/kg bw
Executive summary:

Santoflex 44 antioxidant was administered to fasted albino rats of both sexes through oral gavage of a 392 mg/ml solution in corn oil. The administered volume was adapted to the animal's body weight and the target dose. The rats were observed for clinical signs and mortality for 14 days. After day 15 the surviving animals were sacrificed. Necropsies were performed on all animals.

The acute oral LD50 was calculated to be 271 mg/kg bw, with 95% confidence limits of 146 and 366 mg/kg. Commonly observed clinical abnormalities included lethargy, ataxia, ptosis and abnormal urinary coloration (green and/or red/brown). Necropsy findings including gastrointestinal inflammation (in many cases reaching the severity of hemorrhage), gastrointestinal distension, and red, fluid filled gastric masses indicated that toxicity to gastrointestinal tissue may have contributed to lethality in virtually all of the rats that died on the test.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
271 mg/kg bw
Quality of whole database:
Two K2 studies available.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating conc.
600 mg/m³
Quality of whole database:
No study was selected since weight of evidence approach was applied. Three K4 studies available.

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study OECD 402 (BASF method).
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Principles of method if other than guideline:
According to BASF-internal standard. Young adult laboratory rats in groups of 5 to 10 rats per sex and dose were treated simultaneously with preparations of the test substance in suitable vehicle occlusive on the skin. Group-wise documentation of clinical signs was performed over the 7 to 14 day study period. Body weight was determined before the start of the study only, as it was needed for determination of dose. The clinical signs and findings were reported in summary form. On the basis of the observed lethality, the LD50 value was estimated or determined using a graphical evaluation of the dose response curve on probability paper.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: 12 weeks
- Weight at study initiation: 200 - 300 g
- Housing: single housing in V-II-A-Stahl cages, Type DK-III during exposure, if no skin lesions were identified group housing
- Diet: SSNIFF R, Fa. SSNIFF, Versuchstierdiaeten, Soest
- Water: tap water, ad libitum
- Acclimation period: approximately 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % aqueous
Details on dermal exposure:
TEST SITE
- Area of exposure: 50 cm2, dorsal and dorsolateral areas of the trunk
- Type of wrap if used: inert foil

REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Concentration (if solution): 10% (g/V)
- Amount(s) applied (volume or weight with unit): 3.2, 5.6, 8.3 and 12.1 ml/kg bw
Duration of exposure:
24 hours
Doses:
316, 562, 825 and 1210 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 - Frequency of observations and weighing: observations: several times on the day of application and at least once per working day thereafter, check of moribund and dead animals twice each working day and once on weekends and on public holidays, skin observations: 30 - 60 minutes after removal of the occlusive bandage and at least once during the observation period, body weight: before application and on days 4, 7 and 13 following application - Necropsy of survivors performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
756 mg/kg bw
95% CL:
623 - 903
Mortality:
Male animals: 316 mg/kg bw: no deaths after 14 days; 562 mg/kg bw: 2/5 after 14 days; 825 mg/kg bw: 4/5 after 14 days; 1210 mg/kg bw: 5/5 after 14 days Female animals: 316 and 562 mg/kg bw: no deaths after 14 days; 825 mg/kg bw: 1/5 after 14 days; 1210 mg/kg bw: 5/5 after 14 days
Clinical signs:
Dyspnea, apathy, staggering, trembling (males only), poor general state (all symptoms were observed on day 1)
Local signs: substance residues (day 1), deep necrosis (from day 7 to day 13), edema (from day 1 to day 13)
Body weight:
Mean body weight male animals: 259 g at study start, 294 g after 13 days
Mean body weight female animals: 212 g at study start, 228 g after 13 days
Gross pathology:
Animals that died: congestive hyperpemia; liver: partly clay-coloured peripher markings of lobules; application area: colloidal edema of the subcutis.
Sacrificed animals: nothing abnormal detected; application area: extensive necrosis, status: healing (demarcation).

Table 1. Table for acute dermal toxicity. 

Dose
[mg/kg bw]

Toxicological results*

Duration of clinical signs

Local skin effects

Time of death

Mortality (%)

 

Males

316

0/5

Day 1

substance residues on day 1,

deep necrosis (day 7 – day 13)

edema (day 1 day 13)

---

0

562

2/5

Day 1

substance residues on day 1,

deep necrosis (day 7 – day 13)

edema (day 1 day 13)

Day 1

40

825

4/5

Day 1

substance residues on day 1,

deep necrosis (day 7 – day 13)

edema (day 1 day 13)

Day 1 – Day 2

80

1210

5/5

Day 1

---

Day 1

100

 

Females

316

0/5

Day 1

substance residues on day 1,

deep necrosis (day 7 – day 13)

edema (day 1 day 13)

---

0

562

0/5

Day 1

substance residues on day 1,

deep necrosis (day 7 – day 13)

edema (day 1 day 13)

---

0

825

1/5

Day 1

substance residues on day 1,

deep necrosis (day 7 – day 13)

edema (day 1 day 13)

Day 1

20

1210

5/5

Day 1

---

Day 1

100

 

LD50 = 756 mg/kg bw

* first number = number of dead animals                                 

  second number = number of animals used                               

Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
DSD:Xn, R21
CLP: Cat. 3, H311
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
756 mg/kg bw
Quality of whole database:
Two K2 studies available

Additional information

Oral

The acute oral toxicity of 44PD was evaluated in 2 acute oral gavage studies with male and female Sprague-Dawley rats (Branch, 1983a (key) and Branch, 1983b (supporting)). In the key study, the test substance was administered to fasted albino rats of both sexes through oral gavage of a 392 mg/ml solution in corn oil. The administered volume was adapted to the animal’s body weight and the target doses of 200, 313, 490, 767 and 1200 mg/kg bw, respectively. The rats were observed for clinical signs and mortality for 14 days. Necropsies were performed on all animals.

The acute oral LD50 was calculated to be 271 mg/kg bw with 95% confidence limits of 146 and 366 mg/kg bw.

 

In the supporting study, undiluted test substance was administered to fasted albino rats of both sexes at dosages ranging from 200 to 600 mg/kg bw. An acute oral LD50 of 222 mg/kg bw was calculated for female rats. Frequent deaths and an inconsistent incidence in mortality in male rats precluded calculation of a reliable LD50 value for male rats and the combined sexes. Nevertheless, from the available data, the following extrapolated LD50 values were calculated based on the available test results: LD50 for males: < 200 mg/kg bw; LD50 for males & females: 146 mg/kg bw.

The LD50 used in the Chemical Safety Assessment is the value of 271 mg/kg bw/day.

 

Dermal

Two K2 studies are available for acute dermal toxicity. In the first study (Monsanto Company 1983, report n° ML-82-022) the shaved intact or abraded dorsal surface of albino New Zealand White rabbits of both sexes was exposed to undiluted test substance for approximately 24 hours under occlusive covering. The animals were observed for clinical signs and mortality for 14 days. Necropsies were performed on all animals. The acute dermal LD50 was calculated to be 2806 mg/kg bw with 95% confidence limits of 2537 and 3104 mg/kg bw. Clinical abnormalities included lethargy, ataxia, green coloration of the urine, partial loss of ability to move the limbs and several localized dermal effects that were attributed to direct contact between the test material and the skin.

In the second acute dermal toxicity study young adult laboratory rats in groups of 5 to 10 rats per sex and dose were treated simultaneously with preparations of the test substance in suitable vehicle occlusive on the skin. Group-wise documentation of clinical signs was performed over the 7 to 14 day study period. Body weight was determined before the start of the study only, as it was needed for determination of dose. On the basis of the observed lethality, the LD50 value was determined to be 756 mg/kg bw.

Although no clear indication could be found as to why the results between the two toxicity studies were so different, the fact that different animal species were used could be a contributing factor.

Inhalation

Although only very concise information is available with regard to the acute inhalation toxicity of 44PD, the available test results are in good agreement with one another. As a consequence, a weight of evidence approach was considered to be appropriate to address this endpoint. Three K4 acute inhalation studies with rats are available (Birch MD, 1976; Eastman-Kodak Company, unpublished results; Kodak Company reports 1971), in which the rats were exposed during 6h to the following test concentrations: 79, 200, 600 and 1875 mg/m3. No deaths occurred to animals exposed to concentrations up to and including 600 mg/m3. In the test with 1875 mg/m3, all rats died within 4 hours. The acute LC50 for inhalation thus is > 600 and < 1875 mg/m3.


Justification for classification or non-classification

Oral

With an acute oral LD50 in rats of 146 mg/kg bw, a classification of 44PD for acute toxicity – oral Category 3 is warranted according to regulation 1272/2008 (CLP). The corresponding hazard statement is H301: Toxic if swallowed. For the labelling the GHS06 pictogram (skull and crossbones) and the signal word “Danger” are assigned to this hazard category.

 

The classification according to Directive 67/548 (DSD) is “Toxic if swallowed” with R25 as the corresponding risk phrase.

Dermal

Two K2 studies are available for acute dermal toxicity, one of which yielded an LD50 of 756 mg/kg bw, thus triggering a classification as acute dermal toxicant taking into account the criteria for classification as described in Annex I to regulation 1272/2008 (CLP) and Annex VI to Directive 67/548 (DSD).

Inhalation

Based on an acute inhalation LD50 in rats between 600 and 1875 mg/m3(= 0,6 – 1,87 mg/L air) an acute toxicity – inhalation Category 3 is warranted according to regulation 1272/2008 (CLP). Indeed, although no clear information is given on the facdt whether the substance was administered as a mist or a vapour, based on the boiling point of 44PD (which is 310°C) it was concluded that the substance must have been administered as a mist. The corresponding hazard statement with Acute Cat. 3 is H331: Toxic if inhaled. For the labelling the GHS06 pictogram (skull and crossbones) and the signal word “Danger” are assigned to this hazard category.

 

The classification according to Directive 67/548 (DSD) is “ Toxic by inhalation” with R23 as the corresponding risk phrase.