Alkaline earth metal and zinc hydroxy(substituted)alkanoate and oxoalkanoate

Endpoint summary

Description of key information

oral: OECD 423, GLP, rat, limit test, LD50 > 2000 mg/kg bw

dermal: OECD 402, GLP, rat, limit test, 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:

2018-09-07 to 2018-11-07

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 on 17 December 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Envigo RMS s.r.l., San Pietro al Natisone (UD), Italy
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 - 7 weeks
- Weight range at arrival: 159.0-163.5 g
- Weight at study initiation: 185.6 - 212.2 g
- Fasting period before study: Food was removed fromthe cages overnight prior to dosing (Day -1) and was made available approximately 4 hours after dosing
- Housing: Polisulfone solid bottomed cages measuring 59.5×38×20 cm with nesting material provided into suitable bedding bags
- Animals per cage: 3 during the study; up to 5 during acclimatisation
- Diet (e.g. ad libitum): 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy), ad libitum
- Water (e.g. ad libitum): Drinking water supplied to each cage via a water bottle, ad libitum
- Acclimation period: at least 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2 °C
- Humidity (%): 55±15%
- Air changes (per hr): Approximately 15 to 20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

The formulated test item was administered, by gavage, at a dose volume of 10mL/kg using a plastic feeding tube attached to a graded syringe.

Doses:

During the study, the test item was suspended as follows:
Vehicle: 0.5% aqueous solution of carboxymethylcellulose
Concentration: 200 mg/mL. The concentration was calculated and expressed in terms of test item as supplied.

Treatment: 2000 mg/kg bw
Dose calculation: On the day of dosing (Day 1), the amount of the formulated test item to be administered was calculated for each fasted animal according to body weight.

No. of animals per sex per dose:

2 x 3 animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:

Throughout the study all animals were checked for morbidity and mortality twice daily.

Animals were observed for clinical signs as indicated below:
-Day of dosing
· Session 1: on dosing
· Session 2: approximately 0.5 hour after dosing
· Session 3: approximately 2 hours after dosing
· Session 4: approximately 4 hours after dosing
-Daily thereafter for a total of 14 days (Session 1).

All animals were weighed at allocation to the study (Day -1), on the day of dosing (Day 1) and on Days 2, 8 and 15.

- Necropsy of survivors performed: yes, Necropsy was carried out on all animals (gross necropsy examination for both external and internal abnormalities, with particular attention to the gastro-intestinal tract).

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred and no clinical signs were observed in the first group of 3 females initially dosed at 2000 mg/kg (Group 2, Step 1) and in the further group of 3 females dosed at the same dose level (Group 4, Step 2).

Clinical signs:

No mortality occurred and no clinical signs were observed in the first group of 3 females initially dosed at 2000 mg/kg (Group 2, Step 1) and in the further group of 3 females dosed at the same dose level (Group 4, Step 2).

Body weight:

Changes in body weight observed during the study were within the expected range for this strain and age of animals.

Gross pathology:

No abnormalities were seen at necropsy examination performed on all animals dosed at 2000 mg/kg (Groups 2 and 4) at the end of the observation period.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute toxicity of TP 1740 was investigated following a single oral administration (10mL/kg in 0.5% aqueous solution of carboxymethylcellulose) to the Sprague Dawley rat followed by a 14-day observation period. No mortality occurred and no signs of toxicity were observed in the 6 animals following dosing at 2000mg/kg. These results indicate that the test item TP 1740 did not induce toxic effects in the rat following oral administration of a single dose at a level of 2000mg/kg. The lack of mortality demonstrates the acute toxicity estimate (ATE) to be greater than 2000mg/kg body weight.
European Directives concerning the classification, packaging and labelling of dangerous substances (Council Regulation (EC) No 1272/2008 and subsequent revisions) would indicate the following:
Classification No category
Signal word No signal word required
Hazard statement No hazard statement required

Executive summary:

The acute toxicity of TP1740 was investigated following OECD 429 (Class method) and GLP. A single oral administration to the Sprague Dawley rat was followed by a 14-day observation period. A first group of 3 female animals was initially dosed at 2000 mg/kg (Step 1). No mortality occurred and no clinical signs were observed. A second group of 3 female animals was then dosed at the same dose level (Step 2). No death occurred and no clinical signs were noted. Body weight changes recorded during the study were within the expected range for this strain and age of animals. No abnormalities were seen at necropsy examination performed at the end of the observation period on animals of both groups. These results indicate that the test item did not induce toxic effects in the rat following oral administration of a single dose at a level of 2000 mg/kg. The lack of mortality demonstrates the acute toxicity estimate (ATE) to be greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No animal died during the course of investigation.
Male: > 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: > 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

Clinical observations: No clinical signs were observed during the cours of investigation.

Body weight:

The body weight gain of the male and female animals was in the renage of th historical control data in the test facility.

Gross pathology:

There were no macroscopic pathological findings in the animals.

Other findings:

Skin of the application area: The skin of the application area was not altered.

Interpretation of results:

other: EU GHS criteria not met

Conclusions:

The dermal LD50 in the rat is > 2000 mg/kg bw. The test item in neither a toxic not a hamful substance according to this acute dermal toxicity study.

Executive summary:

Determination of the acute dermal toxicity of the test item was conducted according to OECD guideline 402 and EU method B.3 under GLP compliance. The test item was tested in five female and five male Cooles River Wistar rats, applied at a single dose of 2000 mg/kg bodyweight. The application to a shaved dorsal area of the trunk of the animals was then covered with a gauze patch which was held in contact with the skin with an occlusive dressing. Exposure was for 24 hours. The area to which it was applied was then washed with water. Animals were examined for mortality, clinical signs, alterations of the application area, body weight gain and pathological alterations of organs at the end of a 14-day observation period. None of the animals died during the course of the investigation. Clinical signs, skin alterations on the application area or pathological findings at necropsy were not observed. The body weight gain was not affected.

The dermal LD₅₀ in the rat is > 2000 mg/kg bw.

The source substance contains a major organic moiety (hydroxysulfonatoacetates) that is identical to the target substance. Therefore, this study shows that no acute dermal toxicity can be attributed to the hydroxysulfonatoacetate moiety of the target substance TP 1740.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Oral toxicity

The acute toxicity of TP1740 was investigated following OECD 429 (Class method) and GLP. A single oral administration to the Sprague Dawley rat was followed by a 14-day observation period. A first group of 3 female animals was initially dosed at 2000 mg/kg (Step 1). No mortality occurred and no clinical signs were observed. A second group of 3 female animals was then dosed at the same dose level (Step 2). No death occurred and no clinical signs were noted. Body weight changes recorded during the study were within the expected range for this strain and age of animals. No abnormalities were seen at necropsy examination performed at the end of the observation period on animals of both groups. These results indicate that the test item did not induce toxic effects in the rat following oral administration of a single dose at a level of 2000 mg/kg. The lack of mortality demonstrates the acute toxicity estimate (ATE) to be greater than 2000 mg/kg body weight.

Dermal toxicity

Determination of the acute dermal toxicity of the test item was conducted according to OECD guideline 402 and EU method B.3 under GLP compliance. The test item was tested in five female and five male Cooles River Wistar rats, applied at a single dose of 2000 mg/kg bodyweight. The application to a shaved dorsal area of the trunk of the animals was then covered with a gauze patch which was held in contact with the skin with an occlusive dressing. Exposure was for 24 hours. The area to which it was applied was then washed with water. Animals were examined for mortality, clinical signs, alterations of the application area, body weight gain and pathological alterations of organs at the end of a 14-day observation period. None of the animals died during the course of the investigation. Clinical signs, skin alterations on the application area or pathological findings at necropsy were not observed. The body weight gain was not affected.

The dermal LD₅₀in the rat is > 2000 mg/kg bw.

The source substance contains a major organic moiety (hydroxysulfonatoacetates) that is identical to the target substance. Therefore, this study shows that no acute dermal toxicity can be attributed to the hydroxysulfonatoacetate moiety of the target substance TP 1740.

Justification for classification or non-classification

The results of the limit test according to OECD guideline 423 indicate that the test item TP 1740 did not induce toxic effects in the rat following oral administration of a single dose at a level of 2000 mg/kg. The lack of mortality demonstrates the acute toxicity estimate (ATE) to be greater than 2000 mg/kg body weight. Equally, the results of the dermal toxicity study (conducted following OECD 402) of the source substance demonstrated neither toxic nor harmful effects in rats at a dose level of 2000 mg/kg bw, which can also be attributed to the target substance. Therefore, the test item TP 1740 is not subject to classification in accordance with Regulation (EC) No 1272/2008.