[6R-[6α,7β(Z)]]-7-[2-furyl(methoxyimino)acetamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Endpoint summary

Description of key information

An acute oral toxicity study for the susbtance was conducted in rats, the discriminating dose was 2000 mg/kg bw. Further to this, a dermal toxicity study was also conducted; while there was no overt systemic toxicity, resulting in a discriminating dose of 2000 mg/kg bw, dermal expsoure of the substance did result in limited irritation. An inhalation study was not performed given that inhalation of the substance is unlikely and skin exposure during production is possible.

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

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

yes

Remarks:

At the time of issue/approval the study plan did not contain test item identification, it is however included in the final study report. This deviation was considered to have not affected the integrity or validity of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Specific details on test material used for the study:

Identification: OK (640-2) (Furoxy Hydroxy)
Batch: G316533
Purity: 94.032% w/w
Physical state/Appearance: cream colored solid
Expiry Date: 25 March 2018
Storage Conditions: Store cold at 4° C in the dark

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Animal Information
Female Wistar (RccHan™:WIST) strain rats were supplied by Envigo RMS (UK) Limited,
Oxon, UK. On receipt the animals were randomly allocated to cages. The females were
nulliparous and non-pregnant. After an acclimatization period of at least 5 days the animals
were selected at random and given a number unique within the study by indelible
ink-marking on the tail and a number written on a cage card. At the start of the study the
animals were 8 to 12 weeks of age. The body weight variation did not exceed ±20% of the
mean body weight of any previously dosed animals.
3.2.2 Animal Care and Husbandry
The animals were housed in groups of up to four in suspended solid-floor polypropylene
cages furnished with woodflakes. With the exception of an overnight fast immediately before
dosing and for approximately 3 to 4 hours after dosing, free access to mains drinking water
and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon,
UK) was allowed throughout the study. The diet, drinking water and bedding were routinely
analyzed and were considered not to contain any contaminants that would reasonably be
expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to
70% respectively. The rate of air exchange was at least fifteen changes per hour and the
lighting was controlled by a time switch to give 12 hours continuous light and 12 hours
darkness.
The animals were provided with environmental enrichment items which were considered not
to contain any contaminant of a level that might have affected the purpose or integrity of the
study.

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

For the purpose of the study the test item was freshly prepared, as required, as a solution in
dimethyl sulfoxide. Dimethyl sulfoxide was used as it produced the most suitable
formulation at the required concentration. 30mg substance/Ml or 200 mg substance /ml DMSO
The test item was formulated within 2 hours of being applied to the test system. It is assumed
that the formulation was stable for this duration.
No analysis was conducted to determine the homogeneity, concentration or stability of the
test item formulation. This is an exception with regard to GLP and has been reflected in the
GLP compliance statement.

Doses:

300 mg/kg bw
2000 mg/kg bw

No. of animals per sex per dose:

1 female @ 300 mg/kg bw
5 females @ 2000 mg/kg bw

Control animals:

no

Details on study design:

In the absence of information on the toxicity of the test item, 300 mg/kg was chosen as the
starting dose; a single animal was treated.
In the absence of evident toxicity at a dose level of 300 mg/kg, an additional animal was
treated.
In the absence of toxicity at a dose level of 2000 mg/kg, an additional group of 4 animals was
treated.
A total of five animals were therefore treated at a dose level of 2000 mg/kg in the study.
All animals were dosed once only by gavage, using a metal cannula attached to a graduated
syringe. The volume administered to each animal was calculated according to the fasted
body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was
allowed between each dose group to confirm the survival of the previously dosed animals.
Clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for
up to 14 days. Morbidity and mortality checks were made twice daily, early and late during
normal working days, and once daily at weekends and public holidays.
Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
At the end of the observation period the animals were killed by cervical dislocation. All
animals were subjected to gross necropsy. This consisted of an external examination and
opening of the abdominal and thoracic cavities. The appearance of any macroscopic
abnormalities was recorded. No tissues were retained.

Statistics:

N/A

Sex:

female

Dose descriptor:

discriminating dose

Effect level:

ca. 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was
estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification
System − Unclassified).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

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:

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 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

At the time of issue/approval the study plan did not contain test item identification, it is however included in the final study report. This deviation was considered to have not affected the integrity or validity of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

Identification: OK (640-2) (Furoxy Hydroxy)
Batch: G316533
Purity: 94.032% w/w
Physical state/Appearance: cream colored solid
Expiry Date: 25 March 2018
Storage Conditions: approximately 4 °C in the dark

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animal Information
Five male and five female Wistar (RccHan:WIST) strain rats were supplied by Envigo
RMS (UK) Limited, Oxon, UK. On receipt the animals were randomly allocated to cages.
The females were nulliparous and non-pregnant. After an acclimatization period of at least
5 days the animals were selected at random and given a number unique within the study by
indelible ink-marking on the tail and a number written on a cage card. At the start of the
study the animals weighed at least 200 g, and were 8 to 12 weeks of age. The weight
variation did not exceed ±20% of the mean weight for each sex.

Animal Care and Husbandry
The animals were housed in suspended solid floor polypropylene cages furnished with
woodflakes. The animals were housed individually during the 24-Hour exposure period and
in groups of five, by sex, for the remainder of the study. Free access to mains drinking water
and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon,
UK) was allowed throughout the study. The diet, drinking water and bedding were routinely
analyzed and were considered not to contain any contaminants that could reasonably be
expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 C and 30 to
70% respectively. The rate of air exchange was at least fifteen changes per hour and the
lighting was controlled by a time switch to give 12 hours continuous light and 12 hours
darkness.
The animals were provided with environmental enrichment items which were considered not
to contain any contaminant of a level that might have affected the purpose or integrity of the
study.

Type of coverage:

semiocclusive

Vehicle:

DMSO

Details on dermal exposure:

The appropriate amount of test item, moistened with dimethyl sulfoxide, was applied as
evenly as possible to an area of shorn skin (approximately 10% of the total body surface
area). A piece of surgical gauze was placed over the treatment area and semi-occluded with a
piece of self-adhesive bandage. The animals were caged individually for the 24-Hour
exposure period. Shortly after dosing the dressings were examined to ensure that they were
securely in place.
After the 24-Hour contact period the bandage was carefully removed and the treated skin and
surrounding hair wiped with cotton wool moistened with dimethyl sulfoxide to remove any
residual test item. The animals were returned to group housing for the remainder of the study
period.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 (five)

Control animals:

no

Details on study design:

The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2 and 4 hours
after dosing and subsequently once daily for 14 days.
After removal of the dressings and subsequently once daily for 14 days, the test sites were
examined for evidence of primary irritation.
Any other skin reactions, if present were also recorded.
Individual body weights were recorded prior to application of the test item on Day 0 and on
Days 7 and 14..
At the end of the study the animals were killed by cervical dislocation. All animals were
subjected to gross necropsy. This consisted of an external examination and opening of the
abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was
recorded. No tissues were retained.

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

ca. 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

Dermal Reactions

Signs of dermal irritation noted were dried blood, glossy skin, scab lifting to reveal glossy
skin, small superficial scattered scabs, hardened dark brown/black colored scab and scab
cracking.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found
to be greater than 2000 mg/kg body weight.
The test item did not meet the criteria for classification according to the Globally Harmonized
Classification System.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Justification for classification or non-classification

Based upon the results obtained in the oral and dermal acute toxicity studies in rat, where the discriminating dose was 2000 mg/kg bw, the classification criteria according to 1272/2008/EC are not met.