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Description of key information

REPEAT DOSE ORAL TOXICITY

The oral toxicity of the test material was determined in a 28 day repeat dose toxicity study. No systematic signs of toxicity were observed in the key study (Sauer, 1977) at a concentration of 100 mg/kg and it was concluded that the test material is readily metabolised. Foulger (1948) has been provided as a supporting study which recorded no systemic signs of toxicity at 200 mg/kg.

REPEAT DOSE DERMAL TOXICITY

The dermal toxicity of the test material was determined in a key study (Sauer, 1977). No systematic signs of toxicity were observed at a concentration of 60 mg/kg and it was concluded that the test material is readily metabolised and not readily absorbed by the skin.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed in accordance with generally accepted scientific principles, with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of rats and mice received doses of test material, orally by gavage, five days per week for a period of 28 days. Animals were treated with 100, 50, 25, 12.5, 6.25 and 0 (vehicle control) mg/kg test material. Animals were weighed weekly and following sacrifice organ weights were determined. Histopathological evaluation was performed on the heart, ovary and forestomach since they demonstrated possible lesions of interest at gross pathology.
GLP compliance:
not specified
Limit test:
no
Species:
other: rats & mice
Strain:
other: F-344 rats and B6C3F1 mice
Sex:
male/female
Details on test animals or test system and environmental conditions:
FEMALE RATS F-344
- Housed in groups of 5 per cage.
- Source: Hilltop Lab Animals, Inc. Scottsdale, PA, USA

MALE AND FEMALE MICE B6C3F1
-Males housed individually and females in groups of 5 per cage.
- Source: Harlan Sprague-Dawley, Inc. Indianapolis, IN, USA.

TEST ANIMALS
- Diet (e.g. ad libitum): Teklad 4% Mouse-rat diet, Teklad, Madison, WI, USA. ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: 14 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled.
- Photoperiod (hrs dark / hrs light): 12 hrs light/ 12 hr dark.
Route of administration:
oral: gavage
Vehicle:
other: 0.5% methyl cellulose.
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: dosing solutions were prepared every 2 weeks

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Performed by capillary GC and found to be within 10% of the target concentration.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Treatment performed performed 5 days a week. Treatment was not performed on weekends or holidays, however animals were dosed at least 2 consecutive days before the terminal sacrifice.
Remarks:
Doses / Concentrations:
100, 50, 25, 12.5 and 6.25 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
5 animals per sex per species per dose.
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
- Animals were weighted on the first day of administration, once a week and again at sacrifice.
Sacrifice and pathology:
- Post mortem the following organs were weighed for all animals; liver, thymus, right kidney, right testicle, heart and lungs.
- Histopathological evaluation was performed on the following organs; heart, ovary and forestomach.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
see the field " details on results".
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
Organ weight: A non-significant gain in lung weight was observed.
Lesions: some lesions were noted, however they were not thought to be related to treatment with test material.
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects were observed at this dose level.
Critical effects observed:
not specified

Table 1. Weight gain and relative organ weights for rats and mice after oral exposure to 100 mg/kg of Test Material

Test Animal Body weight Organ Weights % of control
  % of control Liver Heart Kidney Lung
Rats F-344          
Male  102 106 ± 3 105 ± 3 100 ± 1 97 ± 23
Female 101 100 ± 6 102 ± 5 99 ± 6 128 ± 30
Mice B6C3F1    
Male 98 108 ± 5 100 ± 4 106 ± 4 99 ± 7
Female 99 96 ± 6 105 ± 6 103 ± 3 99 ± 6
Conclusions:
The 28-day repeat dose oral toxicity study revealed no evidence of systemic toxicity up to 100 mg/kg. No potential target organs were identified and no sexual differences were seen. The test concludes that the test material is not readily absorbed without first being hydrolysed and conjugated, thus only a small amount of the test material will enter the blood, with less entering the tissue.
Executive summary:

Rats and mice were exposed daily via oral gavage to the test material in varying concentrations. The study was continued for 28 days before termination.The 28-day repeat dose oral toxicity study revealed no evidence of systemic toxicity up to 100 mg/kg. No potential target organs were identified and no sexual differences were seen. The test concludes that the test material is not readily absorbed without first being hydrolysed and conjugated, thus only a small amount of the test material will enter the blood, with less entering the tissue.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
other: rat and mouse
Quality of whole database:
Two studies are available to address the repeated dose (oral) toxicity endpoint, a toxicokinetics study and a repeated dose toxicity sudy conducted over a two week eriod. The toxicokinetics study was assigned a relaibility score of 2 and the toxicity study, a reliability score of 4. The overall quality of the database adequate.

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:
supporting study
Study period:
Not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed in accordance with generally accepted scientific principles, with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of rats and mice were exposed topically to test material at 60, 30, 15, 7.5, 3.75 or 0 (vehicle control) mg/kg. During the study animals were weighed weekly. At sacrifice organ weights were determined and a histopathological evaluation was performed on the heart, ovary and skin. These organs were evaluated because they demonstrated possible lesions of interest at gross pathology.
GLP compliance:
not specified
Limit test:
no
Species:
other: rat & mice
Strain:
other: see the field "details on test animals and environmental conditions".
Sex:
male/female
Details on test animals or test system and environmental conditions:
FEMALE RATS F-344
- Housed in groups of 5 per cage.
- Source: Hilltop Lab Animals, Inc. Scottsdale, PA, USA

MALE AND FEMALE MICE B6C3F1
-Males housed individually and females in groups of 5 per cage.
- Source: Harlan Sprague-Dawley, Inc. Indianapolis IN, USA.

TEST ANIMALS
- Diet (e.g. ad libitum): Teklad 4% Mouse-rat diet, Teklad, Madison, WI, USA. ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: 14 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled.
- Photoperiod (hrs dark / hrs light): 12 hrs light/ 12 hr dark.
Type of coverage:
not specified
Vehicle:
acetone
Details on exposure:
60, 30, 15, 7.5 or 0 (vehicle control) mg/kg test material. Each dose concentration remained constant, and the volume, 2mL/kg for rats, 0.5 mL/kg for mice, was adjusted weekly to maintain accurate mg/kg body weight.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Performed by capillary GC and found to be within 10% of the target concentration.
Remarks:
Doses / Concentrations:
60, 30, 15, 7.5 and 3.75 mg/kg
Basis:
analytical per unit body weight
No. of animals per sex per dose:
5 animals per sex per species per dose.
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
- Animals were weighted on the first day of administration, once weekly and at sacrifice.
Sacrifice and pathology:
- Post mortem the following organs were weighed for all animals; liver, thymus, right kidney, right testicle, heart and lungs.
- Histopathological evaluation was performed on the following organs; heart, ovary and skin.
Clinical signs:
no effects observed
Dermal irritation:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
Lesions: some lesions were noted, however they were not thought to be related to treatment with test material.
Dose descriptor:
NOEL
Effect level:
60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects were seen at this level
Critical effects observed:
not specified

Table 1. Weight gain and relative organ weights for rats and mice after dermal exposure to 60 mg/kg of Test Material

Test Animal Body weight Organ Weights % of control
  % of control Liver Heart Kidney Lung
Rats F-344          
Male  100 99 ± 5 104 ± 4 101 ± 3 99 ± 8
Female 97 102 ± 4 99 ± 5 102 ± 3 95 ± 6
Mice B6C3F1    
Male 99 99 ± 4 105 ± 4 101 ± 6 85 ± 15
Female 101 100 ± 4 97 ± 5 100 ± 5 100 ± 13
Conclusions:
The study revealed no evidence of systemic toxicity at treatment with test material up to 60 mg/kg. No potential target organs were identified and no sexual differences were seen. The test concludes that after dermal exposure the test material is so volatile and absorbed so slowly that very little test material penetrates the skin, thus only a small amount of the test material will enter the body with less entering the target organ.
Executive summary:

Both male and female rat and mice were topically exposed to 60, 30, 15, 7.5, and 3.75 mg/kg of the test material during the study. Under the conditions of the study, no evidence of systemic toxicity at treatment with test material up to 60 mg/kg was seen. No potential target organs were identified and no sexual differences were seen. The test concludes that after dermal exposure the test material is so volatile and absorbed so slowly that very little test material penetrates the skin, thus only a small amount of the test material will enter the body with less entering the target organ.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was assigned a reliability score of 2. The quality of the database is adequate.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

REPEAT DOSE ORAL TOXICITY

The key study (Sauer, 1997) was conducted in line with sound scientific principles providing a sufficient level of detail to assess the quality of the study. Rats and mice were exposed daily via oral gavage to the test material at varying concentrations. The study was continued for 28 days before termination. No evidence of systemic toxicity was observed up to highest concentration 100 mg/kg. No potential target organs were identified and no sexual differences were seen. The test concludes that the test material is not readily absorbed without first being hydrolysed and conjugated, thus only a small amount of the test material will enter the blood, with less entering the tissue. The study was performed to a good standard and was assigned a reliability score of 2 using the principles for assessing data quality as set out in Klimisch (1997).

The supporting study (Foulger, 1948) assessed the repeated dose oral toxicity of the test material by exposing 6 rats to 200 mg/kg administered via oral gavage. The dose was administered 10 times over 2 weeks. All animals survived exposure and were subjected to necropsy 9 days after the last treatment, no remarkable signs of toxicity were observed at pathology. The study was assigned a reliability score of 4, according to Klimisch (1977), as there is incomplete reporting of the methodology used and it is not possible to assess the accuracy of the data.

REPEAT DOSE DERMAL TOXICITY

The key study (Sauer, 1997) was conducted in line with sound scientific principles providing a sufficient level of detail to assess the quality of the study. Both male and female rats and mice were topically exposed to 60, 30, 15, 7.5, and 3.75 mg/kg of the test material in a 28-day repeat dose toxicity study. No evidence of systemic toxicity was observed up to the maximum dose of 60 mg/kg. No potential target organs were identified and no sexual differences were seen. The test concludes that after dermal exposure the test material is so volatile and absorbed so slowly that very little test material penetrates the skin, thus only a small amount will enter the body with even less entering the target organs. The study was performed to a good standard and was assigned a reliability score of 2 using the principles for assessing data quality as set out in Klimisch (1997).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The Sauer reference was assigned a reliability score of 2 according to the principles for assessing data quality set out in Klimisch (1977) whereas the Foulger reference was assigned a reliability score of 4.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

There is only one study available to address this endpoint.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

No observations for local effects were reported in the single repeat dose dermal toxicity available.

Justification for classification or non-classification

REPEAT DOSE ORAL TOXICITY

No classification of the test material is required under Regulation 1272/2008 as the NOEAL concentration has been shown to be > 200 mg/kg.

REPEAT DOSE DERMALTOXICITY

No classification of the test material is required under Regulation 1272/2008 as the NOEAL concentration has been shown to be > 60 mg/kg.