Registration Dossier

Administrative data

Description of key information

The subacute oral NOAEL for GMT is 50 mg/kg bw/day.

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
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11-July-2006 - 30-Nov-2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Remarks:
Dept. of Health, UK
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent.
- Age at study initiation: 8 weeks
- Weight at study initiation: Males: 280 - 379 g; Females: 192 - 260 g
- Housing: All animals were housed in groups of five in polypropylene cages with stainless steel grid floors and tops, suspended over polypropylene trays lined with absorbent paper. During the mating phase, animals were transferred to similar cages on a one male: one female basis.
Following evidence of successful mating, the males were returned to their original cages. Mated females were housed individually during gestation and lactation, in polypropylene cages with solid floors and stainless steel lids, furnished with softwood flakes (Datesand Ltd. Cheshire, UK).
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 28 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 °C
- Humidity (%): 55 ± 15 % relative humidity
- Air changes (per hr): 15 x / h
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
- The test material was administered by gavage to three groups each of ten male and ten female rats, for up to fifty-four consecutive days, at dose levels of 15, 50 and 150 mg/kg/day.
- A control group of ten males and ten females was dosed with vehicle alone (Deoxygenated and demineralised water).
- Two recovery groups, each of five males and five females, were treated with the high dose (150 mg/kg/day) or the vehicle alone for
forty-three consecutive days and then maintained without treatment for a further fourteen days.
Duration of treatment / exposure:
- for up to fifty-five days
Frequency of treatment:
- each day
Remarks:
Doses / Concentrations:
15, 50 and 150 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Positive control:
none
Observations and examinations performed and frequency:
- Clinical Observations: All animals were examined for overt signs of toxicity, ill-health and behavioural change immediately before and alter dosing, and one and five hours after dosing, during the working week. Animals were observed immediately before and after dosing, and one hour after dosing at weekends (except for females during parturition where applicable). During the treatment-free period, animals were observed twice daily, morning and afternoon (once daily at weekends). All observations were recorded.
- Functional Observations: Prior to the start of treatment and at weekly intervals thereafter, all non-recovery animals were observed for signs of functional/behavioural toxicity. Functional performance tests were also performed on tive selected males and females per non-recovery dose level, prior to termination, together with an assessment of sensory reactivity to various stimuli.
- BehaviouralAssessments: Detailed individual clinical observations were performed for each animal using a purpose built arena. The following parameters were observed:
Gait Hyper/Hypothermia, Tremors, Skin colour, Twitches, Respiration, Convulsions, Palpebral closure, Bizarre/Abnonnal/Stereotypic behaviour, Urination, Salivation, Defecation, Pilo-erection, Transfer arousal, Exophthalmia, Tail elevation, Lachrymation
- Functional Performance Tests: Purpose·built 44 infra-red beam automated activity monitors were used to assess motor activity. Animals were randomly allocated to the activity monitors. The tests were performed at approximately the same time each day, under similar laboratory conditions.
- Sensory Reactivity: Each animal was individually assessed for sensory reactivity to auditory, visual and proprioceptive stimuli. The following
parameters were observed: Grasp response, Touch escape, Vocalisation, Pupil reflex, Toe pinch, Startle reflex, Tail pinch, Blink reflex, Finger approach
- Bodyweight: Individual bodyweights were recorded on Day l (prior to dosing) and then weekly for males until termination. Females were weighed weekly until mating was evident. Bodyweights were then recorded on Days 0, 7, 14 and 20 post coitum, and on Days 1 and 4 postpartum. Recovery
animals were weighed on Day 1 (prior to dosing) and then weekly until termination.
- Food Consumption: During the maturation period, weekly food consumption was recorded for each cage of adults.This was continued for males after the mating phase. For females showing evidence of mating, food consumption was recorded for the periods covering Days 0-7, 7-14 and 14-20. For females with live litters, food consumption was recorded on Days 1 and 4 post partum.
- Water Consumption: Water intake was observed daily by visual inspection of water bottles for any overt change.
- Laboratory Investigations: Haematological and blood chemical investigations were performed on five males and five females selected from each non-recovery test and control group on Day 14 (day prior to pairing). Blood samples were obtained from the lateral tail vein. Animals were not fasted prior to sampling.
- Urinalytical investigations were performed on five males selected from non-recovery test and
control group during the final week of treatment and on five males selected from each recovery
group during the final week of the fourteen day treatment-free period.
- Haematology: The following parameters were measured on blood collected into tubes containing potassium EDTA anti-coagulant:
Haemoglobin (Hb), Erythrocyte count (RBC), Haematocrit (Het), Erythrocyte indices, Total leucocyte count (WBC), Differential leucocyte count, Platelet count (PLT), Reticulocyte count
- Blood Chemistry: The following parameters were measured on plasma from blood collected into tubes containing lithium heparin anti-coagulant:
Urea Calcium (Ca++), Glucose Inorganic phosphorus (P), Total protein (Tot.Prot.), Aspartate aminotransferase (ASAT), Albumin Alanine aminotransferase (ALAT), Albumin/Globulin (A/G) ratio (by calculation), Alkaline phosphatase (AP), Sodium (Na+), Creatinine (Creat), Potassium (K+), Total cholesterol (Chol), Chloride (Cl-), Total bilirubin (Bili)
- Urinalysis: The following parameters were recorded on collected urine: Volume, Ketones, Specific Gravity, Bilirubin, pH Urobilinogen, Protein, Reducing Substances, Glucose, Blood


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
- Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight),
weekly bodyweight gain, litter weights, offspring bodyweights and quantitative functional
performance data were assessed for dose response relationships by linear regression analysis,
followed by one way analysis of variance (ANOVA) incorporating Levene’s test for homogeneity
of variance.
- Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett’s test.
- Where Levene’s test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney ‘U’ test.
- The non-parametric methods were also used to analyse implantation loss, offspring sex ratio and
landmark developmental markers.
- The haematology variable basophils was not analysed since consistently greater than 30% of the
data were recorded as the same value.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Females treated with 150 mg/kg/day showed a reduction in group mean bodyweight and bodyweight gain between Day 0 and Day 7 of gestation, although this did not achieve statistical significance [...]. See below.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
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:
no effects observed
Details on results:
Mortality.
There were five interim deaths during the study, these were confined to females treated with 150 mg/kg/day. One female (number 76) died during the maturation phase on Day 10. A second female (number 73) was killed in extremis on Day 23 (Day 7 of gestation). Two females were found dead on their Day 22 of gestation (Day 40 of the main study for female 80 and Day 41 of the main study for female 75), The final of the five females (number 72) was killed in extremis on it’s Day 1 of lactation phase (Day 41 of main study).

Clinical signs.
The only toxicological significant observations were detected for the two interim death females that were killed in extremis (numbers 73 and 72), these included incidents of tip-toe gait, hunched posture and pilo erection. One of the females (number 73) also had red/brown staining around the mouth. The deterioration of the females’ condition subsequently led to their termination. No toxicologically significant findings were detected for animals of either sex after the treatment period, or for animals of either sex after the fourteen-day recovery period.

Histopathology.
There were no treatment-related microscopic changes detected for the pituitary or reproductive tissues examined for terminal kill animals after the treatment period. Here were five unscheduled deaths during the course of the study. Three females were found dead and two were killed in extremis, all five females were from the 150 mg/kg/day treatment group. With the possible exception of pyometria reported for female number 72 and focal gastric ulceration for female 73, factors contributing to the death or moribundity in these animals were not evident from histopathological evaluation.

Neurobehaviour.
No treatment-related effects were detected for animals of either sex from all treatment groups after the treatment period. Formal behavioural assessments were not carried out for recovery group animals.

Organ weights.
No treatment-related intergroup differences in organ weights were detected for all treated animals after the treatment period.

Bodyweights.
Females treated with 150 mg/kg/day showed a reduction in group mean bodyweight and bodyweight gain between Day 0 and Day 7 of gestation, although this did not achieve statistical significance it did lead to a statistically significant reduction in bodyweight for these females at Day 1 of lactation.

No effect on bodyweight was detected during maturation for all treated animals; for all treated males and females treated with 50 or 15 mg/kg/day for the remainder of the treatment period and for animals of either sex after the fourteen day treatment free period.

Food Consumption.
Food consumption was reduced for females treated with 150 mg/kg/day during Days 0 to 7 of gestation and Days 1 to 4 of lactation when compared to controls although statistical significance was not achieved.

No treatment related effects in food consumption were detected for any treated males, females treated with 50 or 15 mg/kg/day or animals of either sex after the fourteen day recovery phase.

Water Consumption.
No overt intergroup differences were detected for all animals after the treatment period or for animals after the fourteen day recovery phase.

Haematology.
No treatment-related effects were detected for the haematological parameters investigated prior to mating. Therefore no further haematological analysis was performed.

Blood Chemistry.
No treatment-related intergroup differences in blood chemical parameters were detected prior to mating. Therefore no further blood chemical analysis was performed.

Urinalysis.
No toxicologically significant effects were detected in treated animals when compared to controls, or for animals of either sex after the fourteen day recovery phase.

Reproductive Screening.
Mating.
No adverse effects on mating performance, fertility or gestation lengths were detected.

Offspring Litter Size and Viability.
No intergroup differences were observed for litter size, sex ratio or viability.

Offspring Development.
No treatment-related effects were detected.

Litter Observations.
There were no clinically observable signs of test material toxicity detected in offspring from treated animals.
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: clinical signs; mortality; body weight during lactation
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Conclusions:
The oral administration of GMT 80% to rats by gavage, at dose levels of 150, 50 and 15 mg/kg bw/day, resulted in no treatment related effects for the males treated with 150 mg/kg bw/day but did result in the death of five females treated with 150 mg/kg bw/day. The
NOEL for systemic toxicity was considered to be 150 mg/kg/day for males and 50 mg/kg bw/day for females.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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:
1977-05-04 to 1979-03-07
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Significant methodological deficiencies
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
only one dose of 2mL/kg; 30 minutes exposure; reporting deficits
GLP compliance:
no
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: Pel·Freez, Inc., USDA No. 7T-B-16, Rogers, Arkansas 72756
- Age at study initiation: 10 - 13 weeks
- Weight at study initiation: 2.38 - 2.84 kg
- Housing: Each animal was housed individually in a suspended, galvanized steel wire cage with dimensions of 14" x 16" x Z4"
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 12 days
- Fasting period before study: 24 h

ENVIRONMENTAL CONDITIONS: No data
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
In preparation of the test, the sides of the back of each rabbit were clipped using electric clippers. A 3-square-inch patch of hair was left above the dorsal midline. The clipped area of each animal constituted approximately 10 percent of the total body surface area. The animals were then returned to their cages and 24 hours allowed to elapse, before the first mixture application was made. The waiting period permitted the skin to recover from the slight disturbance of the stratum corneum caused by the clipping procedure and also permit the healing of any microscopic abrasions possibly produced during the process. The clipping procedure was repeated at least once a week, but more often if necessary. To prevent oral ingestion of the test material, each animal was fitted with a lightweight, flexible plastic collar which was worn throughout the investigational period.

A mixture of 22.3 parts of - Glyceryl Mono Thioglycolate and 77.7 parts of Part Il Base Lotion #709-B9-1C was evaluated. The test material was applied to the unoccluded partially clipped, 3-square-inch test skin sites at a dose level of 2.0 mL/kg.

REMOVAL OF TEST SUBSTANCE
- Washing: Warm tap water
- Time after start of exposure: 30 minutes
Details on analytical verification of doses or concentrations:
Dose calculations were made weekly to adjust for changes in body weight.
Duration of treatment / exposure:
During the exposure period, the rabbits were placed in restrainers and subjected to a warm air flow from hair dryers installed above the rabbits. After
a 30 minute exposure period, the test sites were thoroughly rinsed with warm aerated tap water and then dried with towels and hair dryer.
Frequency of treatment:
These dosing procedures were followed 5 days per week for 4 weeks for a total of 20 applications.
Remarks:
Doses / Concentrations:
2.0 mL/kg bw
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Positive control:
not examined
Observations and examinations performed and frequency:
Mortality: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

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

BODY WEIGHT: Yes
- Time schedule for examinations: days -12, -7, 14, 21, 28

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes / No / No data
- Time schedule for collection of blood: Prior to start of study and after 28 days
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, 24 h
- How many animals: All
- Parameters checked: Total Leukocyte Count, Erythrocyte Count, Hemoglobin Concentration, Hematocrit Value, Differential Leukocyte Count (Pucent and Absolute), Cell Indices (MCV. MCH and MCHC)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to start of study and after 28 days
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, 24 h
- How many animals: All
- Parameters checked: Fasting Blood Glucose Concentration, Blood Urea Nitrogen Concentration (BUN), Serum Alkaline Phosphatase Activity (SAP), Serum Glutamic Pyruvic Transaminase Activity (SGPT), Serum Glutamic Oxalacetic Transaminase Activity (SGOT)


URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
At the conclusion of the investigational period, all rabbits were sacrificed. This was followed by a gross pathologic examination.
Other examinations:
The weights of the brain, liver, kidneys, spleen, heart, gonads, thyroid glands and adrenal glands were recorded.
Statistics:
Kruskal Wallis test and multiple comparison tests
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
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:
no effects observed
Clinical biochemistry findings:
no effects observed
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:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Mortality: One rabbit died. Rabbit 5-M from the untreated control group died during the 7th test day. The animal exhibited diarrhoea on test days 3, 4 and 5 and died two days later over the weekend. The immediate cause of death was not evident from the pathologic studies but was attributed to naturally occurring disease.

Reactions: No treament related pharmacotoxic symptoms were noted. The test animals exhibited severe hair loss upon repeated dermal exposure to the test material.

Effects on Body Weights: No adverse body weight effects were observed.

Hematology Studies and Clinical Blood Chemistry: No treatment related hematologic effects were noted.
Dose descriptor:
NOAEL
Effect level:
2 other: mL/kg bw/day
Based on:
test mat.
Remarks:
22.3% GMT
Sex:
male/female
Critical effects observed:
not specified

Table 1: Summary of Local Skin Reactions

Group

Local skin reactions after:

1 application

3 applications

5 applications

7 applications

untreated

No skin reactions

No skin reactions

No skin reactions

No skin reactions

treated with test substance

No skin reactions

No skin reactions

Noticeable hair 

loss 8/10

fissures 1/10

Noticeable hair 

loss 10/10

fissures 3/10

 

  

 Table 2: Continued summary of Local Skin Reactions 

 

Group

Local skin reactions after:

10 applications

12 applications

15 applications

20 applications

untreated

No skin reactions

No skin reactions

No skin reactions

No skin reactions

treated with test substance

Noticeable hair

 

loss 10/10

fissures 1/10

Noticeable hair loss 6/10, severe hair loss 3/10, complete hair loss 1/10

Noticeable hair loss 4/10, severe hair loss 5/10, complete hair loss 1/10

Noticeable hair loss 2/10, severe hair loss 6/10, complete hair loss 2/10

 

 

 

 

Conclusions:
At 2 mL/kg Glycerol Monothioglycolate 22.3 % showed no treatment related mortality, pharmacotoxic reactions, effects on body weight or hematologic effects. Because no dose finding preleminary studies are available here, these findings can only be used as supporting study.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Significant methodological deficiencies.

Repeated dose toxicity: dermal - local 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:
1977-05-04 to 1979-03-07
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Significant methodological deficiencies
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
only one dose of 2mL/kg; 30 minutes exposure; reporting deficits
GLP compliance:
no
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: Pel·Freez, Inc., USDA No. 7T-B-16, Rogers, Arkansas 72756
- Age at study initiation: 10 - 13 weeks
- Weight at study initiation: 2.38 - 2.84 kg
- Housing: Each animal was housed individually in a suspended, galvanized steel wire cage with dimensions of 14" x 16" x Z4"
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 12 days
- Fasting period before study: 24 h

ENVIRONMENTAL CONDITIONS: No data
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
In preparation of the test, the sides of the back of each rabbit were clipped using electric clippers. A 3-square-inch patch of hair was left above the dorsal midline. The clipped area of each animal constituted approximately 10 percent of the total body surface area. The animals were then returned to their cages and 24 hours allowed to elapse, before the first mixture application was made. The waiting period permitted the skin to recover from the slight disturbance of the stratum corneum caused by the clipping procedure and also permit the healing of any microscopic abrasions possibly produced during the process. The clipping procedure was repeated at least once a week, but more often if necessary. To prevent oral ingestion of the test material, each animal was fitted with a lightweight, flexible plastic collar which was worn throughout the investigational period.

A mixture of 22.3 parts of - Glyceryl Mono Thioglycolate and 77.7 parts of Part Il Base Lotion #709-B9-1C was evaluated. The test material was applied to the unoccluded partially clipped, 3-square-inch test skin sites at a dose level of 2.0 mL/kg.

REMOVAL OF TEST SUBSTANCE
- Washing: Warm tap water
- Time after start of exposure: 30 minutes
Details on analytical verification of doses or concentrations:
Dose calculations were made weekly to adjust for changes in body weight.
Duration of treatment / exposure:
During the exposure period, the rabbits were placed in restrainers and subjected to a warm air flow from hair dryers installed above the rabbits. After
a 30 minute exposure period, the test sites were thoroughly rinsed with warm aerated tap water and then dried with towels and hair dryer.
Frequency of treatment:
These dosing procedures were followed 5 days per week for 4 weeks for a total of 20 applications.
Remarks:
Doses / Concentrations:
2.0 mL/kg bw
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Positive control:
not examined
Observations and examinations performed and frequency:
Mortality: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

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

BODY WEIGHT: Yes
- Time schedule for examinations: days -12, -7, 14, 21, 28

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes / No / No data
- Time schedule for collection of blood: Prior to start of study and after 28 days
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, 24 h
- How many animals: All
- Parameters checked: Total Leukocyte Count, Erythrocyte Count, Hemoglobin Concentration, Hematocrit Value, Differential Leukocyte Count (Pucent and Absolute), Cell Indices (MCV. MCH and MCHC)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to start of study and after 28 days
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, 24 h
- How many animals: All
- Parameters checked: Fasting Blood Glucose Concentration, Blood Urea Nitrogen Concentration (BUN), Serum Alkaline Phosphatase Activity (SAP), Serum Glutamic Pyruvic Transaminase Activity (SGPT), Serum Glutamic Oxalacetic Transaminase Activity (SGOT)


URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
At the conclusion of the investigational period, all rabbits were sacrificed. This was followed by a gross pathologic examination.
Other examinations:
The weights of the brain, liver, kidneys, spleen, heart, gonads, thyroid glands and adrenal glands were recorded.
Statistics:
Kruskal Wallis test and multiple comparison tests
Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
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:
no effects observed
Clinical biochemistry findings:
no effects observed
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:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Mortality: One rabbit died. Rabbit 5-M from the untreated control group died during the 7th test day. The animal exhibited diarrhoea on test days 3, 4 and 5 and died two days later over the weekend. The immediate cause of death was not evident from the pathologic studies but was attributed to naturally occurring disease.

Reactions: No treament related pharmacotoxic symptoms were noted. The test animals exhibited severe hair loss upon repeated dermal exposure to the test material.

Effects on Body Weights: No adverse body weight effects were observed.

Hematology Studies and Clinical Blood Chemistry: No treatment related hematologic effects were noted.
Dose descriptor:
NOAEL
Effect level:
2 other: mL/kg bw/day
Based on:
test mat.
Remarks:
22.3% GMT
Sex:
male/female
Critical effects observed:
not specified

Table 1: Summary of Local Skin Reactions

Group

Local skin reactions after:

1 application

3 applications

5 applications

7 applications

untreated

No skin reactions

No skin reactions

No skin reactions

No skin reactions

treated with test substance

No skin reactions

No skin reactions

Noticeable hair 

loss 8/10

fissures 1/10

Noticeable hair 

loss 10/10

fissures 3/10

 

  

 Table 2: Continued summary of Local Skin Reactions 

 

Group

Local skin reactions after:

10 applications

12 applications

15 applications

20 applications

untreated

No skin reactions

No skin reactions

No skin reactions

No skin reactions

treated with test substance

Noticeable hair

 

loss 10/10

fissures 1/10

Noticeable hair loss 6/10, severe hair loss 3/10, complete hair loss 1/10

Noticeable hair loss 4/10, severe hair loss 5/10, complete hair loss 1/10

Noticeable hair loss 2/10, severe hair loss 6/10, complete hair loss 2/10

 

 

 

 

Conclusions:
At 2 mL/kg Glycerol Monothioglycolate 22.3 % showed no treatment related mortality, pharmacotoxic reactions, effects on body weight or hematologic effects. Because no dose finding preleminary studies are available here, these findings can only be used as supporting study.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Significant methodological deficiencies.

Additional information

The oral administration of GMT 80% to rats by gavage for 28 days OECD 422 at dose levels of 15, 50 and 150 mg/kg bw/day, resulted in no treatment related effects for the males treated with 150 mg/kg bw/day, but did result in the death of five females treated with 150 mg/kg bw/day. The NOEL for systemic toxicity was considered to be 150 mg/kg/day for males and 50 mg/kg bw/day for females. The relative magnitude of the NOEL was confirmed by an oral 90d study with NaTG (OECD 408, Rousseau, 2010). The anion of the NaTG salt is a potential main metabolite of GMT in vivo and very probably responsible for the toxicity of GMT in vivo.

The thioglycolate anion can be formed in vivo after cleavage of the ester bonds of the reaction mass of glycerol and thioglycolic acid. It can be expected that this metabolite of GMT and not glycerol will be responsible for the toxic effects observed in (sub)chronic toxicity studies. Mode of action as well as potential target organs are described in the supporting 90d-study of Rousseau from 2010.

Justification for classification or non-classification

The available data on repeated dose toxicity of the test substance does not meet the criteria for classification according to GHS and are therefore conclusive but not sufficient for classification.