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Administrative data

Description of key information

91 d NOAEL = 500 mg/kg bw/d (rat, combined repeated dose/1 generation reproduction study, no guideline; RL2: 0, 500, 1000, 2000 mg/kg bw/d) (read-across from 2,4,7,9-Tetramethyl-5-decyne-4,7-diol )

91 d NOAEL = 200 mg/kg bw/d (beagle dog, no guideline, RL2: 0, 200, 250 and 300 mg/kg/day) (read-across from 2,4,7,9-Tetramethyl-5-decyne-4,7-diol)

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
- they are manufactured from similar precursors under similar conditions
- they share structural similarities with common functional groups: the substances start with an acetylene group as core structure; geminal hydroxyl groups on the alpha carbon atoms; distal to the geminal hydroxyl groups is an isobutyl group (methyl isopropyl); the target substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3) is further functionalised with ethylene oxide and has an ethoxylation degree of 1.3; the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (3.8) has an ethoxylation degree of 3.8
- they have similar physicochemical properties and thus, show a similar toxicokinetic behaviour
- they are expected to undergo similar metabolism: oxidation of the terminal methyl groups to result in alcohol, aldehyde and finally the corresponding acid

Therefore, read-across from the existing toxicity, ecotoxicity, environmental fate and physicochemical studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
91 days
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 male
20 female
Control animals:
yes
Details on study design:
Ten male and twenty female sexually mature rats were randomly assigned to each group.  Males were sacrificed following the 20th day of breeding and females were sacrificed when their litters were weaned at 21 days of age.  Animals were fed their respective diets from the start of cohabitation until their scheduled sacrifice.  
The weanlings were randomized within their respective groups and carried on the same dose levels as their parents for 91 days.  Test diets were prepared weekly. Analytical monitoring of the test diets was performed.  Statistical analysis of the body weight, food consumption, clinical chemistry, and hematology data was performed using the Student’s t-test.
Observations and examinations performed and frequency:
Males were sacrificed following the 20th day of breeding and females were sacrificed when their litters were weaned at 21 days of age.  Animals were fed their respective diets from the start of cohabitation until their scheduled sacrifice.  
The weanlings were randomized within their respective groups and carried on the same dose levels as their parents for 91 days.  Test diets were prepared weekly. Analytical monitoring of the test diets was performed.  Statistical analysis of the body weight, food consumption, clinical chemistry, and hematology data was performed using the Student’s t-test.
Clinical signs:
no effects observed
Description (incidence and severity):
No rats expired in this phase of the experiment
Mortality:
no mortality observed
Description (incidence):
No rats expired in this phase of the experiment
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Only one pertinent finding: The mean body weight of the high dose female group after weaning its young was significantly lower than the corresponding control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The feed consumption of the high dose female group after weaning its young was significantly lower than the control. There was no other pertinent findings.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross abnormalties were observed in any of the F0 parents, either male or female.
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): All rats survived for the duration of the study. No abnormal clinical signs were observed in any of the rats, either test or control, during the entire study period.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Only one pertinent finding: The mean body weight of the high dose female group after weaning its young was significantly lower than the corresponding control.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): The feed consumption of the high dose female group after weaning its young was significantly lower than the control. There was no other pertinent findings.


GROSS PATHOLOGY (PARENTAL ANIMALS): No gross abnormalities were observed in any of the Fo parents, either male or female.

Hematological Values at 45 Days:

RBC: The mean total RBC counts in the mid dose and the high
dose male test groups were significantly Lower than the control.
All values however, mean as well as individual, were within our normal
range.
HGB: The mean hemoglobin values of the mid dose and high dose
male rats were significantly lower than the control, while the same
value was higher than the control in the high dose female rats.
All values, however, mean as well as individual, were within our
established normal range.
HMCT: The mean HMCT values for the low and high dose group of male
rats were statistically lower than the control, while the mean HMCT value for the high dose female group was statistically higher than
the control. All values, however, mean as well as individual, were
within normal range.
WBC: All total WBC counts, mean as well as individual, were
within our normal range.
WBC Diff: All rats exanined displayed normal differential counts.
Plat. Est : The platelets of all rats examined were deemed to have
been adequate.

Hematological Values at 92 Days:

RBC: All total RBC counts, mean as well as individual, were
within normal range.
HGB: All HGB values, mean as well as individual, except one
were within normal range; high dose female rat #I122 had a HGB of
11.6 g/dl; histologically this rat exhibited mild pulmonary lymphocytosis.
HMCT: All HMCT values, mean as well as individual, were
within normal range.
WBC: The mean total WBC counts of the low and high dose
groups were significantly higher than the control groups. All total
WBC counts, however, mean as well as individual, were within normal
range.
WBC Diff: All rats examined displayed a normal differential counts.
Plat.-Est.: The platele testimate of all rats examined were
deemed to have been adequate.

Urinalysis at 45 and 91 days: There were no significant differences
between the test and control groups, male or female, in any urinalysis
parameters.

Clinical Chemistry:

FBS: Low dose female rat #I1070 had an FBS of 260 mg/dl;
histopathologically this ra t was not remarkable.
BUN: All values, individual as well as mean, were normal.
SGOT: All values, individual as well as mean, were normal.
SGPT: The mean mid dose female and both high dose and female
values were significantly higher than control. These differences
are of no biological significance, however, since all mean
as well as individual values except one were normal; high dose
male rat #1117 had an SGPT wake of 105. Histopathologically this
rat exhibited mild pulmonary Iyphocytosis.
GGTP: All values, individual as well as mean, were normal.
Total Protein: The mean value for the mid dose groups, male
and female, as well as for the high dose groups, both male and female,
was significantly higher than control. All mean as well as individual
values except one were normal; mid dose female rat #1082 had
a Total Protein value of 8.52 g/dl. Histopathologically this rat
exhibited pulmonary lymphocytosis.
Alk. Phos/ase: The low and high dose mean values were
statistically less than the correspondirig control values. This is
of no biological significance, however, since all values, mean as
well as individual, were normal.


HISTOPATHOLOGY (PARENTAL ANIMALS): Histopathology examination of the reproductive organs from all Fo parents revealed no abnormalities.

OTHER FINDINGS (PARENTAL ANIMALS): None
Dose descriptor:
NOAEL
Effect level:
ca. 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
no
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
- they are manufactured from similar precursors under similar conditions
- they share structural similarities with common functional groups: the substances start with an acetylene group as core structure; geminal hydroxyl groups on the alpha carbon atoms; distal to the geminal hydroxyl groups is an isobutyl group (methyl isopropyl); the target substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3) is further functionalised with ethylene oxide and has an ethoxylation degree of 1.3; the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (3.8) has an ethoxylation degree of 3.8
- they have similar physicochemical properties and thus, show a similar toxicokinetic behaviour
- they are expected to undergo similar metabolism: oxidation of the terminal methyl groups to result in alcohol, aldehyde and finally the corresponding acid

Therefore, read-across from the existing toxicity, ecotoxicity, environmental fate and physicochemical studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Species:
dog
Strain:
Beagle
Sex:
male/female
Route of administration:
oral: capsule
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
All groups, treated and control , received 350 grams per day of basic feed. All dosing was done using 1/4 ounce gelatin capsules. The first group, the control group received, by capsule, granulated table sugar. The second group received, by capsule, 50 to 200 mg of test item per kilogram of body weight per day (kg bd.wt./d), the third group received by capsule, 50 to 300 mg of test item/kg bd.wt./d, and the fourth group received, by capsule, 50 to 300 mg of test item/kg bd.wt./d. Capsule administration followed feeding by approximately one hour.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
4 male and 4 female per dose
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
All dogs were inspected daily.

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY: yes

WATER CONSUMPTION AND COMPOUND INTAKE: no

OPHTHALMOSCOPIC EXAMINATION: no

HAEMATOLOGY: Yes
- Time schedule for collection of blood: beginning of the study, at 47 and 48 days for the males and females, respectively, and at 89 and 130 days for both sexes
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Yes
- Parameters: (a) Red Blood Cell Count (RBC); (b) Hemoglobin (Hgb.); (c) Hematocrit (Hmct.); (d) White Blood Cell Count (WBC); (e) White Blood Cell Differential (WBC Diff.); and (g) Platelet Estimate (Plt. Est.).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: beginning of the study, at 47 and 48 days for the males and females, respectively, and at 89 and 130 days for both sexes
- Animals fasted: Yes, 24 h
- Parameters: (a) Alkaline Phosphatase; (b) Fasting Blood Sugar (FBS); (c) Blood Urea Nitrogen (BUN); (d) Gamma Glutamyl Transpeptidase (GGTP); (e) Serum Glutamic Oxaloacetic Transaminase (SGOT); (f) Serum Glutamic Pyruvic Transaminase (SGPT); and (g) Total Protein (T'l. Prot.).

URINALYSIS: Yes
- Time schedule for collection of urine: prior to initiation of the study, at 45 and 47 days for the males and females, respectively, and at 89 and 129 days for both sexes
- Parameters: (a) Color; (b) Appearance; (c) pH; (d) Specific Gravity; (e) Protein (qualitative);(f) Glucose (qualitative); (g) WBC/hpf, and (h) RBC/hpf.

NEUROBEHAVIOURAL EXAMINATION: no

IMMUNOLOGY: no
Clinical signs:
no effects observed
Description (incidence and severity):
Occasional dogs in the mid and high dose treated groups exhibited sporadic compound-related neurologic disturbances throughout the experiment. An occasional dog would exhibit infrequent spontaneous vomiting. With the exception of a few minor injuries in treated and control dogs, there were no other clinical signs noted, either compound-related or otherwise.
Mortality:
no mortality observed
Description (incidence):
All dogs survived for the duration of the experiment.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There was no statistically significant difference in the mean body weight between any of the test groups and the corresponding control groups at any time during the course of the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There was no persistent significant difference in the mean feed consumption between the test groups and the corresponding control groups nor was there any persistent difference in the feed efficiency between the test groups and the corresponding control groups.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
The following determinations were done on all dogs at the beginning of the study, at 47 and 48 days for the males and females, respectively, and at 89 and 130 days for both sexes.
(a) Red Blood Cell Count (RBC);
(b) Hemoglobin (Hgb.);
(c) Hematocrit (Hmct.);
(d) White Blood Cell Count (WBC);
(e) White Blood Cell Differential (WBC Diff.); and
(g) Platelet Estimate (Plt. Est.).
There were no significant biological differences in any of the hematological parameters at any time between the test and the control groups.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
The following blood chemistry determinations were performed on all dogs prior to initiation, at 47 and 48 days for the males and females, respectively, and at 89 and 130 days for both sexes:
(a) Alkaline Phosphatase (Alk. Phos/ase);
(b) Fasting Blood Sugar (FBS);
(c) Blood Urea Nitrogen (BUN);
(d) Gamma Glutamyl Transpeptidase (GGTP);
(e) Serum Glutamic Oxaloacetic Transaminase (SGOT);
(f) Serum Glutamic Pyruvic Transaminase (SGPT); and
(g) Total Protein (T'l. Prot.).
There was statisticaldifference in the mean values in some of these parameters between the test dogs and the corresponding control groups at variousintervals during the course of the study.
With the exception of Alk. Phosphatase, however, 211 mean values were within normal limits.
The mean Alk. Phosphatase value of the mid dose and high dose male dogs at 89 days and of all test groups of male dogs at 130 days were higher than our accepted normal range. The mean Alk. Phospharase values of the high dose female dogs at 48, 89 and 130 days, as well as the female mid doss group at 130 days, were higher than our accepted nomal.
The individual Alk. Phosphatase values of several male and female dogs in all treated groups were elevated at various intervals.
As detailed in the Results section of this report, we do not consider this elevation to be a manifestation of compound toxicity.
Urinalysis findings:
no effects observed
Description (incidence and severity):
The following urine parameters were examined from all dogs prior to initiation of the study, at 45 and 47 days for the males and females, respectively, and at 89 and 129 days for both sexes:
(a) Color;
(b) Appearance;
(c) pH;
(d) Specific Gravity;
(e) Protein (qualitative);
(f) Glucose (qualitative);
(g) WBC/hpf, and
(h) RBC/hpf.
There were no abnormal urinary findings, compound-related or otherwise, in any of the dogs at any time.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The mean hepatic weight of the low dose and high dose male dogs as well as of the treated female groups of dogs was statistically higher than the mean hepatic weight of the corresponding male and female control groups. Histologically, however, there was no hepatic histopathology. The liver-to-body weight ratios of both male and female test dogs were increased as compared to the corresponding control groups. As detailed in the Results section of this report, we consider this to be more a reflection of a possible adaptive hyperplasia of the hepatic endoplasmic reticulum.
The liver-to-brain weight ratios in all groups of treated male and female dogs were increased as compared to the corresponding control groups.

Thyroids: The mean male high dose group was significantly higher than the corresponding control group.
Heart: There was no significance manifested.
Liver: The mean male low dose and high dose male dogs as well as all female test doses were significantly higher than the corresponding control groups.
Kidneys: No significance was observed.
Gonads: There was no significance noted.
Pituitary: No significance was seen.
Brain: There was no significance present.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no compound-related abnormal gross necropsy findings.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no compound-related abnormal histological findings.
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Basis for effect level:
clinical signs
Remarks on result:
other: neurological disturbances at 250 and 300 mg/kg bw/d
Critical effects observed:
no
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
- they are manufactured from similar precursors under similar conditions
- they share structural similarities with common functional groups: the substances start with an acetylene group as core structure; geminal hydroxyl groups on the alpha carbon atoms; distal to the geminal hydroxyl groups is an isobutyl group (methyl isopropyl); the target substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3) is further functionalised with ethylene oxide and has an ethoxylation degree of 1.3; the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (3.8) has an ethoxylation degree of 3.8
- they have similar physicochemical properties and thus, show a similar toxicokinetic behaviour
- they are expected to undergo similar metabolism: oxidation of the terminal methyl groups to result in alcohol, aldehyde and finally the corresponding acid

Therefore, read-across from the existing toxicity, ecotoxicity, environmental fate and physicochemical studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Species:
rat
Strain:
Long-Evans
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- source: Blue Spruce Farms Altamont, New York

- Age at study initiation: 4-5 weeks

- Weight at study initiation:
Males: 195 g (mean) 167 - 218 g (range)
Females: 148 (mean) 127 - 170 (range)

CONDITIONS:

- Housing: Individually in elevated stainless steel wire mesh cages.
- Diet: ad libitum
- Water: ad libitum


Route of administration:
oral: feed
Duration of treatment / exposure:
28 days
Frequency of treatment:
continuous
No. of animals per sex per dose:
6 male and 6 female per dose
Control animals:
yes, concurrent no treatment
Positive control:
yes, 6 male, 6 female, no treatment
Observations and examinations performed and frequency:
For Mortality and Gross
Signs of Toxicologic or
Pharmacologic Effects: Twice daily
Detailed Physical Examination for Signs of Local or Systemic Toxicity and Pharmacologic Effects: Weekly
Palpation for Tissue Masses: Weekly
Food consumption: Weekly, beginning one week prior to treatment
Sacrifice and pathology:
Terminal Necropsy : 8 J u l y 1977
No, of Animals: All
Sacrifice Method: Exsanguination under ether anesthesia .
Tissues Preserved: Only tissues with grossly abnormal findings were preserved.
Preservative: 10 % neutral buffered formalin.
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):
no effects observed
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
5 000 ppm
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Critical effects observed:
no
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Study has been done before the establishment of GLP, Klimisch rating 2 is resulting.

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

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No experimental data on 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(1.3) are available for the assessment of toxicity after repeated administration. However, a subacute (28 d) toxicity study in rat and a subchronic (90 d) toxicity study in beagle dogs and in rats are available for the source substances 2,4,7,9-Tetramethyl-5-decyne-4,7-diol and 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8). A detailed justification for read-across is attached to iuclid section 13.

 

Subacute toxicity

2,4,7,9-Tetramethyl-5-decyne-4,7-diol was administered to Long-Evans rats (6/sex/dose level) at dose levels of 625, 1250, 2500 and 5000 ppm in the diet for a period of 28 days. Evaluation of mortality, physical observations, body weight, and food consumption data, as well as gross necropsy observations did not reveal any adverse effects considered to be attributable to the administration of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol at any of the dose levels. However, histopathology was not performed in this study.

 

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8) was administered to Long-Evans rats at dose levls of 750, 1500, 3000 and 6000 parts per million (ppm) in the diet for a period of twenty-eight days.

Evaluation of mortality, physical observations, body weight, and food consumption data, as well as gross necropsy observations did not reveal any adverse effects considered to be attributable to the adminstration of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8) at any of the dose levels. However, histopathology was not performed in this study.

 

Subchronic toxicity

2,4,7,9-Tetramethyl-5-decyne-4,7-diol was fed to the rat during a single generation reproduction study and for ninety one days to the F1a weanlings. The test material was mixed into the rats’ feed to provide dose levels of 0, 500, 1000, and 2000 mg/kg/day. Sexually mature Sprague-Dawley albino rats were divided into four groups, each consisting of ten male and twenty female rats. All Fo male rats, both test and control, were fed their respective diets until their litters reached the age of 21 days for weaning, when the Fo dams were sacrificed. The weanlings were randomized to their respective groups and carried on the same dose levels to the termination of the experiment. The only pertinent findings observed in the Fo parents were: 1. Slight decrease in the mean weaning weight of both male and female pups of the high-dose group, 2. Slight decrease in lactation indices of the high-dose group, 3. Decreased body weight and feed consumption of the high-dose female group, 4. Normal histology of the reproductive organs in the Fo parents. The following pertinent findings were observed in the F1a rats: 1. Slight decrease in the mean rate of body weight gain in the mid- and high-dose male and female rats; there was also significant decrease in this parameter in the low-dose male group during the first eight weeks, 2. Normal mean hematological findings, clinical chemistry findings, and urinalysis findings after 91 days on test, 3. Significant increase in the liver weight of the mid- and high-dose male and female test groups with corresponding increase in the liver-to-body weight ratios, 4. Corresponding histopathology of the liver of the mid- and high-dose male and female rats, showing mild to moderate centrilobular cloudy swelling of hepatocytes.

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, when fed to rats under the conditions of this experiment, showed no effect at 500 mg/kg/day but did have a toxic effect in the F1a generation at greater than or equal to 1,000 mg/kg/day while in the reproduction phase of this experiment there was a toxic effect at the 2,000 mg/kg/day level, a borderline effect at the 1,000 mg/kg/day level and no effect at 500 mg/kg/day.

 

2,4,7,9-Tetramethyl-5-decyne-4,7-diol was administered orally to beagle dogs in gelatin capsules at dose levels of 0, 200, 250 and 300 mg/kg/day for 91 days. Because the dogs had to be gradually acclimated from 50 mg/kg/day to higher dose levels of the test item to avoid vomiting, the total test period was 130 days. The control animals received capsules of granulated table sugar. Capsule administration followed feeding by approximately one hour. All dogs survived for the duration of this study with few clinical signs. Occasional dogs in the mid- and high-dose groups exhibited sporadic, compound-related, neurological disturbances (convulsions, tremors, incoordination and/or paralysis) during the study. All other observations, including feed consumption, body weight gains, organ weights (except liver), clinical chemistries, hematology, urinalysis, gross pathology, and histology were judged to reflect no compound-related/ biologically significant changes. This study did not establish a no-observed-effect-level (NOEL) of test item in dogs, since mean liver weights and liver-to-body weight ratios in all test item-treated groups were higher than in corresponding control groups. However, since no histological abnormalities were observed in these livers, the liver enlargement was judged to be due to hyperplasia of the hepatic endoplasmic reticulum, where xenobiotic/drug metabolizing enzymes are located. These common adaptive liver changes are generally reversible, after test compound exposure is discontinued. The NOAEL was established at 200 mg/kg bw/d based on neurological disturbances at 250 and 300 mg/kg bw/d. 

 

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8) was fed to the rat during a single generation reproduction study and for ninety one days to the F1a weanlings. The test material was mixed into the rats’ feed to provide dose levels of 0, 500, 1000, and 2000 mg/kg/day. Sexually mature Sprague-Dawley albino rats were divided into four groups, each consisting of ten male and twenty female rats. The animals were mated and the newborn raised to weanling age. The weanlings were randomized to their respective groups according to our Standard Operating Procedures and carried on the same levels to the termination of this 91 day feeding study. Body weight and feed consumption data as well as several reproductive parameters were taken from the F0 rats.

Certain hematological and urine analytical parameters were performed on five male and five female F1a rats per group after 45 days and 91 days. Clinical chemistry determinations were conducted on five male and five female F1a rats per group prior to sacrifice. Gross necropsy was performed on all rats. Organ weights and organ-to-body weight ratios were done on ten male and ten female F1a rats per group. Complete histopathology was done on ten male and ten female rats from the high dose and control groups while the major organs were examined histopathologically from all the remaining survivors.

The only pertinent findings observed in the F0 parents were the following:

1. Decrease in the weaning weight of the male and female high dose pups,

2.Decrease in the number of live born pups both male and female at the high dose level,

3.Decreased body weight in all female test groups after weaning.

4.Normal histology of the reproductive organs.

The only pertinent findings observed in the F1a rats were as follows:

1. Only sporadic significant decrease in the feed consumption of the male test groups during the first: eight weeks on test.

2. Biologically significant decrease in the rate of body weight gain of the high dose male and female groups,

3. Normal clinical chemistry values after 91 days on test.

4. Normal hematology findings after 45 and 91 days on test.

5. Normal urinalysis results after 45 and 91 days on test,

6. Dose related increase in the liver to body weight ratios, particularly striking in the female test groups.

From the data it was concluded that, when the test item is fed to rats under the conditions of this experiment, it does not cause any toxic effect at levels of 500 mg/kg/d and 1,000 mg/kg/d, but it does

cause a toxic effect at 2,000 mg/kg/d.

 

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8) was administered orally to beagle dogs in gelatin capsules at dose levels of 0, 200, 400 and 600 mg/kg/day for 91 days. Increased liver weights and, thus, liver-to-body weight ratios were observed for both male and female dogs in the 'mid' and 'high' dose groups (400 and 600 mg/kg/day, respectively). However, since no histological abnormalities were observed in these livers, the liver enlargement was judged to be due to hyperplasia of the hepatic endoplasmic reticulum, where xenobiotic/drug metabolizing enzymes are located. These common adaptive liver changes are generally reversible, after test compound exposure is discontinued. In this study, the no effect level (NOEL) of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8) in dogs was 200 mg/kg/day.

 

Conclusion 

Both source substances induced liver weight changes and microscopic changes in the liver which are in general associated with increased xenobiotic metabolism and thus, are considered to be adaptive rather than adverse effects.

 

Based on the available data, the overall dose descriptor for repeated dose toxicity of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(1.3) is the subchronic NOAEL of 500 mg/kg bw/d obtained in the 90 d study in rats conducted with the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, since this NOAEL lead to the most conservative DNEL (see iuclid section 7 – Toxicological information).

 

There are no data gaps for the endpoint repeated dose toxicity. No human data are available. However, there is no reason to believe that these results from rat and rabbits would not be applicable to humans.

Justification for classification or non-classification

According to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Part 3 no classification required.