2,5,8,11-tetramethyldodec-6-yne-5,8-diol

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2,5,8,11-tetramethyldodec-6-yne-5,8-diol

EC Number:

269-348-0

EC Name:

2,5,8,11-tetramethyldodec-6-yne-5,8-diol

Cas Number:

68227-33-8

Molecular formula:

C16H30O2

IUPAC Name:

2,5,8,11-tetramethyldodec-6-yne-5,8-diol

Constituent 2

Reference substance name:

2,5,8,11-tetramethyl-6-dodecyne-5,8-diol

IUPAC Name:

2,5,8,11-tetramethyl-6-dodecyne-5,8-diol

Test material form:

other: waxy solid, white

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The standard and sample solutions were analysed by GC using the following conditions:
GC system : Agilent Technologies 5890, incorporating
autosampler and workstation
Column : DB-Wax (30 m x 0.32 mm id x 0.25 μm film)
Oven temperature program : initial 100 ºC for 0 mins
rate 20 ºC/min
final 250 ºC for 15 mins
Injection temperature : 200 ºC
Flame ionisation detector
temperature
: 250 ºC
Injection volume : 1 μl
Retention times : ~ 6.3 mins
~ 8.5 mins

Details on study design:

Methods. The test material was administered by gavage to three groups, each of ten
male and ten female Wistar Han™:HsdRccHan™:WIST strain rats, for up to forty-five
consecutive days (including a two week maturation phase, pairing, gestation and early
lactation for females), at dose levels of 50, 100 and 200 mg/kg/day. Following the early
termination of one 200 mg/kg/day male and one female from this dose group being found
dead, the 200 mg/kg/day dose group was reduced to 125 mg/kg/day from Day 11
onwards. A control group of ten males and ten females was dosed with vehicle alone
(Polyethylene glycol 400). Two recovery groups, each of five males and five females,
were treated with the high dose (200 mg/kg/day reduced to 125 mg/kg/day from Day 11
onwards) or the vehicle alone for forty-two consecutive days and then maintained without
treatment for a further fourteen days.
Clinical signs, behavioural assessments, bodyweight change, and food and water
consumption were monitored during the study.
Pairing of animals within each dose group was undertaken on a one male: one female
basis within each treatment group on Day 15 of the study, with females subsequently
being allowed to litter and rear their offspring to Day 5 of lactation.
During the lactation phase, daily clinical observations were performed on all surviving
offspring, together with litter size and offspring weights and assessment of surface
righting reflex.
Extensive functional observations were performed on five selected males from each
dose group after the completion of the mating phase, and for five selected parental
females from each dose group on Day 4 post partum. Urinalysis was performed on five
non-recovery males per dose group during the final week of treatment and five nonrecovery
males and females from each dose group were selected for haematology and
blood chemistry assessments prior to termination.
Surviving males were terminated on Day 43, followed by the termination of all surviving
females and offspring on Day 5 post partum. All animals were subjected to a gross
necropsy examination and histopathological evaluation of selected tissues was
performed.
Following forty-two days of treatment, recovery group animals were maintained without
treatment for a further fourteen days. Urinalysis was performed on all surviving recovery
group males during the final week of the treatment period. In addition, haematological
and blood chemical assessments were performed on all surviving recovery group
animals at the end of the treatment-free period. These animals were then subjected to a
gross necropsy and histopathological examinations of selected tissues was performed.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

There were no unscheduled deaths that were considered to be related to test material toxicity. The deaths seen at the high dose level, 100 and 50 mg/kg/day are considered to be due to the process of gavage administration of the test material, inducing severe pulmonary lesions, and not the related inherent toxicity of the test material. The clinical observations detected during this study were not considered to be related to systemic toxicity.

Mortality:

no mortality observed

Description (incidence):

There were no unscheduled deaths that were considered to be related to test material toxicity. The deaths seen at the high dose level, 100 and 50 mg/kg/day are considered to be due to the process of gavage administration of the test material, inducing severe pulmonary lesions, and not the related inherent toxicity of the test material. The clinical observations detected during this study were not considered to be related to systemic toxicity.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No adverse effect on bodyweight development or bodyweight gain was detected.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No adverse effect on food consumption or food efficiency was detected.

Food efficiency:

no effects observed

Description (incidence and severity):

No adverse effect on food consumption or food efficiency was detected.

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

No treatment-related intergroup differences in water intake were detected.

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

There was no adverse effect on the haematological parameters measured.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There was no adverse effect on the blood chemical parameters measured.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related intergroup differences were detected in the urinalytical paramenters measured.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

There were no adverse changes in the behavioural assessment measurements.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

An increase in liver and thyroid weights was evident in the non-recovery high dose males, in comp. to contr. No adv. eff. was evident in the non-recovery high dose females, animals or either sex treated with 100 or 50 mg or recovery high dose groups.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Centrilobular hepatocellular hypertrophy was evident in the non-recovery high dose males only. No such effect was evident in the non-recovery high dose females, males treated with 100 or 50 mg/kg/day or recovery high dose males.

Histopathological findings: neoplastic:

not specified

Details on results:

Necropsy: No adverse abnormalities were detected for treated adults in comparison to
controls. No adverse macroscopic abnormalities were detected for offspring dying during lactation or at termination on Day 5 post partum.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No treatment-related effects were observed in females at the high dose level. Therefore, the "No Observed Effect Level" (NOEL) for systemic toxicity for females was considered to be 125 mg/kg/day.

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The oral administration of Surfynol 124 to rats for a period of up to ten days at a dose level of 200 mg/kg/day resulted in three interim deaths. The clinical findings observed in these three animals suggested that their deaths may be attributed to the gavage administration of an irritant test material and not the inherent toxicity of the test material. Therefore, in order to prevent the likelihood of further adult mortalities the high dose level was reduced to 125 mg/kg/day from Day 11 onwards. In total the test material was administered for up to forty five consecutive days at dose levels of up to 125 mg/kg/day resulting in treatment-related effects at the high dose level. Increased organ eight measurements were identified in the liver and thyroid. Furthermore, liver changes were identified as centrilobular hepatocyte hypertrophy. These were considered to be adaptive and not to represent an adverse health effect and therefore the "No Observed Adverse Effect Level" (NOAEL) for systemic toxicity was considered to be 125 mg/kg/day for males only.

No treatment-related effects were observed in females at the high dose level. Therefore, the "No Observed Effect Level" (NOEL) for systemic toxicity for females was considered to be 125 mg/kg/day.
No treatment-related effects were detected in the reproductive parameters measured, therefore the ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 125 mg/kg/day.