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Administrative data

Description of key information

Study

Result

Comment

TEGME

OECD 408 guideline 90 day repeat dose oral toxicity Klimisch 1 study in rats

NOAEL: 400mg/kgbw/day

LOAEL: 1200mg/kgbw/daya

Equivalent to TEGEE doses of 435 and 1300 mg/kgbw/day respectively

US EPA guideline 90 day repeat dose dermal toxicity Klimisch 1 study in rats

NOAEL: 4000mg/kgbw/day (no adverse effects at maximum tested dose)

Equivalent to a TEGEE dose of 4350 mg/kgbw/day

US EPA guideline 90 day repeat dose oral neurotoxicity Klimisch 1 study in rats

NOAEL: 4000mg/kgbw/day (no adverse neurotoxicity effects at maximum tested dose)

Equivalent to a TEGEE dose of 4350 mg/kgbw/day

21 day dermal repeat dose study in rabbits

[NOAEL (local irritation): <1000mg/kgbw/day]

NOAEL (all other effects): 1000mg/kgbw/day - no adverse effects at maximum tested dose

Equivalent to a TEGEE dose of 1090 mg/kgbw/day See same study with TEGEE below.

DEGEE

90 day repeat dose oral toxicity Klimisch 1 study in Beagle dogs

NOAEL: 1000mg/kgbw/day

LOAEL: 1500mg/kgbw/dayb

Equivalent to TEGEE doses of 1320 and 1990 mg/kgbw/day respectively

Similar to OECD 410 guideline 28 day repeat dose dermal toxicity Klimisch 1 study in rabbits

[NOAEL (local irritation): 300mg/kgbw/day]

NOAEL (all other effects): 1000mg/kgbw/day - no adverse effects at maximum tested dose

Equivalent to TEGEE doses of 400 and 1320 mg/kgbw/day respectively

90 day feed study in rats (Klimisch 2).

NOAEL: 800mg/kgbw/day

LOAEL: 4000mg/kgbw/dayb

Equivalent to TEGEE doses of 1060 and 5280 mg/kgbw/day respectively

DEGBE

OECD 408 guideline 90 day repeat dose drinking water toxicity Klimisch 1 study in rats

NOAEL: 250mg/kgbw/day

LOAEL: 1000mg/kgbw/dayc

NOAEL (neurobehavioural): >1000mg/kgbw/day

Equivalent to TEGEE doses of 275 and 1100 mg/kgbw/day respectively.

90 day dermal repeat dose study in rats

NOAEL (local irritation): <200mg/kgbw/day]

NOAEL (all other effects): >2000mg/kgbw/day - no adverse effects at maximum tested dose

Equivalent to TEGEE doses of 220 and 2200 mg/kgbw/day respectively

TEGBE

21 day dermal repeat dose study in rabbits

[NOAEL (local irritation): <1000mg/kgbw/day]

NOAEL (all other effects): >1000mg/kgbw/day - no adverse effects at maximum tested dose

 

TEGEE

21 day dermal repeat dose study in rabbits

[NOAEL (local irritation): <1000mg/kgbw/day]

NOAEL (all other effects): >1000mg/kgbw/day - no adverse effects at maximum tested dose

 

30 day drinking water study in rats

NOAEL: 750mg/kgbw/day

LOAEL: 3300mg/kgbw/dayd

 

a)      Reduced food consumption, body weight and body weight gain.

b)      Reduced food consumption and body weight loss. This was at the higher dose of 2000mg/kgbw/day.

c)      Marginal effects on blood.

d)      Weight loss and blood urea.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Data on TEGME    

In a guideline (OECD 408) and GLP study, SD rats were exposed for 90 days to TEGME in drinking water at concentrations of 400, 1200 and 4000mg/kgbw/day. 14-16 animals were used per sex per dose group (Dow 1990a).

Statistically significant decreases in mean food consumption, body weight, and body weight gain for males and females were seen in the high dose group and trends for decreased food consumption and body weight for males were seen in the mid dose group. Water consumption tended to be decreased at each measurement period for females in the high dose group. Small decreases in mean food consumption, body weight, and body weight gain were also apparent for females in the mid dose group. Dose-related increases in mean liver weight were observed for male animals in all three treatment groups.

Minimal or mild hepatocellular hypertrophy was observed for 10 females in the high-dose treatment group. Fibrous connective tissue was observed around a small number of the bile ducts (cholangiofibrosis) for 7 males in the high-dose treatment group. All lesions were of minimal severity and were not considered to be physiologically significant. Cholangiofibrosis was not observed for males in any other treatment group or for females. Vacuolization or hypertrophy (minimal or mild severity) were also observed in the livers of some males in the low-dose and mid-dose treatment groups and females in the high-dose treatment group. Hypertrophy can be considered a physiological adaptation due to large subchronic doses of the test material, which is likely to be metabolized by alcohol dehydrogenase and aldehyde oxidase in the liver. There were no gross or microscopic lesions found in the nervous system of any rats that were attributed to TEGME ingestion.

Treatment-related degeneration and/or atrophy of seminiferous tubules were observed for most males in the high dose treatment group. The cell types affected in the tubules were spermatocytes and developing spermatids. Similar lesions were not observed for males in the low-dose or mid-dose treatment groups. At the Sponsor's request, testes from all males on the study were examined histologically. Significant seminiferous tubule degeneration and/or atrophy were observed in 12 of 15 males in the high dose treatment group. The target cells in the tubules appeared to be spermatocytes and developing spermatids. Treatment-related lesions were not observed in the low-dose and mid-dose groups. No other potential treatment-related alterations in organ weights, gross pathology, or histopathology were observed in this study. No treatment related effects were observed on the oestrous cycle. On the basis of these findings 1200 mg/kg bw/day is considered to be a subchronic LOAEL for TEGME and 400mg/kg bw/day a NOAEL under the conditions of this study based on minimal to mild toxicity as shown by reduced food consumption (3-7% reduction), reduced body weight and body weight gain (2-8% reduction) and reduction in relative liver weights (the latter being accompanied by minimal to mild hypertrophy was considered an adaptive response.)

In a guideline (EPA TCSA consent) and GLP study, SD rats were exposed dermally to TEGME (>10% of total body surface area, shaved, occluded, 10 animals per sex per dose) at doses of 400, 1200 and 4000 mg/kg bw/day for 6 hours/day, 5 days/week for 13 weeks (Dow 1990b). Parameters evaluated included in-life clinical observations, dermal irritation, body weights, feed consumption, haematology, clinical chemistry, urinalysis, oestrous cyclicity, selected organ weights, gross pathology and histopathology.

The study produced no clearly-defined indications of systemic toxicity, even with additional emphasis on lymphoid, hematopoietic and reproductive organs. The only treatment-related effects noted consisted of focal areas (<2 mm) of dermal irritation in nearly all animals administered TEGME. However, the dermal irritation was considered secondary to small abrasions induced by repeated clipping of the fur. Areas of the skin that were not abraded by clipping were unaffected by treatment with TEGME. All dermal observations noted during the course of the study were not evident at necropsy. Moreover, microscopic examination of tissue from the dermal test site did not indicate pathologic changes. Bilateral microscopic changes were observed in the testes and epididymides of one male (of 10) receiving 4000 mg/kg and one male (of 10) receiving 1200 mg/kg. The mean testes weights for these two groups were not statistically significant from controls. The authors of the study commented that these degenerative changes were not typical of the lesions associated with the glycol ether 2-methoxyethanol. The authors also reported that the background incidence of this lesion from contemporary historical control data for this rat species was in the range 0-17%, concluding that these findings were not attributable to TEGME exposure. The lack of biological relevance of the findings is reinforced by the fact that no similar effects were seen in the oral study at similar doses. Based on these findings, 4000 mg/kg bw/day is considered a subchronic dermal NOEL for TEGME systemic toxicity.

In a guideline (US EPA 40 CFR 799.5000) and GLP neurotoxicity study, SD rats were exposed for 90 days to TEGME in drinking water at concentrations of 400, 1200 and 4000mg/kgbw/day (Dow 1990c). 14-16 animals were used per sex per dose group. Parameters assessed included a functional observation battery and locomotor activity. The study showed no significant clinical signs of toxicity, alterations in the functional observational battery, or gross or microscopic lesions in the nervous system at any dose level. Minor decreases in motor activity were observed in the high dose group at Day 60 (males only) and Day 90 (males and females) evaluation periods. These decreases in motor activity were not considered to be neurotoxicologically significant based on the small magnitude of the changes, the parallel changes observed in body weights at these evaluation periods, and the lack of corroborative behavioral effects from the functional observation battery evaluations or histological changes in central or peripheral nervous system tissues. Based on these findings 4000mg/kg/day is a subchronic NOAEL for TEGME neurotoxicity.

In a study performed similarly to guideline OECD410, NZW male and female rabbits were subject to dermal exclusion exposure for 6 hours/day for 21 days to TEGME at a limit dose of 1000mg/kg. Comprehensive haematology, gross and histopathology was performed and key organs weighed (Leber, 1990).  The only significant effect was slight erythema and oedema from day 6 of study which was apparent in all animals by day 9, although the oedema disappeared by day 18. Some desquamation was seen from days 10-17 at application site and fissuring was seen between days 8 and 16. Histopathology showed that the changes were due to trace acanthosis and trace to moderate dermatitis. HAEMATOLOGY: Some haematological measurements were seen that were statistically significant from controls but these were occasional and random and not thought linked to treatment (and were also within historical control ranges). Male brain absolute but not relative weights were increased by 5.5% relative to controls. Since there were no histopathological changes noted and female brain weights were normal, this finding was not attributed to treatment. A focal testicular degeneration was seen in one rabbit to a slight degree but this lesion is known to occur spontaneously in rabbits and was therefore not regarded as biologically significant. No other significant findings noted.

Whilst this study is not a key study for this end point, due to its short duration, it is notable because it also examined TEGBE and is therefore useful as a bridging study

Data on DEGEE    

In an older 90 -day subchronic study male and female Wistar rats were fed a diet containing 0%, 0.25%, 1.0% or 5% DEGEE (Hall, 1966). Standard body weight and food consumption measurements and haematology, blood urea and urinalysis were conducted as well as necropsy, organ weight determination and histopathology. In the high dose group a decrease in body weight gain associated with lower food intake, and renal effects in the form of increase kidney weight, raised levels of GOT, proteinuria in males, and hydropic degeneration were observed. The high dose group also presented testicular edema and fatty liver changes. No treatment related changes were seen at 0.25% and 1.0% dose groups. The NOEL was established at 1.0% diet, which approximated to 800 mg/kgbw/day with a LOAEL of 5% or 4000mg/kgbw/day.

Data on DEGBE    

A 90 day sub-chronic OECD408 guideline and GLP drinking water study was carried out using Fischer 344 rats using doses of 50, 250 and 1000mg/kg/day of DEGBE (Johnson, 2005). End points studied included cage side and detailed clinical observations, body weight, food and water consumption, ophthalmic observations, haematology, clinical chemistry, urine analysis and neurobehavioural observations (functional observation battery). Sperm analysis was also performed.

Multiple, albeit mild, effects were seen in body and organ weights, water and food consumption and in the haematology, clinical chemistry and urine analysis the high dose group. In the histopathology, the only finding attributed to treatment was in female livers in the high dose groups where slight or very slight lesions were recorded (foci of aggregates of macrophages/histiocytes which are common in F344 rats and were observed in greater numbers in the high dose females). Very slight hypertrophy of periportal hepatocytes was also seen in 6 high dose females. No treatment related histopathological effects were found in the bone marrow or spleen in any cohort. The only treatment related effect seen in the mid dose group were equivocal changes (decreases of around 2 -3%) in erythron (RBC count, Hgb and Hct) that were statistically significant to unusually high concurrent controls but within historical control ranges. The mid dose level of 250mg/kg/day was therefore considered to be the no adverse effect level.

In a well conducted study designed to assess the sub-chronic and reproductive toxicity of DEGBE to SD male and female rats, the test substance was administered by the dermal route for 13 weeks at doses of 200, 600, 2000mg/kgbw/day (Auletta, 1993). The top dose used was the maximum practical concentration attainable. The lower concentrations were diluted in water to give a constant application volume but the top dose was applied neat. 10 animals were used per sex per dose.

The only significant effect of note was dermal irritation at the site of repeated application which occurred at all doses, albeit very slight at the low dose and only in males towards the end of the study. Irritancy was more marked in females than males and produced some necrosis at the highest dose. There were no other adverse findings noted. The NOAEL for local skin irritation was <200mg/kgbw/day. The NOAEL for all other effects was >2000mg/kgbw/day.

Data on TEGBE    

There is data from available from a sub-acute repeat dose toxicity study on TEGBE supplied as supporting evidence for this end point. Whilst this does not meet the requirements for this end point on its own, it has value as a bridging study to the developmental toxicity studies of the source substances. In this study performed similarly to guideline OECD410, NZW male and female rabbits were subject to dermal exclusion exposure for 6 hours/day for 21 days to TEGBE at a limit dose of 1000mg/kg. Comprehensive haematology, gross and histopathology was performed and key organs weighed (Leber, 1990).

The only significant effect was slight local erythema and oedema at the application site, which was manifest in all animals by day 10. Some desquamation was seen from days 10-17 at application site and fissuring was seen between days 8 and 16. Histopathology showed that the changes were due to trace acanthosis and trace to moderate dermatitis. Some haematological measurements were seen that were statistically significant from concurrent controls but these were occasional and random and within historical control ranges and therefore not thought linked to treatment. Male brain absolute but not relative weights were increased by 8.6% relative to concurrent controls. Since there were no histopathological changes noted and female brain weights were normal, this finding was not attributed to treatment. No other significant findings noted. The findings are consistent with those of the source substance.

Note that the same study also examined TEGEE – see next section.

Data on TEGEE    

There is lsome limited sub-acute data on TEGEE which provides supporting information to justify the validity of bridging across data from the source substances.

In a study performed similarly to guideline OECD410, NZW male and female rabbits were subject to dermal exclusion exposure for 6 hours/day for 21 days to TEGBE at a limit dose of 1000mg/kg. Comprehensive haematology, gross and histopathology was performed and key organs were weighed (Leber, 1990). Testicular effects including spermatid giant cells, focal tubular hypospermatogenesis and increased cytoplasmic vacuolization were noticed in a single exposed male. However, the authors noted that the lesion (focal testicular degeneration) was slight and that this is a known spontaneous lesion in NZ white rabbits and they therefore judged the finding to be incidental to TEGEE exposure. The only significant adverse effects seen were dermal irritation associated with repeat application at the same site. These were not manifest for 6 days and exhibited as slight erythema and oedema although only the erythema persisted until the end of the study. The study concluded that no adverse effects were seen at the single tested dose beyond dermal irritation.

In a very old study, but one that is considered to be sufficiently well documented to be reliable, male albino rats were exposed to DEGEE in drinking water at doses of 0.0, 0.12, 0.5, 2.0, or 8.0% levels ad libitum for 30 days (The Dow Chemical Company, 1945). Actual corresponding calculated doses taking into account the water consumption were 0.0, 0.18, 0.75, 3.30, or 3.29g/kg/day. Only the liver and kidney of the organs were examined in detail. Animals at 8% consumed the water sparingly and all died. At 2% solution, animals gained less weight than controls and some showed higher blood urea concentrations. The livers of the animals in the top dose group were examined microscopically which revealed congestion and light cloudy swelling and the kidneys were more severely injured, all having cloudy swelling and half showing in addition degeneration of the epithelium of the convoluted tubules. In the 2% dose group, only one kidney in these 10 was abnormal, with light cloudy swelling, and six livers had the same condition. Based on this study the NOAEL for male rats can be determined at 750mg/kgbw/day and the LOAEL at 3300mg/kgbw/day.

The read across used with the above data is as shown below.

READ ACROSS FROM SOURCE TO TARGET SUBSTANCES

Number of EO units

Alcohol chain length

Methyl

Ethyl

Propyl

Butyl

Pentyl

Hexyl

Mono

Di

Source

Source

Tri

Source

 Target

Tetra

 

 

 

 

 

 

 

 

Substance with no sub-chronic data available

 

Justification for classification or non-classification

Repeat toxicity studies are available for all three source substances by both the dermal and oral routes. (Inhalation is not considered relevant due to the very low vapour pressure of TEGEE). For the oral route, classification is only required if significant toxic effects are seen at a dose of 100mg/kg or lower and 200mg/kg for the dermal route. From the available data it can be concluded with some confidence that TEGEE is not likely to meet these criteria and therefore classification is not required.

The necessity to apply EUH066 for the skin effects seen in the dermal repeat dose studies should be considered. However, since the effects produced by the source substances are not considered sufficient to warrant applying this phrase, it is not considered appropriate to apply it to TEGEE.