Registration Dossier

Administrative data

Description of key information

Based on the available experimental data, Dimethyl 2-methyglutarate in not classified irritant for the eyes and skin according to the criteria of Annexe VI Directive 67/548/EEC and EU GHS.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 26 September 2007 to 08 January 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to international test guidelines and to GLP.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
Harlan Netherlands BV
Kreuzelweg 53, NL-5961 NM Horst/The Netherlands
Postbus 6174, NL-5960 AD Horst/The Netherlands
- Age at study initiation: 13 weeks for the male; 12 weeks for the females
- Weight at study initiation: 2604 to 2850 g
- Housing: individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd, Füllinsdorf) and haysticks 4642 (batch no. 08/07, Provimi Kliba AG) were provided for gnawing.
- Diet: Pelleted standard Provimi Kliba 3418 rabbit maintenance diet, batch no. 31/07 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum. Results of analysis for contaminants are archived at RCC Ltd.
- Water: Community tap water from Füllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23° C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12 (music during the daytime light period)

IN-LIFE DATES: From: 01 Oct 2007 to 11 Oct 2007
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped with an electric clipper
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL/animal
- Concentration (if solution): 100%
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48 and 72 hours as well as 7 and 10 days after exposure (removal of the dressing, gauze patch and test material)
Number of animals:
1 male, 2 females
Details on study design:
TEST SITE
- Area of exposure: approximately 6.25 cm2 (left flank)
- % coverage: approximately 0.4% of the surface area
- Type of wrap if used: The semi-occlusive dressing was wrapped around the abdomen and anchored with tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): after the dressing was removed, the skin was flushed with lukewarm tap water
- Time after start of exposure: 4 hours

SCORING SYSTEM: numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: overall at 24, 48 and 72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 10 days
Remarks on result:
other: Mean of each animal: 0.67; 1; 0.33
Irritation parameter:
edema score
Basis:
mean
Time point:
other: overall at 24, 48 and 72 h
Score:
0.11
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Mean of each animal: 0; 0.33; 0
Irritant / corrosive response data:
The test material did not induce significant or irreversible damage to the skin.

The erythema (grade 1) was observed from the initial evaluation time point, i.e. 1 hour following removal of the patch.
The oedema (grade 1) was observed only at the 24-hour observation time-point.
Other effects:
No other local signs and no staining observed. No clinical signs and body weights were within the normal range.

Table of results:

Score at time point / Reversibility

Erythema

Edema

Max. score: 4

Max. score: 4

60 min

1/1/1

0/0/0 

24 h

1/1/1

0/1/0

48 h

1/1/0 

0/0/0

72 h

0/1/0 

0/0/0

Average 24h, 48h, 72h

 0.67/1/033

0/0.33/0

7 days

0/1/0 

0/0/0

10 days

0/0/0

0/0/0

Reversibility

Yes within 10 days 

Yes within 48 hours  

 

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based upon the referred classification criteria (commission Directive 2001/59/EC of August 2001), dimethyl 2-methylglutarate is considered to be "not irritating" to rabbit skin.
Executive summary:

In a skin irritation study, 3 New Zealand White rabbits were treated by a topical semi-occlusive application of 0.5 mL of undiluted Dimethyl 2-methyl glutarate for 4 hours and were observed 1, 24, 48 and 72 hours as well as 7 and 10 days after exposure.

 

The application of the test material to the skin resulted in mild signs of irritation, including erythema and oedema (maximum mean score of 1 and 0.33, respectively). These effects were reversible and no longer evident 48- or 72 hours and 10 days after treatment, respectively.

 

No other local signs and no staining were observed. There were no clinical signs and body weights were within the normal range.

 

This skin irritation study is classified as acceptable. It does satisfy the guideline requirement for an acute dermal irritation/corrosion study (OECD 404) in the rabbit.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 02 Oct 2007 to 08 Jan 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to international test guidelines and to GLP.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source:
Harlan Netherlands BV
Kreuzelweg 53, NL-5961 NM Horst/The Netherlands
Postbus 6174, NL-5960 AD Horst/The Netherlands
- Age at study initiation: 11 weeks for the male; 13-14 weeks for the females
- Weight at study initiation: 2445 to 2778 g
- Housing: individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd, Füllinsdorf) and haysticks 4642 (batch no. 08/07, Provimi Kliba AG) were provided for gnawing.
- Diet: Pelleted standard Provimi Kliba 3418 rabbit maintenance diet, batch no. 31/07 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum. Results of analysis for contaminants are archived at RCC Ltd.
- Water: Community tap water from Füllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23° C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12 (music during the daytime light period)

IN-LIFE DATES: From: 15 Oct 2007 to 18 Oct 2007
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount applied : 0.1 mL/animal
- Concentration: 100%
Duration of treatment / exposure:
Single instillation
Observation period (in vivo):
1, 24, 48 and 72 hours after administration
Number of animals or in vitro replicates:
1 male, 2 females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing done.

SCORING SYSTEM: according to the numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004. Scleral reddening and ocular discharge were also assessed.

TOOL USED TO ASSESS SCORE: Varta Cliptrix diagnostic-lamp (Roth AG, CH-4153 Reinach/Switzerland)
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Time point:
other: overall at 24, 48 and 72 h
Score:
0.22
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Meaof each animal: 0.33; 0.33; 0
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
other: overall at 24, 48 and 72 h
Score:
0
Max. score:
2
Irritant / corrosive response data:
The test material did not induce significant or irriversible damage to the rabbit eye.

The grade 2 conjunctival redness was observed in all 3 animals at the 1-hour reading time and this effect was still observed (with grade 1) in 2 animals at 24 hours, but was no longer present at 48 hours.

A slight reddening of the sclerae was present in both females at the 1-hour evaluation.
Other effects:
No other local signs and no staining observed.

No clinical signs and body weights were within the normal range.

Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

(redness)

Chemosis

Max. score: 4

Max. score: 2

Max. score: 3

Max. score: 4

60 min

0/0/0

0/0/0

2/2/2 

0/0/0

24 h

0/0/0

0/0/0

 1/1/0

0/0/0

48 h

0/0/0

0/0/0

 0/0/0

0/0/0

72 h

0/0/0

0/0/0

0/0/0

0/0/0

Average 24h, 48h, 72h

0/0/0 

0/0/0

 0.33/0.33/0

0/0/0

Reversibility*)

 -

-

 c (48 hours)

-

 

*) Reversibility: c. = completely reversible.

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based upon the referred classification criteria (Commission Directive 2001/59/EC of August 06, 2001), Dimethyl 2-methylglutarate is considered to be "not irritating" to the rabbit eye.
Executive summary:

In an eye irritation study, 3 New Zealand White rabbits were treated by an ocular instillation of 0.1 mL of undiluted Dimethyl 2-methyl glutarate and were observed 1, 24, 48 and 72 hours after administration.

 

The instillation of the test material into the eye resulted in mild to moderate, early-onset (from 1-hour post-administration) and transient ocular changes, including reddening of the conjunctivae and sclerae (maximum mean score of 0.33 for the conjunctivae). These effects were reversible and no longer evident 24- or 48 hours after treatment.

 

No other local signs and no staining were observed. There were no clinical signs and body weights were within the normal range.

 

This ocular irritation study is classified as acceptable. It does satisfy the guideline requirement for an acute ocular irritation/corrosion study (OECD 405) in the rabbit.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation:

On study of reliability 1 according to Klimisch cotation critera, is available for dermal route (Simon C., 2008) and was selected as a key study. In this study (OECD 404), 3 New Zealand White rabbits were treated by a topical semi-occlusive application of 0.5 mL of undiluted Dimethyl 2-methyl glutarate for 4 hours and were observed 1, 24, 48 and 72 hours as well as 7 and 10 days after exposure.

The application of the test material to the skin resulted in mild signs of irritation, including erythema and oedema (maximum mean score of 1 and0.33,respectively). These effects were reversible and no longer evident 48- or 72 hours and 10 days after treatment, respectively. No other local signs and no staining were observed. There were no clinical signs and body weights were within the normal range.

Based upon the referred classification criteria (commission Directive 2001/59/EC of August 2001), dimethyl 2-methylglutarate is considered to be "not irritating" to rabbit skin.

 

Eye irritation:

On study of reliability 1 according to Klimisch cotation critera, is available for dermal route (Simon C., 2008) and was selected as a key study. In this study (OECD 405). In this study, 3 New Zealand White rabbits were treated by an ocular instillation of 0.1 mL of undiluted Dimethyl 2-methyl glutarate and were observed 1, 24, 48 and 72 hours after administration.

The instillation of the test material into the eye resulted in mild to moderate, early-onset (from 1-hour post-administration) and transient ocular changes, including reddening of the conjunctivae and sclerae (maximum mean score of0.33for the conjunctivae). These effects were reversible and no longer evident 24- or 48 hours after treatment. No other local signs and no staining were observed. There were no clinical signs and body weights were within the normal range.

Based upon the referred classification criteria (Commission Directive 2001/59/EC ofAugust 06, 2001), Dimethyl 2-methylglutarate is considered to be "not irritating" to the rabbit eye.


Justification for selection of skin irritation / corrosion endpoint:
only one study available (GLP and OECD guideline 404 compliant)

Justification for selection of eye irritation endpoint:
only one study available (GLP and OECD guideline 404 compliant)

Justification for classification or non-classification

The incidence and severity of the signs of irritation observed in the skin and eye irritation studies were below the criteria of Annex VI Directive 67/548/EEC or EU Regulation 1272/2008 (CLP), therefore warranting no classification for skin or eye irritation.