Registration Dossier

Administrative data

Description of key information

Acute toxicity - Oral: NDC has an LD50 >5,000 mg/kg b.w .
Acute toxicity - Inhalation: The 4-hour acute inhalation median lethal concentration (LC50) of NDC in rats in a nose-only exposure is > 2.15 mg/L air.
Acute toxicity - Dermal: The acute dermal median lethal dose (LD50) of NDC is > 2,000 mg/kg b.w..

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
November to December 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study run to a reliable method and to GLP.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
The study was performed to evaluate the acute oral toxicity of NDC was prepared as a 50% (w/v) suspension in corn oil and administered by oral gavage to a group of five male and five female Sprague-Dawley rats. The animals were administered 5 g of test article per kg of body weight, at a dosing volume of 10 ml/kg. Mortality, clinical observations, body weights and gross pathology were examined in the test.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: approximately 6 weeks of age
- Weight at study initiation: 116-147 g
- Fasting period before study: 18 hours
- Housing: Housed individually in stainless steel wire cages (24.0 x 17.8 x 17.6 cm) suspended over deotized animal cage boards.
- Diet (e.g. ad libitum): Purina Rodent Chow 5001 (Ralston Purina Co., St. Louis, MO) was provided ad libitum.
- Water (e.g. ad libitum): Reverse-osmosis purified water was supplied ad libitum by means of an automatic watering system.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C
- Humidity (%): 20 %
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

IN-LIFE DATES: From 19 November 1990 To: 3 December 1990

No additional information.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50% (w/v)
- Amount of vehicle (if gavage): 10 mL/kg of body weight
- Justification for choice of vehicle:
- Lot/batch no. (if required): 127F-0373

DOSAGE PREPARATION (if unusual): DM-2,6-NDC was mixed thoroughly with corn oil and homogenized using a Polytron. The suspension was stirred continuously while being administered at a dosing volume of 10 mL/kg of body weight.

No additional information.
Doses:
5 g/kg bw
No. of animals per sex per dose:
A group of five male and five female
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The study animals were observed at approximately 3/4, 1-1/4, 2, 2-1/2, 4-1/4 and 6 hours after dosing and at least once per day for the balance of the 14-day observation period. All study animals were weighed prior to fasting and immediately prior to dosing. All surviving rats were also weighed on days 8 and 14 of the study.
- Necropsy of survivors performed: yes

No additional information
Statistics:
None stated.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
All of the rats appeared normal immediately following NDC administration and remained so for the duration of the study. One male rat developed sores on its forepaws and a female rat exhibited alopecia on its forepaws; these observations were not considered to be treatment-related.
Body weight:
Mean body weights increased during the study.
Gross pathology:
Gross necropsy findings were within normal limits in all rats.
Other findings:
No information provided.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of this study, the median acute lethal oral dose (LD50) of NDC was estimated to be greater than 5 g/kg of body weight in male and female rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
1

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Limited study summary, no guideline and no GLP.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Principles of method if other than guideline:
The test was made to determine the acute inhalation toxicity of Dimethyl-2,6-Naphthalene Dicarboxylate when administered to rats by a single nose-only exposure. A single group of five male and five female rats were exposed to respirable concentration of 2.15 mg/L for 4 hours. Clinical signs observed, body weights and necropsy findings were made during the test.
GLP compliance:
not specified
Test type:
standard acute method
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 Breeding Laboratories, Inc., Portage, MI
- Weight at study initiation: 125-150 g
- Housing: The rats were housed individually in suspended stainless steel cages measuring 15.8 x 15.5 x 17.0 cm.
- Diet (e.g. ad libitum): Purina Rodent Chow 5001 was available ad libitum
- Water (e.g. ad libitum): Water supplied from a reverse-osmosis purifier by an automatic watering system was available ad libitum
-Acclimation period: Approximately four weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C
- Humidity (%): 40%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

IN-LIFE DATES: From 2 October 1987 To: 16 October 1987

No additional information
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The chamber was made of glass and stainless steel.
- Exposure chamber volume: 0.5 m3
- Source and rate of air: 37 L/min.
- System of generating particulates/aerosols: The generator was a dry materials feeder (Model 310, AccuRate, Whitewater, WI) which contained a reservoir into which the ground Dimethyl-2,6-Naphthalene Dicarboxylate was placed.
- Method of particle size determination: The particle size of the aerosol was determined twice during the exposure using an Andersen cascade impactor (Andersen Samplers, Atlanta, GA).
- Treatment of exhaust air: The chamber air was exhausted into a waste collecting drum before being discharged to the outside environment.
- Temperature, humidity, pressure in air chamber: 21°C, relative humidity of 33%.

TEST ATMOSPHERE
- Brief description of analytical method used: The aerosol concentration was determined gravimetrically by drawing a known volume of the test atmosphere across an open-face filter and dividing the weight of Dimethyl-2,6-Naphthalene Dicarboxylate collected by the sample volume.
- Samples taken from breathing zone: yes


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The average particle size was 10.74 microns with a geometric standard deviation of 2.20.

No additional information.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Nominal concentrations: 273 mg/L
Test concentration: 2.15 mg/L
No. of animals per sex per dose:
A single group of five male and five female
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The test rats were observed approximately 1/2 and 3 hours after the exposure, and at least once per day for the balance of the 14-day observation period. All test rats were weighed prior to the exposure, weekly thereafter, and immediately prior to necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: Chamber concentration and chamber condition monitoring.
Statistics:
None stated.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.15 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No rats died during the study.
Clinical signs:
other: Salivation, redness around the nose and eyes, and discolored facial fur were observed immediately following exposure. The inguinal fur of all rats was also soiled due to confinement in the nose-only exposure tubes. A single incident of discolored paws, ab
Body weight:
The mean initial body weights of the male and female rats were 353 g and 242 g, respectively. Mean body weights increased during the study, although several rats lost weight during the first week following exposure.
Gross pathology:
Necropsy findings consisted of grey lungs in nine rats and distended large intestines in one rat. One rat had no gross lesions.
Other findings:
Chamber concentration:The Dimethyl-2,6-Naphthalene Dicarboxylate was generated as a particulate aerosol The nominal concentration based on the total amount of Dimethyl-2,6-Naphthalene Dicarboxylate consumed was 273 mg/L. The gravimetric time weighted average (TWA) concentration was calculated to be 4.03 mg/L with 53.3% of the particles measuring less than 10 microns, thus resulting in an actual respirable concentration of 2.15 mg/L The average particle size was 10.74 microns with a geometric standard deviation of 2.20.
Chamber Conditions: The average chamber temperature was 21°C with a relative humidity of 33%. Temperature and relative humidity could not be monitored during the entire exposure, due to the heavy dust concentration.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The 4-hour acute inhalation median lethal concentration (LC50) of NDC in rats in a nose-only exposure ≥2.15 mg/L.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
2.15 mg/m³
Quality of whole database:
1

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November to December 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study run to a reliable method and to GLP
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
NDC was applied at a dose of 2 g/kg of body weight to the shaved backs of five male and five female rabbits. The test article was left in contact with the skin for 24 hours and then removed. The rabbits were observed during this time and for 14 days thereafter.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Johnson Rabbit Ranch
- Age at study initiation: 3-4 months of age
- Weight at study initiation: 2.33-3.00 kg
- Housing: Housed individually in stainless steel cages measuring 61.0 x 45.5 x 41.0 cm.
- Diet (e.g. ad libitum): Provided with approximately 150 g of Purina Lab Rabbit Chow HF #5326 daily.
- Water (e.g. ad libitum): Reverse osmosis-purified water was supplied ad libitum by means of an automatic watering system.
-Acclimation period: Approximately three weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 20%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

IN-LIFE DATES: From:29 November 1990 To 14 December 14 1990

No additional information
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 240 cm2
- Type of wrap if used: Covered with12.8 x 11.5 cm surgical dressing. The dressing was then covered by plastic film and secured by lint-free cloth and an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The skin was wiped gently with gauze and 0.9% saline to remove residual Dimethyl-2,6-Naphthalene Dicarboxylate.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 g/kg body weight

No additional information.
Duration of exposure:
24 hours
Doses:
2 g/kg of body weigh
No. of animals per sex per dose:
five male and five female
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All test rabbits were observed approximately 3/4, 2, 3, 4-1/4 and 5 hours after dosing and at least once per day for 14 days after removal of the wrappings. All test animals were weighed immediately prior to dosing and the weights used for dosage calculations. The rabbits were also weighed seven days following Dimethyl-2,6-
Naphthalene Dicarboxylate application and at study termination.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

No additional information.
Statistics:
None stated
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Body weight:
The initial mean body weights of the male and female rabbits was 3.07 kg, and 2.99 kg, respectively. Mean body weights increased during the study.
Gross pathology:
Gross necropsy findings was within normal limits in all study rabbits.
Other findings:
No information provided
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median acute lethal dermal dose (LD50) for NDC is greater than 2 g/kg of body weight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
1

Additional information

This registration contains a combined approach for addressing the required endpoints. The required endpoints are addressed using, when available, data on the substance to be registered, dimethyl naphthalene-2,6-dicarboxylate (CAS Number 840-65-3) (NDC). When these data are not available, data from the following close structural analogs is used to address the required endpoints.  

  •  naphthalene-2,6-dicarboxylic acid (CAS number 1141-38-4).

Naphthalene-2,6-dicarboxylic acid is structurally similar to NDC, the registered substance, with a smiles code of c12c(cc(C(O)=O)cc2)ccc(c1)C(O)=O compared to that of c12c(cc(C(OC)=O)cc2)ccc(c1)C(OC)=O of NDC. The additional two methyl groups present in NDC are not expected to cause any significant differences in the toxicological effects of the registered substance nor it's degradation products.

 

Naphthalene-2,6-dicarboxylic acid data are used to address the following endpoints:

  •  Acute oral toxicity (supporting study); and
  •  Acute dernal toxicity (supporting study).

Oral route

Key study:

Following test conditions similar to OECD Guideline 401, conducted according to GLP, using male and female Sprague-Dawley rats,

the median acute oral LD50 of NDC is >5 g/kg b.w. (IIT Research, 1991).

Supporting studies:

In an OECD Guideline 401 study, conducted according to GLP, using male and female Crj: CD(SD) rats

the oral LD50 of NDC is >2,000 mg/kg b.w. (Ministry of Health and Welfare (MHW), 1997).

 

Following test conditions similar to OECD 401 (not conducted to GLP), using male and female Charles River rats,

the oral LD50 of NDC is >15,380 mg/kg (Industrial BIO-TEST Laboratories, Inc., 1974).

 

In a read-across study, following test conditions similar to OECD 401 (not conducted to GLP), using male and female Charles River rats, the oral LD50 of 2,6-Dimethylnaphthalene (CAS 581-42-0 and EC 209-464-0) is ≥ 13,430 mg/kg (Industrial BIO-TEST Laboratories, Inc., 1974).

 

Inhalation route

Following test conditions similar to OECD Guideline 403 (not conducted to GLP), using male and female Sprague-Dawley rats,

the 4 hour inhalation median LC50 of NDC to is >2.15 mg/L air (IIT Research Institute, 1987).  

Dermal route

Key study:

Following test conditions similar to OECD Guideline 402, conducted according to GLP, using male and female New Zealand White rabbits, the dermal LD50 of NDC is >2 g/kg b.w. (IIT Research Institute, 1991).

 

Supporting studies:

Following test conditions similar to OECD 402 (not conducted to GLP), using male and female New Zealand White rabbits, the dermal LD50 of NDC is >3,000 mg/kg b.w. (Industrial BIO-TEST Laboratories, Inc., 1974).

 

In a read-across study, following test conditions similar to OECD 402 (not conducted to GLP), using male and female New Zealand White rabbits, the dermal LD50 of 2,6-Dimethylnaphthalene (CAS 581-42-0 and EC 209-464-0) is > 3,000 mg/kg (Industrial BIO-TEST Laboratories, Inc., 1974).


Justification for selection of acute toxicity – oral endpoint
Well conducted study in accordance with OECD Guideline 401 and GLP.

Justification for selection of acute toxicity – inhalation endpoint
Well conducted study, test conditions similar to OECD 402 (no GLP). Only one inhalation route study available.

Justification for selection of acute toxicity – dermal endpoint
Well conducted study , test conditions similar to OECD Guideline 403, conducted according to GLP.

Justification for classification or non-classification

Oral route:

The oral LD50 of NDC is >5,000 mg/kg b.w., therefore, according to Regulation EC No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, Table 3.1.1, NDC is not classified for Acute Oral Toxicity.

Inhalation route

The 4 hour inhalation median LC50 of NDC is >2.15 mg/L air, therefore, according to Regulation EC No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, Table 3.1.1, NDC is not classified for Acute Inhalation Toxicity.

 

Dermal route

The dermal LD50 of NDC is estimated to be >2 g/kg b.w., therefore, according to Regulation EC No. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, Table 3.1.1, NDC is not classified for Acute Dermal Toxicity.