3(or 4)-methylbenzene-1,2-diamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.002 mg/m³

Most sensitive endpoint:

carcinogenicity

DNEL related information

Modified dose descriptor starting point:

T25

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Modified dose descriptor starting point:

NOAEC

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.001 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

DNEL related information

Modified dose descriptor starting point:

T25

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

DNEL related information

Modified dose descriptor starting point:

NOAEL

Additional information - workers

General Remarks

Ortho-TDA consists of two individual compounds, 3,4-TDA (CAS No. 496-72-0) and 2,3-TDA (CAS No. 2687-25-4), and a commercially supplied mixture in which these isomers are the major constituents in a 60/40 ratio, respectively (CAS No. 25376-45-8 and 26966-75-6 referred to as commercial TDA mixture (2,3/3,4-TDA (40/60))). Only the isometric mixture (2,3/3,4-TDA (40/60)) is available commercially. 2,4-TDA  (CAS number 95-80-7) is a structural analogue of ortho-TDA isomers and is used to address the endpoints for biodegradation,  toxicokinetics and sensitisation.  2,4-TDA is a structural isomer of o-TDA, differing in the substitution pattern of the amine groups on the tolyl ring; having similar physical chemical properties; similar environmental fate; and similar health effects (acute toxicity and genotoxicity). 

As a result, data from 2,4 -TDA can be used for read across to 2,3- TDA,

3,4-TDA and commercial TDA mixture (2,3/3,4-TDA (40/60)).  A comparison of data from the commercial TDA mixture

(2,3/3,4-TDA (40/60)), 2,3-TDA, 3,4-TDA and 2,4-TDA was made in the OECD SIDS Initial Assessment Report for SIAM 25 (16 October 2007), for o-TDA, which supported the use of 2,4 -TDA as an appropriate structural analogue.

DNELS / DMELS were derived from data generated with ortho-TDA, specific isomers of ortho-TDA or for read-across 2,4-TDA or the isomeric mixture (80 % 2,4-TDA).

Route to route extrapolation

Oral => inhalation: default factor 0.5. For 2,4-TDA, however, data from oral and i.v. administration and excretion reveal that TDA is absorbed from the GI tract to an extent of at least 90 %. Therefore, there should be no difference in the effectiveness of oral and inhalative resorption.

NOAELinhal = NOAELoral * (sRVrat)-1 * ABSoral, rat * (ABSinhal, man)-1 * {6.7 / 10}

sRV:standard respiratory volume rat; 0.38 m³/kg/8h or 1.15 m³/kg/24h

{6.7/10}:only needed for NOAEL worker; difference between 8 h breathing volume at rest against light activity.

Extrapolation in time

To extrapolate to studies with longer exposure period, for systemic effects and local effects on the respiratory tract, the following default factors are applied:

Sub-acute to chronic:1/6

Sub-chronic to chronic: 1/2

To extend from 5 d/w to 7 d/w exposure, Haber’s rule is applied: Cn * t = constant; n = 1.

Interspecies

For oral data, scaling factors are applied (1/4 for rat => man). A further default factor of 2/5 is applied for “remaining” differences which covers also differences in toxicodynamics. For loocal effects at the site of contact, only the factor 2/5 is applied.

Intraspecies

For systemic and local effects:

1/5 is used to extrapolate to workers, and

1/10 for the general population.

Acute toxicity

Due to its use as strictly controlled intermediate, a DNELacute is derived for the workplace only. In the two studies the oral LD50 was 660 or 812 mg/kg,and the LC_zero400 and 500 mg/kg respectively.   In dermal LD50 studies the dermal LD50 was between 1000 and 2000 mg/kg and >5700 mg/kg, and the dermal LC_zerowas <500 mg/kg in on study but >5700 mg/kg in the other. Using a factor of 2, the dermal NOAEL will be taken as 250 mg/kg   Limited inhalation data show an inhalation LClow of above 670ppm. 

NOAELrat, oral: 500 mg/kg

NOAECrat, inhal = 670 ppm = 3320 mg/m³ 

NOAELrat, dermal: 250 mg/kg

DNELacute oral, worker = NOAELrat, oral * 1/4 * 2/5 * 1/5: 10 mg/kg.

DNELacute dermal, worker = NOAELdermal, rat * 1/4 * 2/5 * 1/5: 5 mg/kg

DNELacute inhal, worker = NOAECrat, inhal * 6.7/10 * 2/5 * 1/5: 178 mg/m³.

1/4: allometric scaling

2/5: remaining interspecies differences

1/5: worker

6.7/10 corrected sRVworker

Irritation

Ortho-TDA was not irritating to skin or to eyes. 

  

Skin sensitisation

For skin sensitisation, read-across is from meta-TDA. In a GPMT, TDA at 25 % elicited a response in 10/10 animals at the first challenge, and at a concentration of 5 % a response in 5/10 animals on the second challenge. These data do not allow derivation of a DNEL.

Repeated dose toxicity (non-cancer)

The oral administration of ortho-TDA by gavage over a period of 28 days revealed substance-related adverse findings in animals of both sexes at 250 mg/kg bw/day. There were general clinical signs of toxicity at this dose and reduced body weight gain. Changes in some in clinical pathology indices indicates the liver as target organ. The no observed adverse effect level (NOAEL) for the study was 50 mg/kg body weight/day in male and female rats.

NOAELrat, oral: 50 mg/kg

Subacute => chronic * 1/6

Rat => man (allometric scaling and remaining differences) * 1/10

Worker (general population) * 1/5 (* 1/2)

DNELoral, chronic worker:      =  0.16mg/kg

DNELoral, chronic pop:            =  0.08mg/kg

Dermally applied TDA is absorbed up to 25 % per 24 h:

DNELdermal, chronic, worker:     =  0.64mg/kg

DNELdermal, chronic pop:            =  0.32mg/kg

DNELinhal, chronic worker = NOAELrat 3320 * 1/6 * 2/5 1/10 * 1/5: = 4.4 mg/m³

(extra factor 1/10 for inhalation acute – subacute)

DNELinhal, chronic pop = NOAELrat * 1/6 * 1/10 * 2/5* 1/10:          2.2 mg/

DMEL cancer

There are no data for ortho-TDA and cancer and a DMEL is not derived.

Reproduction

There is a guideline screenting study for fertility effects of o-TDA in the rat. There were no effects on fertility and no developmental effects, except in the presence of maternal toxicity. The NOAEL for maternal toxicity and reproductive and developmental effects was 50 mg oTDA/kg/day, with the LOAEL being 250 mg oTDA/kg/day.

There are guideline studies assessing possible developmental effects of o-TDA, one in rats and one in rabbits. Maternal toxicity was evident in rats at 300 mg/kg/day. In rabbits maternal toxicity was seen at 100 mg/kg/day. Overall in two species o-TDA was not teratogenic. Foetotoxicity was seen in the presence of maternal toxicity. The NOAEL for maternal and foetotoxicity was 100mg/kg in rats and 30 mg/kg in rabbits.

Given the closeness of the NOAELs for maternal and foetotoxicity to the subchronic rat NOAEL, 50 mg/kg will be used as the NOAEL for reproduction as well as repeated dose toxicity, and the repeat dose toxicity DNELs apply.   

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.001 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

DNEL related information

Modified dose descriptor starting point:

T25

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.001 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

DNEL related information

Modified dose descriptor starting point:

T25

Acute/short term exposure

DNEL related information

Additional information - General Population

The main health effect, carcinogenicity, has DMELs that are to low (ie 0.001) to be accepted by the data entry fields above. As default 0.001 will be entered.

Acute toxicity

Due to its use as strictly controlled intermediate, a DNELacute is derived for the workplace only.

Repeated Dose Toxicity (non-cancer)

Repeated dose toxicity (non-cancer) In subacute, subchronic and chronic studies either there was no NOAEL detected, or investigations were incomplete (limited nummber f organs investigated). Male rats were more sensitive than female rats. In the NTP 7 w feeding studies, 10 mg/kg were without systemic effects (limited histopathology) and losses in body weight gain were below 10 %. 20 mg/kg caused a loss in body weight gain of 18 %, and at 40 mg/kg histopathological changes became observable in the liver. In Sprague-Dawly rats, 15 mg/kg over ten weeks, applied via drinking water, caused a significant reduced fertility in males; 5 mg/kg were without effects on fertility and hormon levels (other organs than male reproductive organs not investigated). Due to subtle histopathological alterations, the EU RA report regards the 5 mg/kg as a borderline LOAEL for male fertility. Due to the very obvious differences regarding histopathological effects between the 15 mg/kg and 5 mg/kg dose groups, 2 mg/kg are assumed to be an acceptable estimate for the NOAEL. As spermatogenesis seems to be at least as sensitive as liver effects, this NOAEL should be applicable in general. NOAELrat, oral:2 mg/kg Subacute => chronic* 1/6 Rat => man (allometric scaling and remaining differences)* 1/10 Worker (general population)* 1/5 (* ½) DNELoral, chronic pop:3.3 µg/kg

Dermally applied TDA is absorbed upt to 25 % per 24 h:

DNELdermal, chronic pop = 13.2 µg/kg

DNELinhal, chronic pop = NOAELrat * 1.15 -1 * 1/6 * 2/5* 1/10: = 12 µg/m³.

DMEL cancer

DMEL cancer (following chapter R.8) According to RIP 3.2.2, the T25 is the preferred approach. The most sensitive endpoints are tumors in liver of male rats and mammary gland tumors in females. The “linearized approach” is followed, here.

DMEL based on male rat liver tumors (male rat, female rat, female mouse) Most sensitive species: male rat. T25male rat = 5.9 mg/kg * 25 % / 10 % =14.75 mg/kg

DMELcancer, general pop, oral = T25 * ¼ : 250000 =14.8 ng/kg. = 0.9 µg/60 kg person/d (59 ng/ kg /d, dermal route)

I.I.I.ref 11384 , excess risk of 10-6:0.33 µg/person/d.

The main health effect, carcinogenicity, has DMELs that are to low (ie 0.001) to be accepted by the data entry fields above. As default 0.001 will be entered.

Reproduction

For male fertility, a DNEL of 6.7 µg/kg (3.3 µg/kg general population) and 47 µg/m³ (12 µg/m³ for general population), respectively, was derived. There are no data that allow the derivation of DNELs for female fertility or reproductive effects. However, as the male rat in general was more sensitive than the female rat, it is assumed that the DNEL for male fertility is also applicable for female fertility. Due to the large assessment factor, it is assumed that the DMEL for cancer is also sufficiently protecticve for developmental effects.