4-methyl-m-phenylenediamine

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

Toluene diamine DNELs

General Remarks

For the deviation of DNELs for 2,4-TDA, guidance document R.8 from May 2008 was used. Where data for specific isomers were available, 2,4-TDA seems to be the more critical isomer. Therefore, all DNELS / DMELS were derived from data generated with 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 ad 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. The most relevant study was performed with female rats, where the LD50 was 73 mg/kg, 50 mg/kg produced 10 % mortality and 10 mg/kg was without any clinical symptoms. In an acute dermal study with rats, 50 mg/kg did not produce any clinical symptoms.

NOAELrat, oral: 10 mg/kg

NOAECrat, inhal = NOAELrat, oral * sRVrat, 8h: 3.8 mg/kg

NOAELrat, dermal: 50 mg/kg

DNELacute oral, worker = NOAELrat, oral * 1/4 * 2/5 * 1/5: 0.2 mg/kg.

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

DNELacute inhal, worker = NOAECrat, inhal * 6.7/10 * 2/5 * 1/5: 0.2 mg/m³.

1/4: allometric scaling

2/5: remaining interspecies differences

1/5: worker

6.7/10 corrected sRVworker

Irritation

2,4-TDA is reported to be not irritating, whereas 2,6-TDA and the mixed isomers are identified as irritants. 2,6-TDA is a strong eye irritant.

As TDA is a genotoxic carcinogen and is well absorbed through the skin, use of appropriate personal protective equipment is compulsory. The need for DNELirritation skin, therefore, is debatable. Nevertheless, in an acute dermal toxicity study with rats, 50 mg/kg produced no clinical signs. Following the same line of argumentation as given for the DNELacute dermal, worker we have

DNELirritation skin 1 mg/kg.

There are no data available for the derivation of a DNELresp irrit.

Skin sensitisation

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 to derive a DNEL.

Repeated dose toxicity (non-cancer)

In subacute, subchronic and chronic studies either there was no NOAEL detected, or investigations were incomplete (limited number of 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 hormone 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 (* 1/2)

DNELoral, chronic worker:      =  6.7 µg/kg

DNELoral, chronic pop:            =  3.3 µg/kg

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

DNELdermal, chronic, worker:     =  26.4 µg/kg

DNELdermal, chronic pop:            =  13.2 µg/kg

DNELinhal, chronic worker = NOAELrat * 0.38 -1 * 1/6 * 2/5 * 6.7/10 * 1/5: = 47 µg/m³

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

DMEL cancer

According to guidence, 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.

1. DMEL based on mammary gland tumors (female rat only)

Net incidence at 5.9 mg/kg: 86 % - 5 % (background) = 81 %

T25: = 5.9 mg/kg * 25 % / 81 % = 1.82 mg/kg.

DMELcancer, general pop = T25 * 1/4 : 250000               =1.8 ng/kg.

= 108 ng/60 kg person/d.

For the worker, exposure is only 40 years instead of 70 (lifetime). Oral uptake is not relevant. For dermal uptake, it has to be taken into account that only 25 % of the applied dose penetrates the skin per 24 h (factor 4). For the inhalation risk, an 8 h breathing volume of 10 m³ instead of 6.7 m³ is assumed (default) for a 70 kg worker. That is,

DMELcancer, worker, dermal = T25 * 1/4 : 25000 * 70/40 * 4 = 128 ng/kg;

DMELcancer, worker, inhal = T25 * sRVrat-1 : 25000 * 70/40 * (6.7 m³ / 10 m³) = 228 ng/m³.

2.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 = T25 * ¼ : 250000 = 14.8 ng/kg.

= 0.9 µg/60 kg person/d

III ref 11384 (TDA in foam RA), excess risk of 10-6: 0.33 µg/person/d.

For the worker, exposure is only 40 years instead of 70 (lifetime). Oral uptake is not relevant. For dermal uptake, it has to be taken into account that only 25 % of the applied dose penetrates the skin per 24 h (factor 4). For the inhalative risk, a breathing volume of 10 m³ is assumed (default) for a 70 kg worker. That is,

DMELcancer, worker, dermal = T25 * ¼ : 25000 * 70/40 * 4 = 1033 ng/kg

DMELcancer, worker, inhal = T25 * sRVrat-1 * 70/40 : 25000 * (6.7 m³ / 10 m³) = 1822 ng/m³.

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.

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.